Evolution of inner ear neuroanatomy of bats and implications for echolocation.

Phylogenomics of bats suggests that their echolocation either evolved separately in the bat suborders Yinpterochiroptera and Yangochiroptera, or had a single origin in bat ancestors and was later lost in some yinpterochiropterans1-6. Hearing for echolocation behaviour depends on the inner ear, of which the spiral ganglion is an essential structure. Here we report the observation of highly derived structures of the spiral ganglion in yangochiropteran bats: a trans-otic ganglion with a wall-less Rosenthal's canal. This neuroanatomical arrangement permits a larger ganglion with more neurons, higher innervation density of neurons and denser clustering of cochlear nerve fascicles7-13. This differs from the plesiomorphic neuroanatomy of Yinpterochiroptera and non-chiropteran mammals. The osteological correlates of these derived ganglion features can now be traced into bat phylogeny, providing direct evidence of how Yangochiroptera differentiated from Yinpterochiroptera in spiral ganglion neuroanatomy. These features are highly variable across major clades and between species of Yangochiroptera, and in morphospace, exhibit much greater disparity in Yangochiroptera than Yinpterochiroptera. These highly variable ganglion features may be a neuroanatomical evolutionary driver for their diverse echolocating strategies4,14-17 and are associated with the explosive diversification of yangochiropterans, which include most bat families, genera and species.

Mammalian diversification bursts and biotic turnovers are synchronous with Cenozoic geoclimatic events in Asia.

Asia's rich species diversity has been linked to its Cenozoic geodiversity, including active mountain building and dramatic climatic changes. However, prior studies on the diversification and assembly of Asian faunas have been derived mainly from analyses at taxonomic or geographic scales too limited to offer a comprehensive view of this complex region's biotic evolution. Here, using the class Mammalia, we built historical biogeographic models drawn on phylogenies of 1,543 species occurring across Asia to investigate how and when the mammal diversity in Asian regions and mountain hotspots was assembled. We explore the roles of in situ speciation, colonization, and vicariance and geoclimatic events to explain the buildup of Asia's regional mammal diversity through time. We found that southern Asia has served as the main cradle of Asia's mammal diversity. Present-day species richness in other regions is mainly derived from colonization, but by the Miocene, in situ speciation increased in importance. The high biodiversity present in the mountain hotspots (Himalayas and Hengduan) that flank the Qinghai-Tibetan plateau is a product of high colonization instead of in situ speciation, making them important centers of lineage accumulation. Overall, Neogene was marked by great diversification and migrations across Asia and surrounding continents but Paleogene environments already hosted rich mammal assemblages. Our study revealed that synchronous diversification bursts and biotic turnovers are temporally associated with tectonic events (mountain building, continental collisions) and drastic reorganization of climate (aridification of Asian interior, intensification of Asian monsoons, sea retreat) that took place throughout the Cenozoic in Asia.

A targeted proteomics method for quantifying plasma apolipoprotein kinetics in individual mice using stable isotope labeling.

Altered apolipoprotein kinetics play a critical role in promoting dyslipidemia and atherogenesis. Human apolipoprotein kinetics have been extensively evaluated, but similar studies in mice are hampered by the lack of robust methods suitable for the small amounts of blood that can be collected at sequential time points from individual mice. We describe a targeted liquid chromatography tandem mass spectrometry method for simultaneously quantifying the stable isotope enrichment of several apolipoproteins represented by multiple peptides in serial blood samples (15 µl each) obtained after retro-orbital injection of 13C6,15N2-lysine (Lys8) in mice. We determined apolipoprotein fractional clearance rates (FCRs) and production rates (PRs) in WT mice and in two genetic models widely used for atherosclerosis research, LDL receptor-deficient (Ldlr-/-) and apolipoprotein E-deficient (Apoe-/-) mice. Injection of Lys8 produced a unique and readily detectable mass shift of labeled compared with unlabeled peptides with sensitivity allowing robust kinetics analyses. Ldlr-/- mice showed slower FCRs of APOA1, APOA4, total APOB, APOB100, APOCs, APOE and APOM, while FCRs of APOA1, APOB100, APOC2, APOC3, and APOM were not lower in Apoe-/- mice versus WT mice. APOE PR was increased in Ldlr-/- mice, and APOB100 and APOA4 PRs were reduced in Apoe-/- mice. Thus, our method reproducibly quantifies plasma apolipoprotein kinetics in different mouse models. The method can easily be expanded to include a wide range of proteins in the same biospecimen and should be useful for determining the kinetics of apolipoproteins in animal models of human disease.

