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This study was designed to evaluate dry matter intake (DMI), ruminal fermentation, ruminal digesta outflow, omasal flow of N constituents, and ruminal and total-tract digestibility in response to increasing dietary lipid content derived from high-lipid by-product-based pellets for finishing beef cattle. Five ruminally cannulated heifers were used in a 5 × 5 Latin square design. Dietary treatments were iso-nitrogenous with increasing ether extract (EE) concentrations resulting in dietary concentrations of 3.5%, 4.2%, 4.7%, 5.1%, and 5.9% of dry matter. Periods were 28 d in duration with the first 19 d used for dietary adaptation and the last 9 d for sample and data collection. Dry matter intake, ruminal pH, omasal flow of N constituents, and short-chain fatty acid concentrations were not affected by increasing dietary EE content (P ≥ 0.10). Increasing dietary EE content increased outflow of EE from the rumen (P

The objective of this study was to evaluate the use of barley (BS) or corn (CS) silage when fed with dry-rolled barley grain (BG), corn grain (CG), or an equal blend (BCG) of BG and CG for backgrounding cattle. Ruminally cannulated heifers (n = 5) were assigned to an incomplete 6 × 6 Latin square design. Treatments contained either BS or CS in combination with BG, CG, or BCG. Samples were collected to determine dry matter intake, ruminal fermentation, total-tract nutrient digestibility, and nitrogen (N) balance. Interactions between cereal silage and cereal grain sources were detected for the molar proportions of propionate and butyrate where the magnitude of change with the type of cereal grain was increased in heifers fed CS relative to BS. Feeding CS increased estimated microbial N production (silage, P = 0.022) and fecal N excretion (silage, P = 0.042) over BS. Diets containing BG had greater dry matter, organic matter, starch, and gross energy digestibility values compared with CG, but values for BCG were not different (grain, P ≤ 0.043). Based on limited silage × grain interactions, use of CS in backgrounding diets may increase microbial N production relative to BS and dry-rolled CG may reduce apparent total-tract nutrient digestibility relative to dry-rolled BG.

Corn production in Western Canada has increased with development of short-season varieties partially offsetting the use of barley as a silage and grain source. The current study evaluated effects of silage and cereal-grain source on subcutaneous fat (SCF) composition of finishing cattle. Steers (465 ± 28.0 kg) were assigned to 24 pens (12 steers per pen) in a 2 × 3 factorial design for an 89 d finishing study. Diets contained corn silage or barley silage at 8% [dry matter (DM)] combined either dry-rolled barley grain (BG; 86% of DM), corn grain (CG; 85% of DM), or an equal blend of BG and CG (85% of DM). Bone-in ribeyes were collected from four steers per pen, and subcutaneous fatty acids were analyzed by gas chromatography. Feeding dry-rolled CG increased dietary fat and 18:2n-6 concentrations, resulting in small increases in 18:2n-6, total n-6 fatty acids, and n-6/n-3 ratios in SCF (P

Sesquitepenoids inuloxins A-D, belonging to different subgroups, were isolated from Dittrichia viscosa and showed potential biocontrol of some parasitic plants as Pelipanche, Orobanche, and Cuscuta species. The absolute configurations of the first three inuloxins A-C were previously determined by using experimental and computational chiroptical spectroscopic methods. The absolute configuration of inuloxin D remains to be established. The bioactive inuloxin E, closely related to inuloxin D, was recently isolated from the same plant organic extract. The same relative configuration of inuloxin D was assigned to inuloxin E by comparison of their NMR spectroscopic data. The absolute configurations of inuloxin D and inuloxin E are suggested in this work by analysis of the experimental and predicted chiroptical properties of the 4-O-acetyl derivative of inuloxin D.

