Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on ...diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, re-structures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.
Mas-related G protein-coupled receptor D (MrgprD) was first identified in small-diameter sensory neurons of mouse dorsal root ganglion (DRG). The role of MrgprD has been studied in somatosensation, ...especially in pain and itch response. We recently showed that MrgprD also participated in the modulation of murine intestinal motility. The treatment of MrgprD receptor agonist suppressed the spontaneous contractions in the isolated intestinal rings of mice, indicating the intrinsic expression of MrgprD in the murine gastrointestinal (GI) tract. Although the expression of
Mrgprd
in GI tract has been previously detected by the way of quantitative real-time PCR, the cell-type-specific expression of MrgprD in GI tract is no yet determined. Herein, we employed
Mrgprd
-tdTomato reporter mouse line and the whole-mount immunohistochemistry to observe the localization of MrgprD in the smooth muscle layers of ileum and colon. We show that tdTomato-positive cells colocalized with NeuN-immunostaining in the myenteric plexus in the whole-mount preparations of the ileum and the colon. Further immunohistochemistry using the commercially available MrgprD antibody revealed the expression of MrgprD in NeuN-labeled enteric neurons in the myenteric plexus. Our results demonstrate the expression of MrgprD in the enteric neurons in the murine GI tract, highlighting the implications of MrgprD in the physiology and pathophysiology of the GI tract.
Observations of Kuiper Belt objects (KBOs) in Neptune's 5:2 resonance present two puzzles: this third-order resonance hosts a surprisingly large population, comparable to the prominent populations of ...Plutinos and Twotinos in the first order 3:2 and 2:1 resonances, respectively; second, their eccentricities are concentrated near 0.4. To shed light on these puzzles, we investigate the phase space near this resonance with use of Poincaré sections of the circular planar restricted three-body model. We find several transitions in the phase space structure with increasing eccentricity, which we explain with the properties of the resonant orbit relative to Neptune's. The resonance width is narrow for very small eccentricities but widens dramatically for e 0.2, reaching a maximum near e 0.4, where it is similar to the maximum widths of the 2:1 and 3:2 resonances. We confirm these results with N-body numerical simulations, including the effects of all four giant planets and a wide range of orbital inclinations of the KBOs. We find that the boundaries of the stable resonance zone are not strongly sensitive to inclination and remain very similar to those found with the simplified three-body model, with the caveat that orbits of eccentricity above ∼0.53 are unstable; higher-eccentricity orbits are phase-protected from destabilizing encounters with Neptune but not with Uranus. These results show that the 5:2 resonant KBOs are not more puzzling than the Plutinos and Twotinos; however, detailed understanding of the origins of eccentric, inclined resonant KBOs remains a challenge.
Surfactants with opposite charge pack as co-surfactant at low concentration, while catanionic mixtures generate closely-packed adsorption layers at oil/aqueous interfaces at high concentration.
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•Catanionic surfactant mixtures are closely-packed at oil-aqueous interface and the adsorption layer has displayed strong viscoelasticity.•The ratio of anionic/cationic surfactants on the adsorption layer is independent with the ratio in the bulk.•The SDS-C12TAB mixture adsorption layers arrange more closely and possesses higher elasticity than SDDS-C12TAB and DAS-C12TAB.•Long alky chain makes the molecular motion, orientation and rearrangement more difficult and slows down the relaxation processes.
Catanionic surfactant mixtures have shown advantages in many applicable aspects for strong synergetic behavior. In the present work, the adsorption behaviors of catanionic mixtures at oil-aqueous interface have been studied by means of interfacial tension measurements and interfacial dilational rheological experiments. Because of the electrostatic attraction, catanionic mixtures are tightly packed: at low concentration, catanionic surfactant mixtures pack as co-surfactant like Gemini, while at high concentration (≥CMC), catanionic mixtures generate closely-packed network adsorption layers at oil/aqueous interfaces, which are strongly viscoelastic. The interfacial properties indicate the ratio of anionic and cationic surfactant at interface is independent with the ratio in the solution but depends on the molecular structure of surfactants. The interaction between anionic and cationic follows the order: SDS-C12TAB>SDDS-C12TAB>DAS-C12TAB. Therefore the adsorption layer of SDS and C12TAB packs more closely at the interface and possesses higher elasticity. As to the hydrophobic groups, the increase of alkyl chain length enhances the hydrophobic force, but makes the molecular motion, orientation and rearrangement more difficult. These results provide basis for the design of catanionic mixtures to regulate and control the interfacial properties to adapt to the different applications.
