Opposing diet, microbiome, and metabolite mechanisms regulate inflammatory bowel disease in a genetically susceptible host.

Inflammatory bowel diseases (IBDs) are chronic conditions characterized by periods of spontaneous intestinal inflammation and are increasing in industrialized populations. Combined with host genetics, diet and gut bacteria are thought to contribute prominently to IBDs, but mechanisms are still emerging. In mice lacking the IBD-associated cytokine, interleukin-10, we show that a fiber-deprived gut microbiota promotes the deterioration of colonic mucus, leading to lethal colitis. Inflammation starts with the expansion of natural killer cells and altered immunoglobulin-A coating of some bacteria. Lethal colitis is then driven by Th1 immune responses to increased activities of mucin-degrading bacteria that cause inflammation first in regions with thinner mucus. A fiber-free exclusive enteral nutrition diet also induces mucus erosion but inhibits inflammation by simultaneously increasing an anti-inflammatory bacterial metabolite, isobutyrate. Our findings underscore the importance of focusing on microbial functions-not taxa-contributing to IBDs and that some diet-mediated functions can oppose those that promote disease.

Comparative dose effectiveness of intravenous and intrathecal AAV9.CB7.hIDS, RGX-121, in mucopolysaccharidosis type II mice.

Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disease caused by iduronate-2-sulfatase (IDS) deficiency, leading to accumulation of glycosaminoglycans (GAGs) and the emergence of progressive disease. Enzyme replacement therapy is the only currently approved treatment, but it leaves neurological disease unaddressed. Cerebrospinal fluid (CSF)-directed administration of AAV9.CB7.hIDS (RGX-121) is an alternative treatment strategy, but it is unknown if this approach will affect both neurologic and systemic manifestations. We compared the effectiveness of intrathecal (i.t.) and intravenous (i.v.) routes of administration (ROAs) at a range of vector doses in a mouse model of MPS II. While lower doses were completely ineffective, a total dose of 1 × 109 gc resulted in appreciable IDS activity levels in plasma but not tissues. Total doses of 1 × 1010 and 1 × 1011 gc by either ROA resulted in supraphysiological plasma IDS activity, substantial IDS activity levels and GAG reduction in nearly all tissues, and normalized zygomatic arch diameter. In the brain, a dose of 1 × 1011 gc i.t. achieved the highest IDS activity levels and the greatest reduction in GAG content, and it prevented neurocognitive deficiency. We conclude that a dose of 1 × 1010 gc normalized metabolic and skeletal outcomes, while neurologic improvement required a dose of 1 × 1011 gc, thereby suggesting the prospect of a similar direct benefit in humans.

Unravelling specific diet and gut microbial contributions to inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic condition characterized by periods of spontaneous intestinal inflammation and is increasing in industrialized populations. Combined with host genetic predisposition, diet and gut bacteria are thought to be prominent features contributing to IBD, but little is known about the precise mechanisms involved. Here, we show that low dietary fiber promotes bacterial erosion of protective colonic mucus, leading to lethal colitis in mice lacking the IBD-associated cytokine, interleukin-10. Diet-induced inflammation is driven by mucin-degrading bacteria-mediated Th1 immune responses and is preceded by expansion of natural killer T cells and reduced immunoglobulin A coating of some bacteria. Surprisingly, an exclusive enteral nutrition diet, also lacking dietary fiber, reduced disease by increasing bacterial production of isobutyrate, which is dependent on the presence of a specific bacterial species, Eubacterium rectale. Our results illuminate a mechanistic framework using gnotobiotic mice to unravel the complex web of diet, host and microbial factors that influence IBD.

Square-Stepping Exercise Program Effects on Fall-Related Fitness and BDNF Levels in Older Adults in Korea: A Randomized Controlled Trial.

The risk of dementia increases with age. To mitigate this risk, we examined the effect of a square-stepping exercise (SSE) program on fall-related fitness and brain-derived neurotrophic factor (BDNF) levels. Twenty older adults in Korea were randomly assigned to either the experimental or control group (each group n = 10). Participants performed SSE for 70 min per session, twice a week, for 12 weeks with a certified instructor. The average age of the participants was 74.80 ± 6.763 years in the exercise group and 72.50 ± 6.519 years in the control group. The experiment group showed significant improvement (p < 0.01) in the lower muscle strength post-intervention. The paired t-test revealed a significant improvement (p < 0.01) in the experimental group and a significant difference in the interaction effect (p < 0.01) in the BDNF levels. There was a significant improvement (p < 0.05) in the BDNF levels in the experimental group and a significant decrease (p < 0.05) in the control group. The SSE program had a positive effect on fall-related fitness and BDNF levels.