The versatility of the natural products (2S,3S)- and (2S,3R)-3-hydroxy-5-oxotetrahydrofuran-2,3-dicarboxylic acids (1 and 2), isolated in large amounts from tropical plant sources, has been demonstrated by the construction of 3-substituted and 3,4-disubstituted chiral pyrrolidine-2,5-diones. The absolute configurations of chiral pyrrolidine-2,5-diones have been ascertained using chiroptical spectroscopic methods and/or single-crystal XRD data. A combination of different reaction strategies delivering a diverse matrix of fused heterocyclic ring systems is presented. The pyrrolo[2,1-a]isoquinoline alkaloid (+)-crispine A possesses a wide range of pharmacological activities including antidepressant, antiplatelet, antileukemic, and anticancer activities. The analogues of indolizino[8,7-b]indole alkaloids (+)- and (-)-harmicine show strong antileishmanial, antinociceptive, PDE5-inhibitory, antimalarial, and antiviral activities. The bicyclic furo[2,3-b]pyrrolo skeleton is present in many natural products. Thus, the uniqueness of relatively cheap, naturally occurring chiral 2-hydroxycitric acid lactones as chirons has been demonstrated by the construction of some important molecular skeletons that are otherwise difficult to synthesize.

Objective The objective was to evaluate the effects of drinking water sulfate concentrations on DMI, water intake, growth, and serum mineral concentrations in growing beef heifers fed a high forage diet (63% DM). Materials and Methods Two blocks of 16 Hereford-cross heifers were used in a randomized complete block design with 4 treatments. Treatments resulted in water sulfate concentrations of 292 ± 23.5, 1,245 ± 78.7, 2,305 ± 89.7, and 3,376 ± 84.9 mg/L. Heifers were housed in tiestalls, and feed and water intakes were measured daily. Body weight and serum mineral concentrations were measured on 2 consecutive days at the start and end of the 77-d study. Results and Discussion Increasing water sulfate increased and then decreased DMI (quadratic, P Implications and Applications These data suggest that water sulfate concentrations above 2,000 mg/L may decrease DMI and that increasing water sulfate concentrations linearly reduced serum copper.

Obesity alters skeletal muscle lipidome and promotes myopathy, but it is unknown whether aberrant muscle lipidome contributes to the reduction in skeletal muscle contractile force-generating capacity. Comprehensive lipidomic analyses of mouse skeletal muscle revealed a very strong positive correlation between the abundance of lysophosphatidylcholine (lyso-PC), a class of lipids that is known to be downregulated with obesity, with maximal tetanic force production. The level of lyso-PC is regulated primarily by lyso-PC acyltransferase 3 (LPCAT3), which acylates lyso-PC to form phosphatidylcholine. Tamoxifen-inducible skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) was sufficient to reduce muscle lyso-PC content in both standard chow diet- and high-fat diet (HFD)-fed conditions. Strikingly, the assessment of skeletal muscle force-generating capacity ex vivo revealed that muscles from LPCAT3-MKI mice were weaker regardless of diet. Defects in force production were more apparent in HFD-fed condition, where tetanic force production was 40% lower in muscles from LPCAT3-MKI compared to that of control mice. These observations were partly explained by reductions in the cross-sectional area in type IIa and IIx fibers, and signs of muscle edema in the absence of fibrosis. Future studies will pursue the mechanism by which LPCAT3 may alter protein turnover to promote myopathy.

A novel proof-of-concept model for chiral molecular structure determination using just the molecular formula and vibrational optical activity (VOA) spectra is presented. To verify this concept, the molecular formula of a desired compound is used to generate all possible chiral structural isomers and their VOA spectra are predicted. The similarity analyses of predicted VOA spectra were then carried out in two different ways: (a) similarity between VOA spectrum of one structural isomer with those of the rest, referred to as cross-correlations; (b) similarity between VOA spectra of all chiral structural isomers with the experimental VOA spectra of the desired compound. Three different molecular formulae, C4H8O, C3H5ClO, and C6H10O, and their chiral structural isomers (6, 9, and 75 respectively), were investigated. In each case, the correct chiral molecular structure of the desired compound was identified without ambiguity. Cross-correlation analysis revealed the uniqueness of VOA spectra in deducing the chiral molecular structure solely from its molecular formula. Different chiral structural isomers associated with the molecular formula CH3NO2 were also found to have no significant cross-correlations between their VOA spectra, opening a pathway to detect and identify the elusive chiral N-hydroxyoxaziridine from its VOA spectra.