Influenza-related severe pneumonia and acute respiratory distress syndrome (ARDS) are severe threats to human health. The objective of this study was to assess the effects of systematic ...corticosteroid therapy in patients with pneumonia or ARDS. The PubMed, EMBASE, Web of Science and SCOPUS databases were searched up to July, 2019. Nineteen studies including 6637 individuals were identified, and fifteen studies (6427 patients) were included in the meta-analysis of mortality. Eighteen were observational studies and one was a randomized controlled trial (RCT). The meta-analysis results showed that corticosteroid therapy was associated with significantly higher mortality (OR 1.53, 95% CI 1.16, 2.01) and incidence of nosocomial infection (OR 3.15, 95% CI 1.54, 6.45). Subgroup analysis showed that among patients with unadjusted estimates, the odds of mortality were higher in patients receiving corticosteroid treatment (OR 1.98, 95% CI 1.23, 3.17), however, among patients with adjusted estimates, the result showed no statistically significant difference between corticosteroid group and control group (OR 1.31, 95% CI 0.95, 1.80). Current data do not support the routine use of corticosteroids in patients with influenza severe pneumonia or ARDS. RCTs are needed to provide more robust evidence.
The mixing ratio of anionic/cationic surfactants and the hydrophobic chain length of the surfactants influence the foam stability in the presence of oil through the interfacial properties. The fast ...generation of a tightly packed interfacial layer is in favor of the foamability and foam stability in the presence of oil.
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The dynamic interfacial dilational properties of catanionic surfactant mixtures and the relationship with foam stability in the presence of oil are studied in the present work. The dynamic interfacial dilational properties of catanionic mixtures at aqueous-oil interface have been studied by means of oscillating the drop profile method. The mixing ratio of anionic/cationic surfactants and the hydrophobic chain length of the surfactants influence the foam stability in the presence of oil through the interfacial dilational properties. Over a wide range of mixing ratio of SDS/C12TAB, interfacial tension and dilational modulus of the catanionic mixtures reaches similar equilibrium values. But as the mixing ratio approaches 1:1, comparable anionic and cationic surfactants are adsorbed at interface. This significantly speeds up the dynamic adsorption progress, which benefits the fast foaming progress. In addition, the increase of the alkyl chain length of CnTAB in SDS-CnTAB (n = 8, 10, 12, 14, 16) mixtures enhances the equilibrium modulus, but slows down the dynamic adsorption progress. Thus the foamability and stability decreases when surfactants have overlong hydrophobic chains. Overall, the fast generation of a tightly packed interfacial layer is in favor of the foamability and foam stability in the presence of oil.
Retinitis pigmentosa (RP) is an irreversible, inherited retinopathy in which early-onset nyctalopia is observed. Despite the genetic heterogeneity of RP, RPGR mutations are the most common causes of ...this disease. Here, we generated induced pluripotent stem cells (iPSCs) from three RP patients with different frameshift mutations in the RPGR gene, which were then differentiated into retinal pigment epithelium (RPE) cells and well-structured retinal organoids possessing electrophysiological properties. We observed significant defects in photoreceptor in terms of morphology, localization, transcriptional profiling, and electrophysiological activity. Furthermore, shorted cilium was found in patient iPSCs, RPE cells, and three-dimensional retinal organoids. CRISPR-Cas9-mediated correction of RPGR mutation rescued photoreceptor structure and electrophysiological property, reversed the observed ciliopathy, and restored gene expression to a level in accordance with that in the control using transcriptome-based analysis. This study recapitulated the pathogenesis of RPGR using patient-specific organoids and achieved targeted gene therapy of RPGR mutations in a dish as proof-of-concept evidence.