Characterization of AAV-mediated dorsal root ganglionopathy.

Recent studies in non-human primates administered recombinant adeno-associated viruses (rAAVs) have shown lesions in the dorsal root ganglia (DRG) of unknown pathogenesis. In this study, rAAV9s manufactured using different purification methods alongside a non-expressing Null AAV9 vector was administered to groups of cynomolgus monkeys followed by neuropathological evaluation after 4 weeks. Lesions, including neuronal degeneration, increased cellularity, and nerve fiber degeneration, were observed in the DRG, regardless of purification methods. Animals did not develop any neurological signs throughout the study, and there was no loss of function observed in neuro-electrophysiological endpoints or clear effects on intraepidermal nerve fiber density. However, magnetic resonance imaging (MRI) of animals with axonopathy showed an increase in short tau inversion recovery (STIR) intensity and decrease in fractional anisotropy. In animals administered the Null AAV9 vector, DRG lesions were not observed despite vector DNA being detected in the DRG at levels equivalent to or greater than rAAV9-treated animals. This study further supports that DRG toxicity is associated with transgene overexpression in DRGs, with particular sensitivity at the lumbar and lumbosacral level. The data from this study also showed that the nerve fiber degeneration did not correlate with any functional effect on nerve conduction but was detectable by MRI.

Diverse events have transferred genes for edible seaweed digestion from marine to human gut bacteria.

Humans harbor numerous species of colonic bacteria that digest fiber polysaccharides in commonly consumed terrestrial plants. More recently in history, regional populations have consumed edible macroalgae seaweeds containing unique polysaccharides. It remains unclear how extensively gut bacteria have adapted to digest these nutrients. Here, we show that the ability of gut bacteria to digest seaweed polysaccharides is more pervasive than previously appreciated. Enrichment-cultured Bacteroides harbor previously discovered genes for seaweed degradation, which have mobilized into several members of this genus. Additionally, other examples of marine bacteria-derived genes, and their mobile DNA elements, are involved in gut microbial degradation of seaweed polysaccharides, including genes in gut-resident Firmicutes. Collectively, these results uncover multiple separate events that have mobilized the genes encoding seaweed-degrading-enzymes into gut bacteria. This work further underscores the metabolic plasticity of the human gut microbiome and global exchange of genes in the context of dietary selective pressures.

Effect of post-operative anticoagulation management in patients who have undergone On-X mechanical heart valve replacement surgery on post-discharge warfarin therapy.

WHAT IS KNOWN AND OBJECTIVE: We evaluated the effect of the proportion of time maintained within the target international normalized ratio (INR) postoperatively in hospitalized patients who underwent On-X mechanical heart valve replacement on warfarin therapy after discharge. METHODS: Inclusion was patients who were ≥18 years, received warfarin for a minimum of 10 days without any interruptions during hospitalization and followed by the anticoagulation service (ACS) clinic after discharge between June 2006 and June 2016. Patients were excluded if they had incomplete medical records, INR goal changes, known as warfarin resistance, transferred to another facility or expired during the study. The patients were divided into 3 groups according to the proportion of time maintained within therapeutic INR range (TTR) from day 4 to 10 of warfarin initiation (low: <30%, moderate: ≥30% to <70%, and high: ≥70%). The number of days needed to reach target INR for 2 consecutive measurements after discharge and the number of ACS visits was compared among the groups. RESULTS AND DISCUSSION: Among 539 postoperative patients, 273 were included. The baseline demographics were similar among the 3 groups. The mean time needed to reach target INR for 2 consecutive measurements was 68.6 ± 106.1 days. The low group required time needed to reach target INR for 2 consecutive measurements of 94.0 ± 140.9 days compared with 44.8 ± 57.1 days in the high group (P = .007). Additionally, the low group had more ACS visits than the high group (low, 6.6 ± 5.2 vs high, 4.6 ± 3.9; P = .025). Patient compliance affected the time needed to reach target INR for 2 consecutive measurements (compliant, 42.36 ± 58.5 days vs non-compliant, 132.0 ± 157.1 days, P < .001). WHAT IS NEW AND CONCLUSION: The study implicated that high postoperative TTR would reduce the time to require post-discharge target INR and the number of ACS visits.

