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Gut microbiota dysbiosis is already a global problem after antibiotic overuse. This study was to investigate the therapeutic effect of lentinan and the mechanism of recovery of intestinal inflammation on broad-spectrum antibiotic-driven gut microbial dysbiosis in mice. Gut microbiota was elucidated by the Illumina MiSeq platform. Gas chromatography/mass spectrometry was used to investigate short-chain fatty acid content. Colon histology, expression of tight-junction associated proteins and pro-inflammatory cytokines levels were evaluated. The results showed that the gut microbiota of diversity and richness were reduced and various taxonomic levels of the gut microbiota were perturbed after antibiotics gavage. The abundance of Firmicutes and Bacteroidetes shifted to Proteobacteria and increased the relative abundance of harmful microbiota (Parabacteroides and Klebsiella) post-antibiotics, whereas lentinan administration reversed the dysbiosis and increased beneficial microbiota, including S24-7, Lactobacillus, Oscillospira, Ruminococcus and Allobaculum. The concentrations of propionic acid and butyric acid were significantly increased by treatment with lentinan. And lentinan improved colon tissue morphology and reduced pro-inflammatory cytokines via altering NF-κB signaling pathway in antibiotic-driven gut microbial dysbiosis mice. Taken together, the results proved that lentinan can be used as a prebiotic and the result provided a theoretical basis for improving the clinical treatment of broad-spectrum antibiotics side effects.

Nickel sulfide is regarded as a material with tremendous potential for energy storage and conversion applications. However, it exists in a variety of stable compositions and obtaining a pure phase is a challenge. This study demonstrates a potentially scalable, solvent free and phase selective synthesis of uncapped α-NiS, β-NiS and α-β-NiS composites using nickel alkyl (ethyl, octyl) xanthate precursors. Phase transformation and morphology were observed by powder-X-ray diffraction (p-XRD), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The comparative efficiency of the synthesized samples was investigated for energy storage and generation applications, in which superior performance was observed for the NiS synthesized from the short chain xanthate complex. A high specific capacitance of 1,940 F/g, 2,150 F/g and 2,250 F/g was observed at 2 mV/s for bare α-NiS, β-NiS and α-β-NiS composite respectively. At high current density of 1 A/g, α-NiS showed the highest capacitance of 1,287 F/g, with 100% of Coulombic efficiency and 79% of capacitance retention. In the case of the oxygen evolution reaction (OER), β-NiS showed an overpotential of 139 mV at a current density of 10 mA/cm2, with a Tafel slope of only 32 mV/dec, showing a fast and efficient process. It was observed that the increase in carbon chain of the synthesized self-capped nickel sulfide nanoparticles decreased the overall efficiency, both for energy storage and energy generation applications.

Conjugated estrogens (CE) and Bazedoxifene (BZA) combination is used to alleviate menopause-associated symptoms in women. CE+BZA undergo first-pass-metabolism in the liver and deconjugation by gut microbiome via β-glucuronidase (GUS) enzyme inside the distal gut. To date, the impact of long-term exposure to CE+BZA on the gut microbiome or GUS activity has not been examined. Our study using an ovariectomized mouse model showed that CE+BZA administration did not affect the overall cecal or fecal microbiome community except that it decreased the abundance of Akkermansia, which was identified as a fecal biomarker correlated with weight gain. The fecal GUS activity was reduced significantly and was positively correlated with the abundance of Lactobacillaceae in the fecal microbiome. We further confirmed in Escherichia coli K12 and Lactobacillus gasseri ADH that Tamoxifen-, 4-hydroxy-Tamoxifen- and Estradiol-Glucuronides competed for GUS activity. Our study for the first time demonstrated that long-term estrogen supplementation directly modulated gut microbial GUS activity. Our findings implicate that long-term estrogen supplementation impacts composition of gut microbiota and microbial activity, which affects estrogen metabolism in the gut. Thus, it is possible to manipulate such activity to improve the efficacy and safety of long-term administered estrogens for postmenopausal women or breast cancer patients.