The Role of (Co)variation in Shaping the Response to Selection in New World Leaf-Nosed Bats.

AbstractUnderstanding and predicting the evolutionary responses of complex morphological traits to selection remains a major challenge in evolutionary biology. Because traits are genetically correlated, selection on a particular trait produces both direct effects on the distribution of that trait and indirect effects on other traits in the population. The correlations between traits can strongly impact evolutionary responses to selection and may thus impose constraints on adaptation. Here, we used museum specimens and comparative quantitative genetic approaches to investigate whether the covariation among cranial traits facilitated or constrained the response to selection during the major dietary transitions in one of the world's most ecologically diverse mammalian families-the phyllostomid bats. We reconstructed the set of net selection gradients that would have acted on each cranial trait during the major transitions to feeding specializations and decomposed the selection responses into their direct and indirect components. We found that for all transitions, most traits capturing craniofacial length evolved toward adaptive directions owing to direct selection. Additionally, we showed instances of dietary transitions in which the complex interaction between the patterns of covariation among traits and the strength and direction of selection either constrained or facilitated evolution. Our work highlights the importance of considering the within-species covariation estimates to quantify evolvability and to disentangle the relative contribution of variational constraints versus selective causes for observed patterns.

Effects of Diet versus Gastric Bypass on Metabolic Function in Diabetes.

BACKGROUND: Some studies have suggested that in people with type 2 diabetes, Roux-en-Y gastric bypass has therapeutic effects on metabolic function that are independent of weight loss. METHODS: We evaluated metabolic regulators of glucose homeostasis before and after matched (approximately 18%) weight loss induced by gastric bypass (surgery group) or diet alone (diet group) in 22 patients with obesity and diabetes. The primary outcome was the change in hepatic insulin sensitivity, assessed by infusion of insulin at low rates (stages 1 and 2 of a 3-stage hyperinsulinemic euglycemic pancreatic clamp). Secondary outcomes were changes in muscle insulin sensitivity, beta-cell function, and 24-hour plasma glucose and insulin profiles. RESULTS: Weight loss was associated with increases in mean suppression of glucose production from baseline, by 7.04 µmol per kilogram of fat-free mass per minute (95% confidence interval [CI], 4.74 to 9.33) in the diet group and by 7.02 µmol per kilogram of fat-free mass per minute (95% CI, 3.21 to 10.84) in the surgery group during clamp stage 1, and by 5.39 (95% CI, 2.44 to 8.34) and 5.37 (95% CI, 2.41 to 8.33) µmol per kilogram of fat-free mass per minute in the two groups, respectively, during clamp stage 2; there were no significant differences between the groups. Weight loss was associated with increased insulin-stimulated glucose disposal, from 30.5±15.9 to 61.6±13.0 µmol per kilogram of fat-free mass per minute in the diet group and from 29.4±12.6 to 54.5±10.4 µmol per kilogram of fat-free mass per minute in the surgery group; there was no significant difference between the groups. Weight loss increased beta-cell function (insulin secretion relative to insulin sensitivity) by 1.83 units (95% CI, 1.22 to 2.44) in the diet group and by 1.11 units (95% CI, 0.08 to 2.15) in the surgery group, with no significant difference between the groups, and it decreased the areas under the curve for 24-hour plasma glucose and insulin levels in both groups, with no significant difference between the groups. No major complications occurred in either group. CONCLUSIONS: In this study involving patients with obesity and type 2 diabetes, the metabolic benefits of gastric bypass surgery and diet were similar and were apparently related to weight loss itself, with no evident clinically important effects independent of weight loss. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT02207777.).

Ultraconserved elements resolve phylogenetic relationships and biogeographic history of African-Malagasy bent-winged bats (Miniopterus).