Body Weight as a Determining Factor in the Predominance of Adverse Drug Reactions Induced by Fixed-Dose Adalimumab Injections in Female Patients in a Korean Hospital Setting.

Adalimumab is used at 40-mg dose to treat systemic inflammatory diseases. Given the impact of adverse drug reactions (ADRs), which particularly result in the discontinuation of adalimumab therapy in female patients, this study examined whether sex affects the frequency and type of ADRs induced by adalimumab. In this study, the prescription records and laboratory data of patients aged ≥19 years who had been admitted to the Seoul National University Hospital (SNUH) and prescribed adalimumab were analyzed using an electronic medical record database. The analysis revealed that female patients more frequently experienced adalimumab-induced ADRs compared with male patients (63.2% vs. 52.2%). The incidence of ADRs was significantly higher in female patients with ankylosing spondylitis or rheumatoid arthritis than in male patients with similar conditions (81.5% vs. 60.7% or 64.4% vs. 50.0%, respectively). The median body weight (BW) was lower in female patients than in male patients (54.0 vs. 66.0 kg). Moreover, the incidence of ADRs in patients with a BW of <54.0 kg (i.e., the median female BW) was higher than for those with a BW of ≥54.0 kg, in both males and females. Our results suggested that the predominance of ADRs induced by adalimumab in females was because of their relatively lower BW. This suggests the importance of BW as a determining factor in sex disparity of ADR occurrences.

Dehydration affects exercise-induced asthma and anaphylaxis.

Allergies are generally triggered by food, medication, physical exercise, stress, alcohol consumption, and dehydration. There are reports that indicate dehydration affects various kinds of physical allergies. However, there are few studies that have focused on the effects of dehydration on asthma and allergy anaphylaxis. Therefore, we analyzed the effects of dehydration on several kinds of allergy responses and exercise-induced asthma especially during the endurance exercise. PubMed was searched from April to July of 2019 using predefined search terms "dehydration," "exercise," and "allergy responses." Based on the reference search, more than one-hundred articles were identified but eighteen papers met the inclusion criteria and were analyzed for connections among exercise and dehydration, dehydration and exercise-induced asthma, and allergy responses in the main text. Results suggest that dehydration directly impairs stroke volume, cardiac output, and skin blood flow. This results in larger increases in core temperature, heart rate, and stroke volume. Additionally, exercise-induced dehydration reduces airway surface hydration, which results in an amplified brocnchoconstriction. This response to exercise occurs in those who suffer from exercise-induced asthma. Moreover, damage to the gut and impaired gut function relates to increased intestinal permeability after endurance exercise. Endurance exercise changes the immunological profiles to activate antibody-mediated immunity. Also, numerous mast cells and eosinophils were recruited, therefore isotype switching to IgE antibodies occur, this hypersensitivity activates mast cell degranulation. After degranulation, proteases, leukotrienes, prostaglandins, and histamine lead to many kinds of allergy symptoms.

Future Directions of Pharmacovigilance Studies Using Electronic Medical Recording and Human Genetic Databases.

Adverse drug reactions (ADRs) constitute key factors in determining successful medication therapy in clinical situations. Integrative analysis of electronic medical record (EMR) data and use of proper analytical tools are requisite to conduct retrospective surveillance of clinical decisions on medications. Thus, we suggest that electronic medical recording and human genetic databases are considered together in future directions of pharmacovigilance. We analyzed EMR-based ADR studies indexed on PubMed during the period from 2005 to 2017 and retrospectively acquired 1161 (29.6%) articles describing drug-induced adverse reactions (e.g., liver, kidney, nervous system, immune system, and inflammatory responses). Of them, only 102 (8.79%) articles contained useful information to detect or predict ADRs in the context of clinical medication alerts. Since insufficiency of EMR datasets and their improper analyses may provide false warnings on clinical decision, efforts should be made to overcome possible problems on data-mining, analysis, statistics, and standardization. Thus, we address the characteristics and limitations on retrospective EMR database studies in hospital settings. Since gene expression and genetic variations among individuals impact ADRs, pharmacokinetics, and pharmacodynamics, appropriate paths for pharmacovigilance may be optimized using suitable databases available in public domain (e.g., genome-wide association studies (GWAS), non-coding RNAs, microRNAs, proteomics, and genetic variations), novel targets, and biomarkers. These efforts with new validated biomarker analyses would be of help to repurpose clinical and translational research infrastructure and ultimately future personalized therapy considering ADRs.