Chronic kidney disease (CKD) poses a formidable challenge for public healthcare worldwide as vast majority of patients with CKD are also at risk of accelerated cardiovascular disease and death. Renal fibrosis is the common manifestation of CKD that usually leads to end-stage renal disease although the molecular events leading to chronic renal fibrosis and eventually chronic renal failure remain to be fully understood. Nonetheless, emerging evidence suggests that an aberrant activation of PI3Kγ signaling may play an important role in regulating profibrotic phenotypes. Here, we investigate whether a blockade of PI3Kγ signaling exerts any beneficial effect on alleviating kidney injury and renal fibrosis. Using a mouse model of angiotensin II (Ang II)-induced renal damage, we demonstrate that PI3Kγ inhibitor AS605240 effectively mitigates Ang II-induced increases in serum creatinine and blood urea nitrogen, renal interstitial collagen deposition, the accumulation of ECM proteins and the expression of α-Sma and fibrosis-related genes in vivo. Mechanistically, we reveal that AS605240 effectively inhibits Ang II-induced cell proliferation and phosphorylation of Akt in fibroblast cells. Furthermore, we demonstrate that Ang II-upregulated expression of IL-6, Tnf-α, IL-1β and Tgf-β1 is significantly attenuated in the mice treated with AS605240. Taken together, our results demonstrate that PI3Kγ may function as a critical mediator of Ang II-induced renal injury and fibrosis. It is thus conceivable that targeted inhibition of PI3Kγ signaling may constitute a novel therapeutic approach to the clinical management of renal fibrosis, renal hypertension and/or CKD.

Cones are responsible for daylight, central, high acuity and color vision. Three proteins found in human cones, i.e. long-wavelength (L)-, middle-wavelength (M)-, and short-wavelength sensitive (S)-opsins, are responsible for red, green and blue color recognition, respectively. Human blue cone monochromacy (BCM) is characterized by functional loss of both L- and M-cone opsins due to mutations in the OPN1LW/OPN1MW gene cluster on the X chromosome. BCM patients, who rely on their vision from only S-cones and rods, suffer severely reduced visual acuity and impaired color vision. Recent studies show that there is sufficient cone structure remaining in the central fovea of BCM patients to consider AAV-mediated gene augmentation therapy. In contrast, mouse retina has only two opsins, S-opsin and M-opsin, but no L-opsin. We generated an M-opsin knockout mouse (Opn1mw

Cardiovascular mortality risk is high for peritoneal dialysis (PD) patients but it varies considerably among individuals. There is no clinical tool to predict cardiovascular mortality for PD patients yet. Therefore, we developed a cardiovascular mortality risk nomogram in a PD patient cohort. We derived and internally validated the nomogram in incident adult PD patients randomly assigned to a training (N = 918) or a validation (N = 460) dataset. The nomogram was built using the LASSO Cox regression model. Increasing age, history of cardiovascular disease or diabetes were consistent predictors of cardiovascular mortality. Low hemoglobin and serum albumin, high hypersensitive C-reactive protein and decreasing 24 hours urine output were identified as non-traditional cardiovascular risk predictors. In the validation dataset, the above nomogram performed good discrimination (1 year c-statistic = 0.83; 3 year c-statistic = 0.78) and calibration. This tool can classify patients between those at high risk of cardiovascular mortality (high-risk group) and those of low risk (low-risk group). Cardiovascular mortality was significantly different in the internal validation set of patients for the high-risk group compared to the low-risk group (HR 3.77, 2.14–6.64; p