African-Malagasy species of the bat genus Miniopterus are notable both for the dramatic increase in the number of newly recognized species over the last 15 years, as well as for the profusion of new taxa from Madagascar and the neighboring Comoros. Since 2007, seven new Malagasy Miniopterus species have been described compared to only two new species since 1936 from the Afrotropics. The conservative morphology of Miniopterus and limited geographic sampling in continental Africa have undoubtedly contributed to the deficit of continental species. In addition to uncertainty over species limits, phylogenetic relationships of Miniopterus remain mostly unresolved, particularly at deeper backbone nodes. Previous phylogenetic studies were based on limited taxon sampling and/or limited genetic sampling involving no more than five loci. Here, we conduct the first phylogenomic study of the Afrotropical Miniopteridae by analyzing up to 3772 genome-wide ultraconserved elements (UCEs) from historic and modern samples of 70 individuals from 25 Miniopterus species/lineages. We analyze multiple datasets of varying degrees of completeness (70, 90, and 100 percent complete) using partitioned concatenated maximum likelihood and multispecies coalescent methods. Our well-supported, species-level phylogenies resolved most (6/8 or 7/8) backbone nodes and strongly support for the first time the monophyly of the Malagasy radiation. We inferred the crown age of African Miniopteridae in the late Miocene (10.4 Ma), while the main lineages of Miniopterus appear to have contemporaneously diversified in two sister radiations in the Afrotropics and Madagascar. Species-level divergence of 23 of 25 African + Malagasy Miniopterus were estimated to have 95 % HPDs that overlap with the late Miocene (5.3-10.4 Ma). We present ancestral range estimates that unambiguously support a continental African radiation that originated in the Zambezian and Somalian/Ethiopian biogeographic regions, but we cannot rule out back colonization of Africa from Madagascar. The phylogeny indicates genetic support for up to seven new species.

Renewable CO2 recycling and synthetic fuel production in a marine environment.

A massive reduction in CO2 emissions from fossil fuel burning is required to limit the extent of global warming. However, carbon-based liquid fuels will in the foreseeable future continue to be important energy storage media. We propose a combination of largely existing technologies to use solar energy to recycle atmospheric CO2 into a liquid fuel. Our concept is clusters of marine-based floating islands, on which photovoltaic cells convert sunlight into electrical energy to produce H2 and to extract CO2 from seawater, where it is in equilibrium with the atmosphere. These gases are then reacted to form the energy carrier methanol, which is conveniently shipped to the end consumer. The present work initiates the development of this concept and highlights relevant questions in physics, chemistry, and mechanics.

Effects of Mindfulness Training and Exercise on Cognitive Function in Older Adults: A Randomized Clinical Trial.

Importance: Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. Objective: To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Interventions: Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. Main Outcomes and Measures: The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Results: Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Conclusions and Relevance: Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. Trial Registration: ClinicalTrials.gov Identifier: NCT02665481.

Insectivory leads to functional convergence in a group of Neotropical rodents.

The mandible of vertebrates serves as insertion area for masticatory muscles that originate on the skull, and its functional properties are subject to selective forces related to trophic ecology. The efficiency of masticatory muscles can be measured as mechanical advantage on the mandible, which, in turn, has the property of correlating with bite force and shape. In the present work, we quantify the mechanical advantage of the mandible of akodontine rodents, which present a diverse radiation of insectivorous specialists, to assess their relationship to the estimated bite force and diet. We also tested the degree of morphofunctional convergence in response to insectivory on the group. We found the mechanical advantages to be convergent on insectivorous species, and associated with the estimated bite force, with higher mechanical advantages in species with a stronger bite and short, robust mandibles and lower mechanical advantages in insectivorous species with weaker bites and more elongated, dorso-ventrally compressed mandibles. Insectivorous species of Akodontini are functional specialists for the consumption of live prey and may exploit the resources that shrews, moles and hedgehogs consume elsewhere.

A single bout of resistance exercise improves postprandial lipid metabolism in overweight/obese men with prediabetes.