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•HiPSC-derived 3D retinae with outer segments and electrophysiological properties•RPGR mutation results in diseased photoreceptor in patient iPSC-derived 3D retinae•Mutation correction rescues defects in photoreceptor morphology and electrophysiology•Ciliogenesis defects appear in RPGR patient-specific iPSCs, iPSC-RPE, and 3D retinae
Jin and colleagues demonstrate that patient-specific iPSC-derived 3D retinae can recapitulate disease progress of retinitis pigmentosa through presenting defects in photoreceptor morphology, gene profile, and electrophysiology, as well as the defective ciliogenesis in iPSCs, iPSC-RPE, and 3D retinae. CRISPR/Cas9-mediated gene correction can rescue not only photoreceptor structure and electrophysiological property but also observed ciliopathy.
Background/aim
To assess the correlation between serum uric acid (UA) level and diabetic kidney disease among adult-onset Type 1 diabetes mellitus (T1DM) patients in China.
Methods
A total of 184 ...patients with adult-onset T1DM between January 2014 and December 2016 were recruited, with demographics and medical data collected. Comparisons were performed between according to different serum UA gender-specific quartiles. Relationship between serum UA level with urinary ACR and eGFR was also assessed.
Results
Median urinary ACR and eGFR were 21.55 10.79, 45.02 mg/g and 113.86 88.43, 143.61 ml/min/1.73 m
2
, respectively. The median UA was 257.4 (208.2–334.8) μmol/L. Participants with higher serum UA levels had higher urinary ACR and lower eGFR than those with lower UA (
P
< 0.05). Higher serum UA level was significantly associated with higher urinary ACR in Spearman's correlational analysis (
P
= 0.006) and multiple stepwise regression analysis (
P
= 0.013). The association between serum UA and urinary ACR was not linear, but showed a curve correlation, which also showed in the sensitivity analysis. Serum UA in the upper gender-specific quartile, was associated with lower eGFR (
P
< 0.001) and showed an independent negative correlation with eGFR in multiple stepwise regression analysis (
P
< 0.001).
Conclusions
The serum UA level was negatively correlated with eGFR and had a curve correlation with urinary ACR in adult-onset T1DM patients of China.
ABSTRACT
Neuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas‐related GPCR D (MrgprD) is specifically expressed in small‐diameter, nociceptive neurons of dorsal ...root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)–induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)‐A1 was the ion channel downstream of MrgprD, and the β‐alanine–induced calcium signal was attributed mostly to TRP‐A1 function. We further showed that PKA serves as a downstream mediator of β‐alanine–activated MrgprD signaling to activate TRP‐A1 in DRG neurons and in human embryonic kidney 293 cells, to coexpress MrgprD and TRP‐A1 plasmids. Finally, we found that the β‐alanine–induced pain behavior was increased, whereas the itching behavior was unchanged in CCI models compared with sham‐injured animals. Knockout of TRPA1 also attenuated the β‐alanine–induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI‐induced neuropathic pain through the PKA–TRP‐A1 pathway. TRP‐A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain.—Wang, C., Gu, L., Ruan, Y., Geng, X., Xu, M., Yang, N., Yu, L., Jiang, Y., Zhu, C., Yang, Y., Zhou, Y., Guan, X., Luo, W., Liu, Q., Dong, X., Yu, G., Lan, L., Tang, Z. Facilitation of MrgprD by TRP‐A1 promotes neuropathic pain. FASEB J. 33, 1360–1373 (2019). www.fasebj.org
Epidemiological evidence on the relationship between serum iron and liver diseases is limited. This study aims to investigate whether serum iron is associated with nonalcoholic fatty liver disease ...(NAFLD) and advanced hepatic fibrosis (AHF). Cross-sectional data for adults aged ≥ 18 years who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were analyzed. Odds ratio (ORs) and 95% confidence intervals (CIs) of NAFLD and AHF associated with serum iron were estimated using multivariable logistic regression models. A total of 18,031 males and 18,989 females were included in the analysis. After multivariable adjustment for potential confounders, serum iron was significantly and inversely associated with NAFLD in both genders (P-trend < 0.001) and AHF in females (P-trend = 0.018). Compared to the bottom quartile, those in higher quartiles of serum iron had no significant ORs for AHF in males, but the trend across the quartiles was significant (P-trend = 0.046). In conclusion, higher serum iron level was associated with lower risk of NAFLD in males and females, and with lower risk of AHF in females but not in males. No significant racial/ethnical differences in these associations were observed.
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