The objective of this study was to evaluate the effects of the source of silage, cereal grain, and their interaction on growth performance, digestibility, and carcass characteristics of finishing beef cattle. Using a completely randomized design within an 89-d finishing study, 288 steers were randomly assigned to 1 of 24 pens (12 steers/pen) with average steer body weight (BW) within a pen of 464 kg ± 1.7 kg (mean ± SD). Diets were arranged in a 2 × 3 factorial with corn silage (CS) or barley silage (BS) included at 8% (dry matter [DM] basis). Within each silage source, diets contained dry-rolled barley grain (BG; 86% of DM), dry-rolled corn grain (CG; 85% of DM), or an equal blend of BG and CG (BCG; 85% of DM). Total tract digestibility of nutrients was estimated from fecal samples using near-infrared spectroscopy. Data were analyzed with pen as the experimental unit using the Mixed Model of SAS with the fixed effects of silage, grain, and the two-way interaction. Carcass and fecal kernel data were analyzed using GLIMMIX utilizing the same model. There were no interactions detected between silage and grain source. Feeding CG increased (P < 0.01) DM intake by 0.8 and 0.6 kg/d relative to BG and BCG, respectively. Gain-to-feed ratio was greater (P = 0.04) for BG (0.172 kg/kg) than CG (0.162 kg/kg) but did not differ from BCG (0.165 kg/kg). Furthermore, average daily gain (2.07 kg/d) and final body weight did not differ among treatments (P ≥ 0.25). Hot carcass weight (HCW) was 6.2 kg greater (372.2 vs. 366.0 kg; P < 0.01) and dressing percentage was 0.57 percentage units greater (59.53 vs. 58.96 %; P = 0.04) for steers fed CS than BS, respectively. There was no effect of dietary treatment on the severity of liver abscesses (P ≥ 0.20) with 72.0% of carcasses having clear livers, 24.4% with minor liver abscesses, and 3.6% with severe liver abscesses. Digestibility of DM, organic matter, crude protein, neutral detergent fiber, and starch were greater for BG (P < 0.01) than CG or BCG. As expected, grain source affected the appearance of grain kernels in the feces (P ≤ 0.04). Feeding CS silage increased the appearance of fractured corn kernels (P = 0.04), while feeding BS increased fiber appearance in the feces (P = 0.02). Current results indicate that when dry rolled, feeding BG resulted in improved performance and digestibility compared with CG and BCG. Even at low inclusion levels (8% of DM), CS resulted in improved carcass characteristics relative to BS.

The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins.1,2 Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca2+-ATPase (SERCA) to affect cellular metabolism.3-5 Recent evidence suggests that transport efficiency (Ca2+ uptake / ATP hydrolysis) of skeletal muscle SERCA can be uncoupled to increase energy expenditure and protect mice from diet-induced obesity.6,7 In isolated SR vesicles, membrane phospholipid composition is known to modulate SERCA efficiency.8-11 Here we show that skeletal muscle SR phospholipids can be altered to decrease SERCA efficiency and increase whole-body metabolic rate. The absence of skeletal muscle phosphatidylethanolamine (PE) methyltransferase (PEMT) promotes an increase in skeletal muscle and whole-body metabolic rate to protect mice from diet-induced obesity. The elevation in metabolic rate is caused by a decrease in SERCA Ca2+-transport efficiency, whereas mitochondrial uncoupling is unaffected. Our findings support the hypothesis that skeletal muscle energy efficiency can be reduced to promote protection from obesity.

Vijay et al. identify that phosphatidylserine exposed on dead or dying red blood cell membranes signals via Axl on B cells to promote polyclonal B cell activation and plasmablast differentiation during infections that are associated with hemolysis., Antimalarial antibody responses are essential for mediating the clearance of Plasmodium parasite–infected RBCs from infected hosts. However, the rapid appearance of large numbers of plasmablasts in Plasmodium-infected hosts can suppress the development and function of durable humoral immunity. Here, we identify that the formation of plasmablast populations in Plasmodium-infected mice is mechanistically linked to both hemolysis-induced exposure of phosphatidylserine on damaged RBCs and inflammatory cues. We also show that virus and Trypanosoma infections known to trigger hemolytic anemia and high-grade inflammation also induce exuberant plasmablast responses. The induction of hemolysis or administration of RBC membrane ghosts increases plasmablast differentiation. The phosphatidylserine receptor Axl is critical for optimal plasmablast formation, and blocking phosphatidylserine limits plasmablast expansions and reduces Plasmodium parasite burden in vivo. Our findings support that strategies aimed at modulating polyclonal B cell activation and phosphatidylserine exposure may improve immune responses against Plasmodium parasites and potentially other infectious diseases that are associated with anemia.