AIMS/HYPOTHESIS: Prediabetes is associated with postprandial hypertriacylglycerolaemia. Resistance exercise acutely lowers postprandial plasma triacylglycerol (TG); however, the changes in lipid metabolism that mediate this reduction are poorly understood. The aim of this study was to identify the constitutive metabolic mechanisms underlying the changes in postprandial lipid metabolism after resistance exercise in obese men with prediabetes. METHODS: We evaluated the effect of a single bout of whole-body resistance exercise (seven exercises, three sets, 10-12 repetitions at 80% of one-repetition maximum) on postprandial lipid metabolism in ten middle-aged (50 ± 9 years), overweight/obese (BMI: 33 ± 3 kg/m2), sedentary men with prediabetes (HbA1c >38 but <48 mmol/mol [>5.7% but <6.5%]), or fasting plasma glucose >5.6 mmol/l but <7.0 mmol/l or 2 h OGTT glucose >7.8 mmol/l but <11.1 mmol/l). We used a randomised, crossover design with a triple-tracer mixed meal test (ingested [(13C4)3]tripalmitin, i.v. [U-13C16]palmitate and [2H5]glycerol) to evaluate chylomicron-TG and total triacylglycerol-rich lipoprotein (TRL)-TG kinetics. We used adipose tissue and skeletal muscle biopsies to evaluate the expression of genes regulating lipolysis and lipid oxidation, skeletal muscle respirometry to evaluate oxidative capacity, and indirect calorimetry to assess whole-body lipid oxidation. RESULTS: The single bout of resistance exercise reduced the lipaemic response to a mixed meal in obese men with prediabetes without changing chylomicron-TG or TRL-TG fractional clearance rates. However, resistance exercise reduced endogenous and meal-derived fatty acid incorporation into chylomicron-TG and TRL-TG. Resistance exercise also increased whole-body lipid oxidation, skeletal muscle mitochondrial respiration, oxidative gene expression in skeletal muscle, and the expression of key lipolysis genes in adipose tissue. CONCLUSIONS/INTERPRETATION: A single bout of resistance exercise improves postprandial lipid metabolism in obese men with prediabetes, which may mitigate the risk for cardiovascular disease and type 2 diabetes.

Mindfulness, Education, and Exercise for age-related cognitive decline: Study protocol, pilot study results, and description of the baseline sample.

BACKGROUND/AIMS: Age-related cognitive decline is a pervasive problem in our aging population. To date, no pharmacological treatments to halt or reverse cognitive decline are available. Behavioral interventions, such as physical exercise and Mindfulness-Based Stress Reduction, may reduce or reverse cognitive decline, but rigorously designed randomized controlled trials are needed to test the efficacy of such interventions. METHODS: Here, we describe the design of the Mindfulness, Education, and Exercise study, an 18-month randomized controlled trial that will assess the effect of two interventions-mindfulness training plus moderate-to-vigorous intensity exercise or moderate-to-vigorous intensity exercise alone-compared with a health education control group on cognitive function in older adults. An extensive battery of biobehavioral assessments will be used to understand the mechanisms of cognitive remediation, by using structural and resting state functional magnetic resonance imaging, insulin sensitivity, inflammation, and metabolic and behavioral assessments. RESULTS: We provide the results from a preliminary study (n = 29) of non-randomized pilot participants who received both the exercise and Mindfulness-Based Stress Reduction interventions. We also provide details on the recruitment and baseline characteristics of the randomized controlled trial sample (n = 585). CONCLUSION: When complete, the Mindfulness, Education, and Exercise study will inform the research community on the efficacy of these widely available interventions improve cognitive functioning in older adults.

Molecular phylogenetics of the African horseshoe bats (Chiroptera: Rhinolophidae): expanded geographic and taxonomic sampling of the Afrotropics.