Sex-Dependent Adverse Drug Reactions to 5-Fluorouracil in Colorectal Cancer.

Sex-related incidence and outcomes were reported in various cancers, including colorectal cancer. 5-Fluorouracil (5-FU) is widely used as an essential chemotherapeutic agent for colorectal cancer. However, sex-based differences in 5-FU toxicity have yet to be reported in human cancer cell lines and xenograft mouse models to date. Here, we investigated, for the first time, sex-based differences in 5-FU toxicity using human colon cancer cell lines, xenograft mouse models, and Korean patients' data. Female-derived colon cancer cell lines exhibited greater 5-FU-induced cytotoxicity than male-derived colon cancer cell lines. We established two xenograft mouse models: one with a male-derived human colon cancer cell line injected into male mice (a male-xenograft model) and another involving a female-derived human colon cancer cell line injected into female mice (a female xenograft model). Treatment with 5-FU inhibited tumor growth and led to hematological toxicity in a female xenograft model more potently than in a male xenograft model. We analyzed the data obtained from Korean patients with colorectal cancer to examine sex differences in adverse drug reactions caused by 5-FU. Korean female patients with colorectal cancer who received 5-FU chemotherapy experienced more frequent adverse drug reactions including alopecia and leukopenia than male patients. Taken together, we demonstrated that female may be associated with increased risk of toxicity to 5-FU treatment in colorectal cancer based on in vitro and in vivo investigations and clinical data analysis. Our study suggests sex as an important clinical factor, which predicts induction of toxicity related to 5-FU treatment.

Dynamics of Human Gut Microbiota and Short-Chain Fatty Acids in Response to Dietary Interventions with Three Fermentable Fibers.

Production of short-chain fatty acids (SCFAs), especially butyrate, in the gut microbiome is required for optimal health but is frequently limited by the lack of fermentable fiber in the diet. We attempted to increase butyrate production by supplementing the diets of 174 healthy young adults for 2 weeks with resistant starch from potatoes (RPS), resistant starch from maize (RMS), inulin from chicory root, or an accessible corn starch control. RPS resulted in the greatest increase in total SCFAs, including butyrate. Although the majority of microbiomes responded to RPS with increases in the relative abundance of bifidobacteria, those that responded with an increase in Ruminococcus bromii or Clostridium chartatabidum were more likely to yield higher butyrate concentrations, especially when their microbiota were replete with populations of the butyrate-producing species Eubacterium rectale RMS and inulin induced different changes in fecal communities, but they did not generate significant increases in fecal butyrate levels.IMPORTANCE These results reveal that not all fermentable fibers are equally capable of stimulating SCFA production, and they highlight the importance of the composition of an individual's microbiota in determining whether or not they respond to a specific dietary supplement. In particular, R. bromii or C. chartatabidum may be required for enhanced butyrate production in response to RS. Bifidobacteria, though proficient at degrading RS and inulin, may not contribute to the butyrogenic effect of those fermentable fibers in the short term.

Bacterial Dissemination to the Brain in Sepsis.

RATIONALE: Sepsis causes brain dysfunction and neuroinflammation. It is unknown whether neuroinflammation in sepsis is initiated by dissemination of bacteria to the brain and sustained by persistent infection, or whether neuroinflammation is a sterile process resulting solely from circulating inflammatory mediators. OBJECTIVES: To determine if gut bacteria translocate to the brain during sepsis, and are associated with neuroinflammation. METHODS: Murine sepsis was induced using cecal ligation and puncture, and sepsis survivor mice were compared with sham and unoperated control animals. Brain tissue of patients who died of sepsis was compared with patients who died of noninfectious causes. Bacterial taxa were characterized by 16S ribosomal RNA gene sequencing in both murine and human brain specimens; compared among sepsis and nonsepsis groups; and correlated with levels of S100A8, a marker of neuroinflammation using permutational multivariate ANOVA. MEASUREMENTS AND MAIN RESULTS: Viable gut-associated bacteria were enriched in the brains of mice 5 days after surviving abdominal sepsis (P < 0.01), and undetectable by 14 days. The community structure of brain-associated bacteria correlated with severity of neuroinflammation (P < 0.001). Furthermore, bacterial taxa detected in brains of humans who die of sepsis were distinct from those who died of noninfectious causes (P < 0.001) and correlated with S100A8/A9 expression (P < 0.05). CONCLUSIONS: Although bacterial translocation is associated with acute neuroinflammation in murine sepsis, bacterial translocation did not result in chronic cerebral infection. Postmortem analysis of patients who die of sepsis suggests a role for bacteria in acute brain dysfunction in sepsis. Further work is needed to determine if modifying gut-associated bacterial communities modulates brain dysfunction after sepsis.