Congenital cavitary optic disc anomalies (CODA) is clinically typified by an enlarged excavation of optic disc in diverse degrees. Here, we report the clinical and genetic findings in a four-generation Chinese family with a complicated form of autosomal dominant CODA. Cardinal manifestations included bilateral excavated optic disc with multiple cilioretinal vessels emerging and bilateral retinoschisis with great variability in the range of extension and severity. Other intra-familial phenotypic diversities were also noted, including severity in retinal atrophy, onset age of visual impairment and presence of congenital nystagmus and strabismus. Genome-wide linkage analysis and fine mapping mapped a novel locus for CODA to a 34.3 cM interval between D14S972 and D14S139 at 14q12-q22.1. A maximum multi-point log odds score of 3.901 was reached at D14S275. However, no mutation was identified by exome sequencing or direct sequencing of PAX6 and PAX2 genes, suggesting that the mutation may reside within a regulatory element. In conclusion, we find retinoschisis as a necessary consequence of optic nerve head (ONH) anomalies. The complicated phenotype observed in the family provided additional insights into the inherited ONH anomalies. Mapping of a novel locus, 14q12-q22.1, implies a new disease-causing gene and potential distinct pathogenesis for CODA.

Cones are responsible for daylight, central, high acuity and color vision. Three proteins found in human cones, i.e. long-wavelength (L)-, middle-wavelength (M)-, and short-wavelength sensitive (S)-opsins, are responsible for red, green and blue color recognition, respectively. Human blue cone monochromacy (BCM) is characterized by functional loss of both L- and M-cone opsins due to mutations in the OPN1LW/OPN1MW gene cluster on the X chromosome. BCM patients, who rely on their vision from only S-cones and rods, suffer severely reduced visual acuity and impaired color vision. Recent studies show that there is sufficient cone structure remaining in the central fovea of BCM patients to consider AAV-mediated gene augmentation therapy. In contrast, mouse retina has only two opsins, S-opsin and M-opsin, but no L-opsin. We generated an M-opsin knockout mouse (Opn1mw−/−) expressing only S-opsin as a model for human BCM. We show that recombinant M-opsin delivered by AAV5 vectors rescues M-cone function in Opn1mw−/− mice. We also show that AAV delivered M-opsin localizes in the dorsal cone outer segments, and co-localizes with S-opsin in the ventral retina. Our study demonstrates that cones without M-opsin remain viable and respond to gene augmentation therapy, thereby providing proof-of-concept for cone function restoration in BCM patients.

Cadmium (Cd2+) is a common toxic heavy metal ion. We investigated the roles of hydrogen sulfide (H2S) and cysteine (Cys) in plant responses to Cd2+ stress. The expression of H2S synthetic genes LCD and DES1 were induced by Cd2+ within 3 h, and endogenous H2S was then rapidly released. H2S promoted the expression of Cys synthesis-related genes SAT1 and OASA1, which led to endogenous Cys accumulation. The H2S and Cys cycle system was stimulated by Cd2+ stress, and it maintained high levels in plant cells. H2S inhibited the ROS burst by inducing alternative respiration capacity (AP) and antioxidase activity. H2S weakened Cd2+ toxicity by inducing the metallothionein (MTs) genes expression. Cys promoted GSH accumulation and inhibited the ROS burst, and GSH induced the expression of phytochelatin (PCs) genes, counteracting Cd2+ toxicity. In summary, the H2S and Cys cycle system played a key role in plant responses to Cd2+ stress. The Cd2+ tolerance was weakened when the cycle system was blocked in lcddes1-1 and oasa1 mutants. This paper is the first to describe the role of the H2S and Cys cycle system in Cd2+ stress and to explore the relevant and specificity mechanisms of H2S and Cys in mediating Cd2+ stress.