BACKGROUND: The Old World insectivorous bat genus Rhinolophus is highly speciose. Over the last 15 years, the number of its recognized species has grown from 77 to 106, but knowledge of their interrelationships has not kept pace. Species limits and phylogenetic relationships of this morphologically conservative group remain problematic due both to poor sampling across the Afrotropics and to repeated instances of mitochondrial-nuclear discordance. Recent intensive surveys in East Africa and neighboring regions, coupled with parallel studies by others in West Africa and in Southern Africa, offer a new basis for understanding its evolutionary history. RESULTS: We investigated phylogenetic relationships and intraspecific genetic variation in the Afro-Palearctic clade of Rhinolophidae using broad sampling. We sequenced mitochondrial cytochrome-b (1140 bp) and four independent and informative nuclear introns (2611 bp) for 213 individuals and incorporated sequence data from 210 additional individuals on GenBank that together represent 24 of the 33 currently recognized Afrotropical Rhinolophus species. We addressed the widespread occurrence of mito-nuclear discordance in Rhinolophus by inferring concatenated and species tree phylogenies using only the nuclear data. Well resolved mitochondrial, concatenated nuclear, and species trees revealed phylogenetic relationships and population structure of the Afrotropical species and species groups. CONCLUSIONS: Multiple well-supported and deeply divergent lineages were resolved in each of the six African Rhinolophus species groups analyzed, suggesting as many as 12 undescribed cryptic species; these include several instances of sympatry among close relatives. Coalescent lineage delimitation offered support for new undescribed lineages in four of the six African groups in this study. On the other hand, two to five currently recognized species may be invalid based on combined mitochondrial and/or nuclear phylogenetic analyses. Validation of these cryptic lineages as species and formal relegation of current names to synonymy will require integrative taxonomic assessments involving morphology, ecology, acoustics, distribution, and behavior. The resulting phylogenetic framework offers a powerful basis for addressing questions regarding their ecology and evolution.

Novel circulating tumor cell-based blood test for the assessment of PD-L1 protein expression in treatment-naïve, newly diagnosed patients with non-small cell lung cancer.

We evaluated the analytical and clinical performance of a novel circulating tumor cell (CTC)-based blood test for determination of programmed death ligand 1 (PD-L1) protein expression status in real time in treatment-naïve non-small cell lung cancer (NSCLC) patients. CTCs were detected in 86% of patients with NSCLC (I-IV) at the time of diagnosis, with a 67% PD-L1 positivity rate (≥ 1 PDL + CTC). Among 33 NSCLC patients with PD-L1 results available via both tissue immunohistochemistry (IHC) and CTC assays, 78.9% were positive according to both methods. The CTC test identified an additional ten cases that were positive for PD-L1 expression but that tested negative via IHC analysis. Detection of higher PD-L1 expression on CTCs compared to that in the corresponding tissue was concordant with data obtained using other platforms in previously treated patients. The concordance in PD-L1 expression between tissue and CTCs was approximately 57%, which is higher than that reported by others. In summary, evaluation of PD-L1 protein expression status on CTCs isolated from NSCLC patients is feasible. PD-L1 expression status on CTCs can be determined serially during the disease course, thus overcoming the myriad challenges associated with tissue analysis.

Experimental station Bernina at SwissFEL: condensed matter physics on femtosecond time scales investigated by X-ray diffraction and spectroscopic methods.

The Bernina instrument at the SwissFEL Aramis hard X-ray free-electron laser is designed for studying ultrafast phenomena in condensed matter and material science. Ultrashort pulses from an optical laser system covering a large wavelength range can be used to generate specific non-equilibrium states, whose subsequent temporal evolution can be probed by selective X-ray scattering techniques in the range 2-12 keV. For that purpose, the X-ray beamline is equipped with optical elements which tailor the X-ray beam size and energy, as well as with pulse-to-pulse diagnostics that monitor the X-ray pulse intensity, position, as well as its spectral and temporal properties. The experiments can be performed using multiple interchangeable endstations differing in specialization, diffractometer and X-ray analyser configuration and load capacity for specialized sample environment. After testing the instrument in a series of pilot experiments in 2018, regular user operation begins in 2019.

The SwissFEL soft X-ray free-electron laser beamline: Athos.

The SwissFEL soft X-ray free-electron laser (FEL) beamline Athos will be ready for user operation in 2021. Its design includes a novel layout of alternating magnetic chicanes and short undulator segments. Together with the APPLE X architecture of undulators, the Athos branch can be operated in different modes producing FEL beams with unique characteristics ranging from attosecond pulse length to high-power modes. Further space has been reserved for upgrades including modulators and an external seeding laser for better timing control. All of these schemes rely on state-of-the-art technologies described in this overview. The optical transport line distributing the FEL beam to the experimental stations was designed with the whole range of beam parameters in mind. Currently two experimental stations, one for condensed matter and quantum materials research and a second one for atomic, molecular and optical physics, chemical sciences and ultrafast single-particle imaging, are being laid out such that they can profit from the unique soft X-ray pulses produced in the Athos branch in an optimal way.