Two crispine A analogs and tetrahydrofuro[2,3-b]furan-3,3a(6aH)-diol, endowed with hydroxyl groups that can participate in intramolecular hydrogen bonding, have been synthesized and experimental vibrational circular dichroism (VCD) spectra and optical rotatory dispersion (ORD) data have been measured in CD3OD/CH3OH solvents. The absolute configurations (ACs) of these compounds have been determined using their synthetic schemes, supplemented wherever possible with X-ray diffraction data. The ACs are also analyzed with quantum chemical (QC) calculations of VCD and ORD utilizing implicit solvation as well as explicit solvation models, with the later employing classical molecular dynamics (MD) simulations. It is found that VCD calculations with implicit solvation model are adequate for determining the ACs, despite propensity of studied compounds for intermolecular hydrogen bonding between solute and solvent molecules. This observation is important because time-consuming MD simulations may not be necessary in the type of situations studied here. Additionally, it is found that the QC predicted VCD spectra provided enough diastereomer discrimination for determining the correct AC of studied compounds independently. The same observation did not apply to ORD.

Excess reactive oxygen species (ROS) induced by physical inactivity is associated with muscle atrophy and muscle weakness. However, the role of mitochondrial ROS on disuse-induced muscle atrophy is not fully understood. The purpose of this study was to utilize a genetic strategy to examine the effect of neutralizing mitochondrial ROS on disuse-induced skeletal muscle atrophy. This was accomplished by placing wild-type (WT) and mitochondrial-targeted catalase-expressing (MCAT) littermate mice on 7 days of hindlimb unloading. After assessment of body weight and composition, muscles were analyzed for individual muscle mass, force-generating capacity, fiber type, cross-sectional area, and mitochondrial function, including H(2)O(2) production. Despite a successful attenuation of mitochondrial ROS, MCAT mice were not protected from muscle atrophy. No differences were observed in body composition, lean mass, individual muscle masses, force-generating capacity, or muscle fiber cross-sectional area. These data suggest that neutralizing mitochondrial ROS is insufficient to suppress disuse-induced loss of skeletal muscle mass and contractile function. NEW & NOTEWORTHY The premise of this study was to examine the efficacy of genetic suppression of mitochondrial reactive oxygen species (ROS) to attenuate disuse-induced muscle atrophy and muscle weakness. Neutralization of mitochondrial ROS by MCAT expression was insufficient to rescue muscle atrophy and muscle weakness.

Peroxisomes perform essential functions in lipid metabolism, including fatty acid oxidation and plasmalogen synthesis. Here, we describe a role for peroxisomal lipid metabolism in mitochondrial dynamics in brown and beige adipocytes. Adipose tissue peroxisomal biogenesis was induced in response to cold exposure through activation of the thermogenic coregulator PRDM16. Adipose-specific knockout of the peroxisomal biogenesis factor Pex16 (Pex16-AKO) in mice impaired cold tolerance, decreased energy expenditure, and increased diet-induced obesity. Pex16 deficiency blocked cold-induced mitochondrial fission, decreased mitochondrial copy number, and caused mitochondrial dysfunction. Adipose-specific knockout of the peroxisomal β-oxidation enzyme acyl-CoA oxidase 1 (Acox1-AKO) was not sufficient to affect adiposity, thermogenesis, or mitochondrial copy number, but knockdown of the plasmalogen synthetic enzyme glyceronephosphate O-acyltransferase (GNPAT) recapitulated the effects of Pex16 inactivation on mitochondrial morphology and function. Plasmalogens are present in mitochondria and decreased with Pex16 inactivation. Dietary supplementation with plasmalogens increased mitochondrial copy number, improved mitochondrial function, and rescued thermogenesis in Pex16-AKO mice. These findings support a surprising interaction between peroxisomes and mitochondria regulating mitochondrial dynamics and thermogenesis.