Vascular endothelial growth factor B (VEGF-B) was discovered a long time ago. However, its role in hyperglycemia- and VEGF-A inhibition-induced retinal apoptosis remains unknown thus far. Yet, drugs that can block VEGF-B are being used to treat patients with diabetic retinopathy and other ocular neovascular diseases. It is therefore urgent to have a better understanding of the function of VEGF-B in these pathologies. Here, we report that both streptozotocin (STZ)-induced diabetes in rats and Macugen intravitreal injection in mice leads to retinal apoptosis in retinal ganglion cell and outer nuclear layers respectively. Importantly, VEGF-B treatment by intravitreal injection markedly reduced retinal apoptosis in both models. We further reveal that VEGF-B and its receptors, vascular endothelial growth factor 1 (VEGFR1) and neuropilin 1 (NP1), are abundantly expressed in rat retinae and choroids and are upregulated by high glucose with concomitant activation of Akt and Erk. These data highlight an important function of VEGF-B in protecting retinal cells from apoptosis induced by hyperglycemia and VEGF-A inhibition. VEGF-B may therefore have a therapeutic potential in treating various retinal degenerative diseases, and modulation of VEGF-B activity in the eye needs careful consideration.

We aim to characterize the clinical features and genetic causes for two affected siblings from a Chinese family with cone dystrophy (CD). Two patients and four unaffected family members were recruited and received complete ophthalmic examinations. Genomic DNA was isolated from the peripheral blood samples from all patients. Targeted next-generation sequencing (NGS) approach followed by intrafamilal cosegregation and in silico analyses were employed to determine the genetic defects. Ophthalmic evaluations finalized the clinical diagnosis of CD for the two patients in this family, both of whom presented macular atrophy with no remarkable changes in the peripheral retina. Comprehensive genetic screening approach revealed biallelic missense mutations in the Leber congenital amaurosis 5 (LCA5) gene, p.[Ala212Pro];[Tyr441Cys], as disease causative for this family. Both mutations were novel. The first substitution was predicted to eliminate a hydrogen bond and alter the tertiary structure of lebercilin, protein encoded by LCA5. We for the first time report novel biallelic LCA5 mutations in causing CD. Our study extends the phenotypic and genotypic spectrums for LCA5-associated retinopathies and better illustrates its genotype-phenotype correlations, which would help with better genetic diagnosis, prognosis and personalized treatment for CD patients.

Although great attention has been paid to wearable electronic devices in recent years, flexible lightweight batteries or supercapacitors with high performance are still not readily available due to the limitations of the flexible electrode inventory. In this work, highly flexible, bendable and conductive rGO-PEDOT/PSS films were prepared using a simple bar-coating method. The assembled device using rGO-PEDOT/PSS electrode could be bent and rolled up without any decrease in electrochemical performance. A relatively high areal capacitance of 448 mF cm−2 was achieved at a scan rate of 10 mV s−1 using the composite electrode with a high mass loading (8.49 mg cm−2), indicating the potential to be used in practical applications. To demonstrate this applicability, a roll-up supercapacitor device was constructed, which illustrated the operation of a green LED light for 20 seconds when fully charged.

Genome-wide network analysis is well implemented to study proteins of unknown function. Here, we effectively explored protein functions and the biological mechanism based on inferred high confident protein-protein interaction (PPI) network in cyanobacteria. We integrated data from seven different sources and predicted 1,997 PPIs, which were evaluated by experiments in molecular mechanism, text mining of literatures in proved direct/indirect evidences and “interologs” in conservation. Combined the predicted PPIs with known PPIs, we obtained 4,715 no-redundant PPIs (involving 3,231 proteins covering over 90% of genome) to generate the PPI network. Based on the PPI network, terms in Gene ontology (GO) were assigned to function-unknown proteins. Functional modules were identified by dissecting the PPI network into sub-networks and analyzing pathway enrichment, with which we investigated novel function of underlying proteins in protein complexes and pathways. Examples of photosynthesis and DNA repair indicate that the network approach is a powerful tool in protein function analysis. Overall, this systems biology approach provides a new insight into posterior functional analysis of PPIs in cyanobacteria.