Personalized nutrition: pretreatment glucose metabolism determines individual long-term weight loss responsiveness in individuals with obesity on low-carbohydrate versus low-fat diet.

BACKGROUND/OBJECTIVES: The interaction between fasting plasma glucose (FPG) and fasting insulin (FI) concentrations and diets with different carbohydrate content were studied as prognostic markers of weight loss as recent studies up to 6 months of duration have suggested the importance of these biomarkers. SUBJECTS/METHODS: This was a retrospective analysis of a clinical trial where participants with obesity were randomized to an ad libitum low-carbohydrate diet or a low-fat diet with low energy content (1200-1800 kcal/day [≈ 5.0-7.5 MJ/d]; ≤ 30% calories from fat) for 24 months. Participants were categorized (pretreatment) as normoglycemic (FPG < 5.6 mmol/L) or prediabetic (FPG ≥ 5.6-6.9 mmol/L) and further stratified by median FI. Linear mixed models were used to examine outcomes by FPG and FI values. RESULTS: After 2 years, participants with prediabetes and high FI lost 7.2 kg (95% CI 2.1;12.2, P = 0.005) more with the low-fat than low-carbohydrate diet, whereas those with prediabetes and low FI tended to lose 6.2 kg (95% CI -0.9;13.3, P = 0.088) more on the low-carbohydrate diet than low-fat diet [mean difference: 13.3 kg (95% CI 4.6;22.0, P = 0.003)]. No differences between diets were found among participants with normoglycemia and either high or low FI (both P ≥ 0.16). CONCLUSIONS: Fasting plasma glucose and insulin are strong predictors of the weight loss response to diets with different macronutrient composition and might be a useful approach for personalized weight management.

Effect of sleep on overnight cerebrospinal fluid amyloid ß kinetics.

Sleep disturbances are associated with future risk of Alzheimer disease. Disrupted sleep increases soluble amyloid ß, suggesting a mechanism for sleep disturbances to increase Alzheimer disease risk. We tested this response in humans using indwelling lumbar catheters to serially sample cerebrospinal fluid while participants were sleep-deprived, treated with sodium oxybate, or allowed to sleep normally. All participants were infused with 13 C6 -leucine to measure amyloid ß kinetics. We found that sleep deprivation increased overnight amyloid ß38, amyloid ß40, and amyloid ß42 levels by 25 to 30% via increased overnight amyloid ß production relative to sleeping controls. These findings suggest that disrupted sleep increases Alzheimer disease risk via increased amyloid ß production. Ann Neurol 2018;83:197-204.

Blunted fat oxidation upon submaximal exercise is partially compensated by enhanced glucose metabolism in children, adolescents, and young adults with Barth syndrome.

Barth syndrome (BTHS) is a rare X-linked condition resulting in abnormal mitochondria, cardioskeletal myopathy, and growth delay; however, the effects of BTHS on substrate metabolism regulation and their relationships with tissue function in humans are unknown. We sought to characterize glucose and fat metabolism during rest, submaximal exercise, and postexercise rest in children, adolescents, and young adults with BTHS and unaffected controls and examine their relationships with cardioskeletal energetics and function. Children/adolescents and young adults with BTHS (n = 29) and children/adolescent and young adult control participants (n = 28, total n = 57) underwent an infusion of 6'6'H2 glucose and U-13 C palmitate and indirect calorimetry during rest, 30-minutes of moderate exercise (50% V˙O2peak ), and recovery. Cardiac function, cardioskeletal mitochondrial energetics, and exercise capacity were examined via echocardiography, 31 P magnetic resonance spectroscopy, and peak exercise testing, respectively. The glucose turnover rate was significantly higher in individuals with BTHS during rest (33.2 ± 9.8 vs 27.2 ± 8.1 µmol/kgFFM/min, P < .01) and exercise (34.7 ± 11.2 vs 29.5 ± 8.8 µmol/kgFFM/min, P < .05) and tended to be higher postexercise (33.7 ± 10.2 vs 28.8 ± 8.0 µmol/kgFFM/min, P < .06) compared to controls. Increases in total fat (-3.9 ± 7.5 vs 10.5 ± 8.4 µmol/kgFFM/min, P < .0001) and plasma fatty acid oxidation rates (0.0 ± 1.8 vs 5.1 ± 3.9 µmol/kgFFM/min, P < .0001) from rest to exercise were severely blunted in BTHS compared to controls. Conclusion: An inability to upregulate fat metabolism during moderate intensity exercise appears to be partially compensated by elevations in glucose metabolism. Derangements in fat and glucose metabolism are characteristic of the pathophysiology of BTHS. A severely blunted ability to upregulate fat metabolism during a modest level of physical activity is a defining pathophysiologic characteristic in children, adolescents, and young adults with BTHS.