Predicting augmented renal clearance using estimated glomerular filtration rate in critically-ill children
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AIMS: Measured glomerular filtration rate (mGFR) is often used to identify augmented renal clearance (ARC). However, in the clinical setting, estimated GFR (eGFR) is obtained more quickly and inexpensively. We aimed to determine whether eGFR can identify ARC by evaluating the correlation between the eGFR and vancomycin trough level (VTL). MATERIALS AND METHODS: We retrospectively reviewed the records of patients aged ≤ 18 years who underwent vancomycin therapeutic drug monitoring at our tertiary hospital from July 2009 to June 2014. VTL, serum creatinine concentration, eGFR, and clinical factors affecting VTL were analyzed. RESULTS: Of 101 patients, 76 (75.25%) had a subtherapeutic VTL. Patient age (p = 0.006), the daily vancomycin dose (p = 0.041) and dosing interval (p = 0.006), and eGFR (p < 0.001) affected the VTL. Multivariate analysis showed a significant relationship between eGFR and VTL (adjusted R2, 0.812; p < 0.001). An increased eGFR (odds ratio, 1.002; 95% confidence interval, 1.001 - 1.003; p = 0.001) was a risk factor for a subtherapeutic vancomycin level. The cutoff eGFR value predicting a subtherapeutic vancomycin level was 110.51 mL/min/1.73m2 (area under the curve, 0.753). CONCLUSIONS: The eGFR correlates with the VTL, and the eGFR cutoff value can predict a subtherapeutic vancomycin level. eGFR is a reliable and efficient alternative to mGFR for identifying ARC.
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Multidisciplinary approach to improve spontaneous ADR reporting in the pediatric outpatient setting: a single-institute experience in Korea.

In order to improve the reporting of adverse drug reactions (ADRs) as part of the routine practice at the pediatric outpatient department (OPD), we modified our ADR reporting strategy into one that facilitates the reporting process by means of a multi-disciplinary approach. In this study, we retrospectively reviewed ADR records during the period from March to September 2014 when we changed our reporting process as a part of institutional quality assurance (QA) activity. Yearly differences in the number and composition of ADRs were compared, and the descriptive analyses were done for cases reported from OPD during the QA activity in terms of the suspected drugs, type, causality, and severity of ADRs. There were 1211 pediatric ADR reports including 520 cases with underlying hemato-oncologic diseases during the period of 2014. Among the 691 non-oncologic cases, 76 were reported from the OPD, which was a significant increase (347 %) from the 17 cases reported during the previous year. Further analyses of these 76 cases revealed that the caregivers (47.4 %) initiated about half of the reports, the most frequently affected organ was the skin (32.9 %), and the most frequent suspected drugs were anticonvulsants (14.5 %). In contrast to the in-ward system, moderate cases were more frequent (51.3 %) than mild ones. In conclusion, this study provides a profile of pediatric ADRs in the OPD, which were largely under-reported during the usual clinical practice. A multi-disciplinary approach would improve spontaneous ADR reporting at the pediatric OPD.

Discharging a Li-S battery with ultra-high sulphur content cathode using a redox mediator.

Lithium-sulphur batteries are under intense research due to the high specific capacity and low cost. However, several problems limit their commercialization. One of them is the insulating nature of sulphur, which necessitates a large amount of conductive agent and binder in the cathode, reducing the effective sulphur load as well as the energy density. Here we introduce a redox mediator, cobaltocene, which acts as an electron transfer agent between the conductive surface and the polysulphides in the electrolyte. We confirmed that cobaltocene could effectively convert polysulphides to Li2S using scanning electron microscope, X-ray absorption near-edge structure and in-situ X-ray diffraction studies. This redox mediator enabled excellent electrochemical performance in a cathode with ultra-high sulphur content (80 wt%). It delivered 400 mAh g(-1)cathode capacity after 50 cycles, which is equivalent to 800 mAh g(-1)S in a typical cathode with 50 wt% sulphur. Furthermore, the volumetric capacity was also dramatically improved.