Retinitis pigmentosa (RP) shows progressive loss of photoreceptors involved with heterogeneous genetic background. Here, by exome sequencing and linkage analysis on a Chinese family with autosomal dominant RP, we identified a putative pathogenic variant, p.Gly97Arg, in the gene SPP2, of which expression was detected in multiple tissues including retina. The p.Gly97Arg was absent in 800 ethnically matched chromosomes and 1400 in-house exome dataset and was located in the first of the two highly conserved disulfide bonded loop of secreted phosphoprotein 2 (Spp-24) encoded by SPP2. Overexpression of p.Gly97Arg and another signal peptide mutation, p.Gly29Asp, caused cellular retention of both endogenous wild type and exogenous mutants in vitro and primarily affected rod photoreceptors in zebrafish mimicking cardinal feature of RP. Taken together, our data indicate that the two mutations of SPP2 have dominant negative effects and cellular accumulation of Spp-24 might be particularly toxic to photoreceptors and/or retinal pigment epithelium. SPP2 has a new role in retinal degeneration.

EYS mutations demonstrate great genotypic and phenotypic varieties, and are one of the major causes for patients with autosomal recessive retinitis pigmentosa (ARRP). Here, we aim to determine the genetic lesions with phenotypic correlations in two Chinese families with ARRP. Medical histories and ophthalmic documentations were obtained from all participants from the two pedigrees. Targeted next-generation sequencing (NGS) on 189 genes was performed to screen for RP causative mutations in the two families. Two biallelic mutations in EYS, p.[R164*];[C2139Y] and p.[W2640*];[F2954S], were identified in the two families, respectively. EYS p.R164* and p.F2954S are novel alleles associated with RP, while p.C2139Y and p.W2640* are known mutations. Crystal structure modeling on the protein eyes shut homolog encoded by the EYS gene revealed abnormal hydrogen bonds generated by p.C2139Y and p.F2954S, which would likely affect the solubility and cause significant structural changes of the two mutated proteins. In conclusion, our study expands the genotypic spectrums for EYS mutations, and may provide novel insights into the relevant pathogenesis for RP. We also demonstrate targeted NGS approach as a valuable tool for genetic diagnosis.

Controlling complex networked systems to desired states is a key research goal in contemporary science. Despite recent advances in studying the impact of network topology on controllability, a comprehensive understanding of the synergistic effect of network topology and individual dynamics on controllability is still lacking. Here we offer a theoretical study with particular interest in the diversity of dynamic units characterized by different types of individual dynamics. Interestingly, we find a global symmetry accounting for the invariance of controllability with respect to exchanging the densities of any two different types of dynamic units, irrespective of the network topology. The highest controllability arises at the global symmetry point, at which different types of dynamic units are of the same density. The lowest controllability occurs when all self-loops are either completely absent or present with identical weights. These findings further improve our understanding of network controllability and have implications for devising the optimal control of complex networked systems in a wide range of fields.

Previous studies have indicated the association between C2 rs547154 polymorphism and polypoidal choroidal vasculopathy (PCV) risk, while the results are controversial and inconsistent. Herein, we perform a meta-analysis to gain a precise estimation of the association using 5 eligible studies involving 4076 subjects, of which 1220 were PCV cases, 1073 were age-related macular degeneration (AMD) cases and 1783 were controls. Allelic frequencies of C2 rs547154 polymorphism between PCV and AMD were also compared. Both crude and adjusted odds ratios (OR) with their 95% confidence interval (CI) were included to assess the strength of the association. The pooled OR in random-effect model for allele T versus G was 0.64 (95% CI, 0.52–0.80; p < 0.0001), for genotype TG versus GG was 0.65 (95% CI, 0.52–0.83; p, 0.0004) and for genotype TT + TG versus GG was 0.64 (95% CI, 0.51–0.80; p, 0.0002). No difference in allelic frequency was observed between PCV and AMD (OR, 0.86; 95% CI, 0.64–1.16; p, 0.32). Sensitivity analysis proved the robustness of our data. No significant ethnic divergence was suggested by subgroup analysis and no publication bias was detected via Egger's test. In conclusion, our data indicate that C2 rs547154 polymorphism plays a protective role in the development of PCV.