Showing papers by "Clay F. Semenkovich published in 2019"
TL;DR: Identifying ingredients in complementary foods, consumed during the transition from exclusive milk feeding to a fully weaned state, that increase the representation and expressed beneficial functions of growth-promoting bacterial taxa in the developing microbiota could provide an effective, affordable, culturally acceptable, and sustainable approach to treatment.
Abstract: To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF that changes the abundances of targeted bacteria and increases plasma biomarkers and mediators of growth, bone formation, neurodevelopment, and immune function in children with MAM.
251 citations
TL;DR: It is found that FA synthesis is essential to sustain adult OPC-derived OLs and efficient remyelination, and plays key roles in CNS myelination and remyElination.
Abstract: Oligodendrocytes (OLs) support neurons and signal transmission in the central nervous system (CNS) by enwrapping axons with myelin, a lipid-rich membrane structure. We addressed the significance of fatty acid (FA) synthesis in OLs by depleting FA synthase (FASN) from OL progenitor cells (OPCs) in transgenic mice. While we detected no effects in proliferation and differentiation along the postnatal OL lineage, we found that FASN is essential for accurate myelination, including myelin growth. Increasing dietary lipid intake could partially compensate for the FASN deficiency. Furthermore, FASN contributes to correct myelin lipid composition and stability of myelinated axons. Moreover, we depleted FASN specifically in adult OPCs to examine its relevance for remyelination. Applying lysolecithin-induced focal demyelinating spinal cord lesions, we found that FA synthesis is essential to sustain adult OPC-derived OLs and efficient remyelination. We conclude that FA synthesis in OLs plays key roles in CNS myelination and remyelination.
80 citations
TL;DR: It is suggested that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic Syndrome in humans but is unlikely to be clinically useful in this setting.
Abstract: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting. Trial registration ClinicalTrials.gov (NCT00455325, NCT00455403), both posted 03 April 2007
17 citations
TL;DR: Serum cFAS is higher in patients with diabetes and CAS, appears to originate from the liver, and is LDL cholesterol associated, and it is postulate that LDL may be serving as a carrier for cFas that contributes to atheroprogression in carotid arteries of patients with Diabetes.
13 citations
TL;DR: This protocol describes the use of such an analyzer to measure contributions to retinal energy supply through its two principle arms - oxidative phosphorylation and glycolysis - by quantifying changes in oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) as proxies for these pathways.
Abstract: High acuity vision is a heavily energy-consuming process, and the retina has developed several unique adaptations to precisely meet such demands while maintaining transparency of the visual axis. Perturbations to this delicate balance cause blinding illnesses, such as diabetic retinopathy. Therefore, the understanding of energy metabolism changes in the retina during disease is imperative to the development of rational therapies for various causes of vison loss. The recent advent of commercially-available extracellular flux analyzers has made the study of retinal energy metabolism more accessible. This protocol describes the use of such an analyzer to measure contributions to retinal energy supply through its two principle arms - oxidative phosphorylation and glycolysis - by quantifying changes in oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) as proxies for these pathways. This technique is readily performed in explanted retinal tissue, facilitating assessment of responses to multiple pharmacologic agents in a single experiment. Metabolic signatures in retinas from animals lacking rod photoreceptor signaling are compared to wild-type controls using this method. A major limitation in this technique is the lack of ability to discriminate between light-adapted and dark-adapted energy utilization, an important physiologic consideration in retinal tissue.
10 citations
TL;DR: In this article, the authors defined the transcriptional profile of satellite glial cells (SGC) and identified Fabp7/BLBP as a novel marker of SGC.
Abstract: Peripheral sensory neurons switch to a regenerative state after nerve injury to enable axon regeneration and functional recovery. Whether satellite glial cells (SGC), which completely surround the neuronal soma, contribute to the regenerative responses remains unexplored. Here we defined the transcriptional profile of SGC and identified Fabp7/BLBP as a novel marker of SGC. We report that nerve injury changes gene expression in SGC, which is mostly related to lipid metabolism, specifically fatty acid synthesis and PPARa signaling. Conditional deletion of Fatty acid synthase (Fasn), the committed enzyme in de novo fatty acid synthesis in SGC impairs axon regeneration. Treatment with the PPARa agonist fenofibrate rescues axon regeneration in mice lacking Fasn in SGC. This results indicates that PPARa functions downstream of fatty acid synthesis in SGC to promote axon regeneration. These results identify fatty acid synthesis in SGC as a fundamental novel mechanism mediating axon regeneration in adult peripheral nerves.
9 citations
5 citations
TL;DR: A simple yet powerful F1 reciprocal cross model is used to test the hypothesis that non-imprinted genes can generate complex POE on metabolic traits through genetic interactions with imprinted genes, and identifies two classes of parent-of-origin-dependent allele-specific expression and biallelic genes that are differentially expressed by reciprocal cross.
Abstract: Parent-of-origin effects (POE) are unexpectedly common in complex traits, including metabolic and neurological diseases. POE can also be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific POE on metabolic traits were mapped in the F16 generation of an advanced intercross between LG/J and SM/J inbred mice. However, these QTL were not enriched for known imprinted genes, suggesting another mechanism is needed to explain these POE phenomena. Here, we use a simple yet powerful F1 reciprocal cross model to test the hypothesis that non-imprinted genes can generate complex POE on metabolic traits through genetic interactions with imprinted genes. Male and female mice from a F1 reciprocal cross of LG/J and SM/J strains were fed either high or low fat diets. We generated expression profiles from three metabolically-relevant tissues: hypothalamus, white adipose, and liver. We identified two classes of parent-of-origin expression biases: genes showing parent-of-origin-dependent allele-specific expression and biallelic genes that are differentially expressed by reciprocal cross. POE patterns of both gene classes are highly tissue- and context-specific, sometimes occurring only in one sex and/or diet cohort in a particular tissue. We then constructed tissue-specific interaction networks among genes from these two classes of POE. Some gene pairs show significant epistasis in the F16 LG/J × SM/J advanced intercross data in cases where the biallelic gene fell within a previously-identified metabolic POE QTL interval. We highlight one such interaction in adipose, between Nnat and Mogat1, which associates with variation in multiple adiposity traits. The genes and networks we present here represent a set of actionable interacting candidates that can be probed to further identify the machinery driving POE on complex traits.
1 citations