The successful accomplishment of nutritional and clinical outcomes via the implementation of a multidisciplinary nutrition support team in the neonatal intensive care unit.

BACKGROUND: Nutritional support is critical for preterm infants in the neonatal intensive care unit (NICU). A multidisciplinary nutritional support team (NST) that focuses on providing optimal and individualized nutrition care could be helpful. We conducted a thorough evaluation of clinical and nutritional outcomes in a tertiary NICU following the implementation of an NST. METHODS: This study used a retrospective approach with historical comparisons. Preterm neonates < 30 weeks gestational age or weighing < 1250 g were enrolled. Clinical and nutritional outcomes were compared before and after the establishment of the NST. Medical records were reviewed, and clinical and nutritional outcomes were compared between the two groups. RESULTS: In total, 107 patients from the pre-NST period and 122 patients from the post-NST period were included. The cumulative energy delivery during the first week of life improved during the post-NST period (350.17 vs. 408.62 kcal/kg, p < 0.001). The cumulative protein and lipid deliveries also significantly increased. The time required to reach full enteric feedings decreased during the post-NST period (6.4 ± 5.8 vs. 4.7 ± 5.1 days, p = 0.016). Changes of Z-score in weight from admission to discharge exhibited more favorable results in the post-NST period (-1.13 ± 0.99 vs.-0.91 ± 0.74, p = 0.055), and the length of ICU stay significantly decreased in the post-NST period (81.7 ± 36.6 vs. 72.2 ± 32.9 days, p = 0.040). CONCLUSIONS: NST intervention in the NICU resulted in significant improvements in the provision of nutrition to preterm infants in the first week of life. There were also favorable clinical outcomes, such as increased weight gain and reduced length of ICU stay. Evaluable data remain sparse in the NICU setting with premature neonatal populations; therefore, the successful outcomes identified in this study may provide support for NST practices.

Higher plasma bilirubin predicts veno-occlusive disease in early childhood undergoing hematopoietic stem cell transplantation with cyclosporine.

AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease (VOD) in non-adult patients undergoing hematopoietic stem cell transplantation (HSCT) during cyclosporine therapy. METHODS: A total of 123 patients taking cyclosporine were evaluated using an electronic medical system at the Seoul National University Children's Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions (ADRs) including VOD. RESULTS: The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease (aGVHD) and VOD. Although the incidences of aGVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level (BILmax) of ≥ 1.4 mg/dL correlated with VOD incidence after cyclosporine therapy. CONCLUSION: HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/dL, suggestive of more sensitive VOD indication in this age group.

Epigenetic Modulation of Human Induced Pluripotent Stem Cell Differentiation to Oligodendrocytes.

Pluripotent stem cells provide an invaluable tool for generating human, disease-relevant cells. Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, characterized by myelin damage. Oligodendrocytes are the myelinating cells of the central nervous system (CNS); they differentiate from progenitor cells, and their membranes ensheath axons, providing trophic support and allowing fast conduction velocity. The current understanding of oligodendrocyte biology was founded by rodent studies, where the establishment of repressive epigenetic marks on histone proteins, followed by activation of myelin genes, leads to lineage progression. To assess whether this epigenetic regulation is conserved across species, we differentiated human embryonic and induced pluripotent stem cells to oligodendrocytes and asked whether similar histone marks and relative enzymatic activities could be detected. The transcriptional levels of enzymes responsible for methylation and acetylation of histone marks were analyzed during oligodendrocyte differentiation, and the post-translational modifications on histones were detected using immunofluorescence. These studies showed that also in human cells, differentiation along the oligodendrocyte lineage is characterized by the acquisition of multiple repressive histone marks, including deacetylation of lysine residues on histone H3 and trimethylation of residues K9 and K27. These data suggest that the epigenetic modulation of oligodendrocyte identity is highly conserved across species.

Enhancement of cycle performance of Li-S batteries by redistribution of sulfur.

A practically available strategy is employed to improve the cycle life of lithium-sulfur batteries. The simple process of activation cycling at the polysulfide dissolution region leads to the partial dissolution of polysulfides and the redistribution of sulfur on the electrode. After 50 cycles, the modified activation-cycled sulfur cathode exhibits a capacity that is roughly double that of a cathode without activation cycling.