The complete mitochondrial genome of the rodent flea Nosopsyllus laeviceps: genome description, comparative analysis, and phylogenetic implications.

BACKGROUND: Fleas are one of the most common and pervasive ectoparasites worldwide, comprising at least 2500 valid species. They are vectors of several disease-causing agents, such as Yersinia pestis. Despite their significance, however, the molecular genetics, biology, and phylogenetics of fleas remain poorly understood. METHODS: We sequenced, assembled, and annotated the complete mitochondrial (mt) genome of the rodent flea Nosopsyllus laeviceps using next-generation sequencing technology. Then we combined the new mitogenome generated here with mt genomic data available for 23 other flea species to perform comparative mitogenomics, nucleotide diversity, and evolutionary rate analysis. Subsequently, the phylogenetic relationship within the order Siphonaptera was explored using the Bayesian inference (BI) and maximum likelihood (ML) methods based on concentrated data for 13 mt protein-coding genes. RESULTS: The complete mt genome of the rodent flea N. laeviceps was 16,533 base pairs (bp) in a circular DNA molecule, containing 37 typical genes (13 protein-coding genes, 22 transfer RNA [tRNA] genes, and two ribosomal RNA [rRNA] genes) with one large non-coding region (NCR). Comparative analysis among the order Siphonaptera showed a stable gene order with no gene arrangement, and high AT content (76.71-83.21%) with an apparent negative AT and GC skew except in three fleas Aviostivalius klossi bispiniformis, Leptopsylla segnis, and Neopsylla specialis. Moreover, we found robust evidence that the cytochrome c oxidase subunit 1 (cox1) gene was the most conserved protein-coding gene (Pi = 0.15, non-synonymous/synonymous [Ka/Ks] ratio = 0.13) of fleas. Phylogenomic analysis conducted using two methods revealed different topologies, but both results strongly indicated that (i) the families Ceratophyllidae and Leptopsyllidae were paraphyletic and were the closest to each other, and (ii) the family Ctenophthalmidae was paraphyletic. CONCLUSIONS: In this study, we obtained a high-quality mt genome of the rodent flea N. laeviceps and performed comparative mitogenomics and phylogeny of the order Siphonaptera using the mt database. The results will enrich the mt genome data for fleas, lay a foundation for the phylogenetic analysis of fleas, and promote the evolutionary analysis of Siphonaptera.

Gamma-band-based dynamic functional connectivity in pigeon entopallium during sample presentation in a delayed color matching task.

Birds have developed visual cognitions, especially in discriminating colors due to their four types of cones in the retina. The entopallium of birds is thought to be involved in the processing of color information during visual cognition. However, there is a lack of understanding about how functional connectivity in the entopallium region of birds changes during color cognition, which is related to various input colors. We therefore trained pigeons to perform a delayed color matching task, in which two colors were randomly presented in sample stimuli phrases, and the neural activity at individual recording site and the gamma band functional connectivity among local population in entopallium during sample presentation were analyzed. Both gamma band energy and gamma band functional connectivity presented dynamics as the stimulus was presented and persisted. The response features in the early-stimulus phase were significantly different from those of baseline and the late-stimulus phase. Furthermore, gamma band energy showed significant differences between different colors during the early-stimulus phase, but the global feature of the gamma band functional network did not. Further decoding results showed that decoding accuracy was significantly enhanced by adding functional connectivity features, suggesting the global feature of the gamma band functional network did not directly contain color information, but was related to it. These results provided insight into information processing rules among local neuronal populations in the entopallium of birds during color cognition, which is important for their daily life.

Correction to: Gamma-band-based dynamic functional connectivity in pigeon entopallium during sample presentation in a delayed color matching task.

[This corrects the article DOI: 10.1007/s11571-022-09916-w.].

Reproductive outcomes after pregnancy-induced displacement of preexisting microchimeric cells.