Two studies were conducted to evaluate the effects of treating oat hulls with calcium oxide (CaO) prior to inclusion in a high-lipid by-product pellet (HLP) on dry matter intake (DMI), ruminal fermentation, and total-tract digestibility (Study 1) and growth performance (Study 2). In Study 1, six ruminally cannulated heifers were used in a replicated 3 × 3 Latin square design. Study 2 used 210 steers in 21 pens in a 113 d finishing study. Dietary treatments for both studies included a barley-based control diet (CON), a diet where HLP partially replaced barley grain (NT-HLP), and a diet where HLP contained oat hulls treated with 7.5% CaO [dry matter (DM) basis; CaO-HLP]. For Study 1, DMI and ruminal pH were not affected. Apparent total-tract digestibility of DM and organic matter (OM) were greater (P −1) and gain:feed (G:F) (0.16 kg kg−1) were not different. Thus, HLP can partially replace barley grain in finishing diets without negatively affecting ruminal fermentation or growth performance, but treatment with CaO has no effect.

Barth Syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy and muscle weakness. The underlying cause of BTHS is a mutation in the tafazzin (TAZ) gene, a key enzyme of cardiolipin biosynthesis. The lack of CL arising from loss of TAZ function results in destabilization of the electron transport system, promoting oxidative stress that is thought to contribute to development of cardioskeletal myopathy. Indeed, in vitro studies demonstrate that mitochondria-targeted antioxidants improve contractile capacity in TAZ-deficient cardiomyocytes. The purpose of the present study was to determine if resolving mitochondrial oxidative stress would be sufficient to prevent cardiomyopathy and skeletal myopathy in vivo using a mouse model of BTHS. To this end we crossed mice that overexpress catalase in the mitochondria (MCAT mice) with TAZ-deficient mice (TAZKD) to produce TAZKD mice that selectively overexpress catalase in the mitochondria (TAZKD+MCAT mice). TAZKD+MCAT mice exhibited decreased mitochondrial H(2)O(2) emission and lipid peroxidation compared to TAZKD littermates, indicating decreased oxidative stress. Despite the improvements in oxidative stress, TAZKD+MCAT mice developed cardiomyopathy and mild muscle weakness similar to TAZKD littermates. These findings indicate that resolving oxidative stress is not sufficient to suppress cardioskeletal myopathy associated with BTHS.

(R)-Metacycloprodigiosin can exist in three different tautomeric forms, each with hydrogens at C9' and C12 in syn or anti orientation. With the addition of HCl, this structural diversity reduces to syn-(R)-metacycloprodigiosin-HCl (1a) and anti-(R)-metacycloprodigiosin-HCl (1b), each with multiple conformers. Energetics and chiroptical properties, namely, electronic circular dichroism (ECD) and specific optical rotation (SOR), of (R)-metacycloprodigiosin-HCl have been investigated at B3LYP/6-311++G(2d,2p) level. The experimental ECD spectra of (R)-metacycloprodigiosin-HCl have also been measured. Calculations indicated that the lowest energy conformer of 1b is approximately 2.7 kcal/mol lower in energy than that of 1a, and the energy barrier for anti to syn conversion is approximately 13 kcal/mol. The population weighted calculated SORs of 1a and 1b are, respectively, positive and negative. The respective calculated ECD spectra of these pseudoenantiomers show an almost mirror image relationship between them. The experimental SOR and ECD compare well with those predicted for 1b. Thus, 1b is expected to be predominant, a situation confirmed also by nuclear Overhauser effect (NOE) data, with a similar conclusion reached for prodigiosin R1.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analyses of primary myocytes from lean insulin-sensitive (LN) and obese insulin-resistant (OB) individuals revealed several species of lysophospholipids (lyso-PL) that were differentially-abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with greater insulin sensitivityin vivoand insulin-stimulated skeletal muscle glucose uptakeex vivo. Absence of LPCAT3 reduced phospholipid packing of the cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