Molecular phylogenetics of slit-faced bats (Chiroptera: Nycteridae) reveal deeply divergent African lineages.

The bat family Nycteridae contains only the genus Nycteris, which comprises 13 currently recognized species from Africa and the Arabian Peninsula, one species from Madagascar, and two species restricted to Malaysia and Indonesia in South-East Asia. We investigated genetic variation, clade membership, and phylogenetic relationships in Nycteridae with broad sampling across Africa for most clades. We sequenced mitochondrial cytochrome b (cytb) and four independent nuclear introns (2,166 bp) from 253 individuals. Although our samples did not include all recognized species, we recovered at least 16 deeply divergent monophyletic lineages using independent mitochondrial and multilocus nuclear datasets in both gene tree and species tree analyses. Mean pairwise uncorrected genetic distances among species-ranked Nycteris clades (17% for cytb and 4% for concatenated introns) suggest high levels of phylogenetic diversity in Nycteridae. We found a large number of designated clades whose members are distributed wholly or partly in East Africa (10 of 16 clades), indicating that Nycteris diversity has been historically underestimated and raising the possibility that additional unsampled and/or undescribed Nycteris species occur in more poorly sampled Central and West Africa. Well-resolved mitochondrial, concatenated nuclear, and species trees strongly supported African ancestry for SE Asian species. Species tree analyses strongly support two deeply diverged subclades that have not previously been recognized, and these clades may warrant recognition as subgenera. Our analyses also strongly support four traditionally recognized species groups of Nycteris. Mitonuclear discordance regarding geographic population structure in Nycteris thebaica appears to result from male-biased dispersal in this species. Our analyses, almost wholly based on museum voucher specimens, serve to identify species-rank clades that can be tested with independent datasets, such as morphology, vocalizations, distributions, and ectoparasites. Our analyses highlight the need for a comprehensive revision of Nycteridae.

Diabetes adversely affects phospholipid profiles in human carotid artery endarterectomy plaques.

Patients with diabetes are at higher risk of developing carotid artery stenosis and resultant stroke. Arachidonoyl phospholipids affect plaque inflammation and vulnerability, but whether diabetic patients have unique carotid artery phospholipidomic profiles is unknown. We performed a comprehensive paired analysis of phospholipids in extracranial carotid endarterectomy (CEA) plaques of matched diabetic and nondiabetic patients and analyzed mass spectrometry-derived profiles of three phospholipids, plasmenyl-phosphatidylethanolamine (pPE), phosphatidylserine (PS), and phosphatidylinositol (PI), in maximally (MAX) and minimally (MIN) diseased CEA segments. We also measured levels of arachidonic acid (AA), produced by pPE hydrolysis, and choline-ethanolamine phosphotransferase 1 (CEPT1), responsible for most pPE de novo biosynthesis. In paired analysis, MIN CEA segments had higher levels than MAX segments of pPE (P < 0.001), PS (P < 0.001), and PI (P < 0.03). MIN diabetic plaques contained higher levels than MAX diabetic plaques of arachidonoyl pPE38:4 and pPE38:5 and CEPT1 was upregulated in diabetic versus nondiabetic plaques. AA levels were relatively greater in MIN versus MAX segments of all CEA segments, and were higher in diabetic than nondiabetic plaques. Our findings suggest that arachidonoyl phospholipids are more likely to be abundant in the extracranial carotid artery plaque of diabetic rather than nondiabetic patients.