Pregnancy confers partner-specific protection against complications in future pregnancy that parallel persistence of fetal microchimeric cells (FMcs) in mothers after parturition. We show that preexisting FMcs become displaced by new FMcs during pregnancy and that FMc tonic stimulation is essential for expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells (Treg cells). Maternal microchimeric cells and accumulation of Treg cells with noninherited maternal antigen (NIMA) specificity are similarly overturned in daughters after pregnancy, highlighting a fixed microchimeric cell niche. Whereas NIMA-specific tolerance is functionally erased by pregnancy, partner-specific resiliency against pregnancy complications persists in mothers despite paternity changes in intervening pregnancy. Persistent fetal tolerance reflects FOXP3 expression plasticity, which allows mothers to more durably remember their babies, whereas daughters forget their mothers with new pregnancy-imprinted immunological memories.

iPSC-derived neural precursor cells engineering GBA1 recovers acid ß-glucosidase deficiency and diminishes α-synuclein and neuropathology.

Mutations in GBA1, encoding the lysosomal acid ß-glucosidase (GCase), cause neuronopathic Gaucher disease (nGD) and promote Parkinson disease (PD). The mutations on GBA1 include deletion and missense mutations that are pathological and lead to GCase deficiency in Gaucher disease. Both nGD and PD lack disease-modifying treatments and are critical unmet medical needs. In this study, we evaluated a cell therapy treatment using mouse iPSC-derived neural precursor cells (NPCs) engineered to overexpress GCase (termed hGBA1-NPCs). The hGBA1-NPCs secreted GCase that was taken up by adjacent mouse Gba -/- neurons and improved GCase activity, reduced GCase substrate accumulation, and improved mitochondrial function. Short-term in vivo effects were evaluated in 9H/PS-NA mice, an nGD mouse model exhibiting neuropathology and α-synuclein aggregation, the typical PD phenotypes. Intravenously administrated hGBA1-NPCs were engrafted throughout the brain and differentiated into neural lineages. GCase activity was increased in various brain regions of treated 9H/PS-NA mice. Compared with vehicle, hGBA1-NPC-transplanted mice showed ∼50% reduction of α-synuclein aggregates in the substantia nigra, significant reduction of neuroinflammation and neurodegeneration in the regions of NPC migration, and increased expression of neurotrophic factors that support neural cell function. Together, these results support the therapeutic benefit of intravenous delivery of iPSC-derived NPCs overexpressing GCase in mitigating nGD and PD phenotypes and establish the feasibility of combined cell and gene therapy for GBA1-associated PD.

SAFFRON-103: a phase 1b study of the safety and efficacy of sitravatinib combined with tislelizumab in patients with locally advanced or metastatic non-small cell lung cancer.

BACKGROUND: Some patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) respond poorly to anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) treatments. Combination with other agents may improve the outcomes. This open-label, multicenter, phase 1b trial investigated the combination of sitravatinib, a spectrum-selective tyrosine kinase inhibitor, plus anti-PD-1 antibody tislelizumab. METHODS: Patients with locally advanced/metastatic NSCLC were enrolled (Cohorts A, B, F, H, and I; N=22-24 per cohort). Cohorts A and F included patients previously treated with systemic therapy, with anti-PD-(L)1-resistant/refractory non-squamous (cohort A) or squamous (cohort F) disease. Cohort B included patients previously treated with systemic therapy, with anti-PD-(L)1-naïve non-squamous disease. Cohorts H and I included patients without prior systemic therapy for metastatic disease, no prior anti-PD-(L)1/immunotherapy, with PD-L1-positive non-squamous (cohort H) or squamous (cohort I) histology. Patients received sitravatinib 120 mg orally one time per day plus tislelizumab 200 mg intravenously every 3 weeks, until study withdrawal, disease progression, unacceptable toxicity, or death. The primary endpoint was safety/tolerability among all treated patients (N=122). Secondary endpoints included investigator-assessed tumor responses and progression-free survival (PFS). RESULTS: Median follow-up was 10.9 months (range: 0.4-30.6). Treatment-related adverse events (TRAEs) occurred in 98.4% of the patients, with ≥Grade 3 TRAEs in 51.6%. TRAEs led to discontinuation of either drug in 23.0% of the patients. Overall response rate was 8.7% (n/N: 2/23; 95% CI: 1.1% to 28.0%), 18.2% (4/22; 95% CI: 5.2% to 40.3%), 23.8% (5/21; 95% CI: 8.2% to 47.2%), 57.1% (12/21; 95% CI: 34.0% to 78.2%), and 30.4% (7/23; 95% CI: 13.2% to 52.9%) in cohorts A, F, B, H, and I, respectively. Median duration of response was not reached in cohort A and ranged from 6.9 to 17.9 months across other cohorts. Disease control was achieved in 78.3-90.9% of the patients. Median PFS ranged from 4.2 (cohort A) to 11.1 months (cohort H). CONCLUSIONS: In patients with locally advanced/metastatic NSCLC, sitravatinib plus tislelizumab was tolerable for most patients, with no new safety signals and overall safety profiles consistent with known profiles of these agents. Objective responses were observed in all cohorts, including in patients naïve to systemic and anti-PD-(L)1 treatments, or with anti-PD-(L)1 resistant/refractory disease. Results support further investigation in selected NSCLC populations. TRIAL REGISTRATION NUMBER: NCT03666143.