Five ruminally cannulated heifers were used in an incomplete 6 × 6 Latin square design to determine the effects of cereal silage (barley vs. corn), cereal grain (barley vs. corn vs. a 50:50 blend of barley and corn), and their interaction (S × G) on dry matter intake, ruminal fermentation, total tract digestibility, nitrogen balance, and in situ degradation. Corn silage (CS) or barley silage (BS) was included at 8% of dietary dry matter (DM). Within each silage source, diets contained (DM basis) either dry-rolled barley (BG; 86%), dry-rolled corn (CG; 85%), or an equal blend of barley and corn (BLEND; 85%). Periods were 25 d, with 5 d of dietary transition, 13 d of dietary adaptation, and 7 d of data and sample collection. Samples collected included feed and refusals, total urine and feces, and ruminal fluid. All data were analyzed using the Mixed model of SAS with the fixed effects of silage, grain, and the S × G. Dry matter intake (P ≥ 0.19) and mean ruminal pH (P ≥ 0.096) were not affected by the silage, grain, or S × G. Total short-chain fatty acid concentrations were greater for BLEND than BG or CG (grain, P = 0.003) and for CS (silage, P = 0.009) relative to BS. The molar proportion of acetate was greater for BS-BG and BS-CG (S × G, P < 0.001), while molar proportion of propionate was greater for CS-BG (S × G, P < 0.001) relative to other silage and grain source combinations. Rumen ammonia-N concentration was greater for CG than BG, or BLEND (grain, P < 0.001), and greater for CS compared to BS (silage, P = 0.023). Apparent total tract digestibility of DM, organic matter, neutral detergent fiber, starch, and gross energy were greatest for BG (grain, P ≤ 0.035). Digestible energy content (Mcal/kg) was greater for BG (grain, P = 0.029) than CG and BLEND. Total nitrogen retention (g/d and % of intake) was greatest for CS-BG (S × G, P ≤ 0.033) relative to all other treatments. In situ degradation rates of DM, crude protein, and starch were greater for BG than CG (P ≤ 0.004). The potentially degradable fraction of DM, crude protein, and starch was greater for CG (P ≤ 0.031), while the undegradable fraction was greater for BG (P ≤ 0.046). For silage sources, CS had greater 24 h in situ DM digestibility (P = 0.009) and starch digestibility (24, 48, and 72 h incubations, P ≤ 0.034) relative to BS. Results suggest that while feeding a combination of CS and BG promotes propionate production and greater N retention; few other additive effects were observed.

Mitochondrial membrane lipids adapt to exercise or disuse, underscoring an essential role for PE in energy transduction., Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has been extensively studied, there is limited information on how mitochondrial membrane lipids are regulated. Here, we show that exercise training or muscle disuse alters mitochondrial membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, whereas removal of PE diminished, mitochondrial respiratory capacity. Unexpectedly, skeletal muscle–specific inhibition of mitochondria-autonomous synthesis of PE caused respiratory failure because of metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. These findings highlight the previously underappreciated role of mitochondrial membrane phospholipids in dynamically controlling skeletal muscle energetics and function.

Objective Phosphatidylethanolamine methyltransferase (PEMT) generates phosphatidylcholine (PC), the most abundant phospholipid in the mitochondria and an important acyl chain donor for cardiolipin (CL) biosynthesis. Mice lacking PEMT (PEMTKO) are cold-intolerant when fed a high-fat diet (HFD) due to unclear mechanisms. The purpose of this study was to determine whether PEMT-derived phospholipids are important for the function of uncoupling protein 1 (UCP1) and thus for maintenance of core temperature. Methods To test whether PEMT-derived phospholipids are important for UCP1 function, we examined cold-tolerance and brown adipose (BAT) mitochondria from PEMTKO mice with or without HFD feeding. We complemented these studies with experiments on mice lacking functional CL due to tafazzin knockdown (TAZKD). We generated several conditional mouse models to study the tissue-specific roles of PEMT, including mice with BAT-specific knockout of PEMT (PEMT-BKO). Results Chow- and HFD-fed PEMTKO mice completely lacked UCP1 protein in BAT, despite a lack of difference in mRNA levels, and the mice were accordingly cold-intolerant. While HFD-fed PEMTKO mice exhibited reduced mitochondrial CL content, this was not observed in chow-fed PEMTKO mice or TAZKD mice, indicating that the lack of UCP1 was not attributable to CL deficiency. Surprisingly, the PEMT-BKO mice exhibited normal UCP1 protein levels. Knockout of PEMT in the adipose tissue (PEMT-AKO), liver (PEMT-LKO), or skeletal muscle (PEMT-MKO) also did not affect UCP1 protein levels, suggesting that lack of PEMT in other non-UCP1-expressing cells communicates to BAT to suppress UCP1. Instead, we identified an untranslated UCP1 splice variant that was triggered during the perinatal period in the PEMTKO mice. Conclusions PEMT is required for UCP1 splicing that yields functional protein. This effect is derived by PEMT in nonadipocytes that communicates to BAT during embryonic development. Future research will focus on identifying the non-cell-autonomous PEMT-dependent mechanism of UCP1 splicing., Highlights • Whole-body ablation of PEMT results in a complete loss of UCP1 protein. • While PEMT-derived PC may participate in CL biosynthesis, changes in mitochondrial PC or CL do not explain the loss of UCP1 protein. • PEMT regulates brown adipose UCP1 in a non-cell-autonomous manner. • PEMT deletion promotes the use of an alternative 3’ splice junction in exon 5 of UCP1, preventing UCP1 protein expression.

Electronic circular dichroism (ECD) and discrete wavelength resolved specific optical rotations, referred to as optical rotatory dispersion (ORD), have been remeasured for inuloxin C and analysed with corresponding quantum chemical (QC) predicted data for all diastereomers of inuloxin C. The QC‐predicted sign of ORD and of a major ECD band are found to match the experimental observations for more than one diastereomer. However, these ECD and ORD analyses combined with electronic dissymmetry factor analyses narrowed the choices of absolute configuration (AC) of inuloxin C to (5R,7S,8R,10R) and (5S,7S,8S,10S). Supplementing these analyses with corresponding analyses for acetylated inuloxin C resulted in a unique choice for the AC of inuloxin C as (5S,7S,8S,10S). This result is independent of NMR analysis. Furthermore, this AC is in full agreement with previously determined relative configuration by NMR and the AC derived therefrom using ECD and ORD. Therefore, the present study identifies a pathway for determining the ACs of chiral molecules with multiple stereogenic centers when relative configurations are not known, or when it is desired to deduce ACs independent of the known relative configurations.

Background: Precursor T-cell acute lymphoblastic leukemia (pre-T-ALL) may cause ocular pathologies such as cotton-wool spots, retinal hemorrhage, and less commonly, retinal detachment or leukemic infiltration of the retina itself. However, these findings are typically accompanied by the pathognomonic hematological signs of acute leukemia. CasePresentation: In this case report and review of the literature, we describe a particularly unusual case of a 25-year-old man who presented to our hospital with bilateral exudative retinal detachments associated with posterior pole thickening without any hematological or neurological findings. The patient, who had a history of previously treated pre-T-ALL in complete remission, was found to have leukemia cell infiltration on retinal biopsy. Conclusion: Our case underscores the fact that the ophthalmologist may be the first provider to detect the relapse of previously treated leukemia, and that ophthalmic evaluation is critical for detecting malignant ocular infiltrates.

We have isolated mixtures of [5]- and [3]-ladderanoic acids 1a and 2a from the biomass of an anammox bioreactor and have separated the acids and their phenacyl esters for the first time by HPLC. The absolute configurations of the naturally occurring acids and their phenacyl esters are assigned as R at the site of side-chain attachment by comparison of experimental specific rotations with corresponding values predicted using quantum chemical (QC) methods. The absolute configurations for 1a and 2a were independently verified by comparison of experimental Raman optical activity spectra with corresponding spectra predicted using QC methods. The configurational assignments of 1a and 2a and of the phenacyl ester of 1a were also confirmed by X-ray crystallography.