Bacteriostasis and cleaning effect of trace ozone replacing personal care products.

Ozone is widely used to inactivate bacteria, fungi, and viruses. In recent years, the treatment of itchy skin diseases (eczema and atopic dermatitis) using trace ozone has also received attention. However, the feasibility of using trace ozone to replace personal care products (PCPs) has rarely been analyzed. In this study, the applicability of trace ozone was evaluated in terms of its efficiency for microbial inactivation in three types of skin microbiomes, cleaning performance on simulated human hair and epidermis, safety for simulated human hair, and contribution to emission reduction. The results revealed that at a 10:1 ratio of ozonated water to bacterial suspension, the inactivation ratios of Malassezia, C. albicans, and S. epidermidis reached 99.63%, 83.47%, and 100%, respectively. In addition, the cleaning performance of an ozone solution (0.4 mg/L) for simulated human skin contaminated with carbon black and sebum could reach 95.89% and 95.63%, respectively, with 5 min of washing. The average scores were 0.40 and 0.37 after 5 min and 10 min of ozone treatments, respectively, indicating that trace ozone does not significantly damage simulated human hair. Results also revealed that the total emissions of COD, TP, and TN would be reduced by 1.29×106, 3.55×103, and 3.63×103 mg/ (household · year), respectively, if PCPs are replaced by trace ozone. In short, our findings indicate that trace ozone is a potential alternative to PCPs. By replacing PCPs with trace ozone, the use of synthetic chemical products can be reduced and carbon emissions from oil extraction can be countered.

Early Assessment of Cardiac Function by Echocardiography in Patients with Gestational Diabetes Mellitus.

Objective: To offer a baseline for clinical diagnosis, echocardiography was performed to evaluate the disparities in heart function comparing pregnant women with diabetes mellitus (GDM) and ordinary pregnant women. Methods: A prospective case-control study is being conducted on pregnant women with or without gestational diabetes. The sample size for both the intervention and control groups is the same: no diabetes diagnosis or previous forms, a single pregnancy, and no issues (such as preeclampsia or fetal growth restriction). The females were all subjected to routine echocardiograms to examine the morphology and function of their left and right hearts. Results: In the research, 51 women with GDM and 50 healthy controls volunteered. Women with GDM had a significantly higher heartrate (82 ± 9 vs. 74 ± 8), left ventricular (LV) relative wall thickness (0.39 ± 0.06 vs. 0.31 ± 0.07; P < 0.001), LV early diastolic transmitral valve velocity (E) (0.79 ± 0.14 vs. 0.72 ± 0.13 m/s; P = 0.031), and LV late diastolic implementing regulations valve velocity (0.6). Speckle-tracking analysis showed significant decrease in LV right ventricular (RV). A study indicated a reduced pulmonary acceleration time (59 ± 9 vs. 68 ± 12 ms; P = 0.001), RV E/A ratio (1.21 ± 0.19 vs. 1.31 ± 0.31; P = 0.022), and a greater RV myocardial systolic annular velocity (0.17 ± 0.03 vs. 0.12 ± 0.03; P = 0.023). Conclusions: Our results revealed that the heart function of diabetic pregnant women differed considerably from that of the control group, such as LV-RWT, LV diastolic transmitral valve speed, and LV late diastolic transmitral valve speed. Given these results, further research into the postpartum cardiovascular healing of pregnant women with gestational diabetes mellitus is required.

Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter.

The high-affinity copper transporter CTR1 is encoded by CTR1 (SLC31A1), a gene locus for which no detailed genotype-phenotype correlations have previously been reported. We describe identical twin male infants homozygous for a novel missense variant NM_001859.4:c.284 G > A (p.Arg95His) in CTR1 with a distinctive autosomal recessive syndrome of infantile seizures and neurodegeneration, consistent with profound central nervous system copper deficiency. We used clinical, biochemical and molecular methods to delineate the first recognized examples of human CTR1 deficiency. These included clinical phenotyping, brain imaging, assays for copper, cytochrome c oxidase (CCO), and mitochondrial respiration, western blotting, cell transfection experiments, confocal and electron microscopy, protein structure modeling and fetal brain and cerebral organoid CTR1 transcriptome analyses. Comparison with two other critical mediators of cellular copper homeostasis, ATP7A and ATP7B, genes associated with Menkes disease and Wilson disease, respectively, revealed that expression of CTR1 was highest. Transcriptome analyses identified excitatory neurons and radial glia as brain cell types particularly enriched for copper transporter transcripts. We also assessed the effects of Copper Histidinate in the patients' cultured cells and in the patients, under a formal clinical protocol. Treatment normalized CCO activity and enhanced mitochondrial respiration in vitro, and was associated with modest clinical improvements. In combination with present and prior studies, these infants' clinical, biochemical and molecular phenotypes establish the impact of this novel variant on copper metabolism and cellular homeostasis and illuminate a crucial role for CTR1 in human brain development. CTR1 deficiency represents a newly defined inherited disorder of brain copper metabolism.

Deeper insights into the effects of substrate to inoculum ratio selection on the relationship of kinetic parameters, microbial communities, and key metabolic pathways during the anaerobic digestion of food waste.

The substrate to inoculum ratio (S/I) is a crucial factor that affects not only the stability of the anaerobic digestion (AD) of food waste (FW) but also the methanogenic capacity of the substrate. This is of great significance for the start-up of small-scale batch reactors and the directional regulation of methanogenesi and organic acid production. Most studies have merely clarified the optimal S/I ratio for methane production and revealed the basic composition of microbial communities. However, the mechanism of microbial interactions and the metabolic pathways behind the optimal S/I ratio still remain unclear. Herein, the effects of different S/I ratios (VS basis) on the relationship of kinetic parameters, microbial communities, and metabolic pathways during the AD process of FW were holistically explored. The results revealed that high S/I ratios (4:1, 3:1, 2:1, and 1:1) were prone to irreversible acidification, while low S/I ratios (1:2, 1:3, and 1:4) were favorable for methanogenesis. Moreover, a kinetic analysis demonstrated that the methane yield of S/I = 1:3 were the highest. A bioinformatics analysis found that the diversity of bacteria and archaea of S/I = 1:3 were the most abundant, and the enrichment of Bacteroides and Synergistetes could help to establish a syntrophic relationship with hydrogenotrophic methanogens, which could aid in the fulfillment of a unique niche in the system. In contrast to the findings with the other S/I ratios, the cooperation among microbes in S/I = 1:3 was more apparent. Notably, the abundances of genes encoding key enzymes involved in the methanogenesis pathway under S/I = 1:3 were all the highest. This knowledge will be helpful for revealing the influence mechanism of the ratio relationship between microorganisms and substrates on the biochemical metabolic process of anaerobic digestion, thereby providing effective guidance for the directional regulation of FW batch anaerobic reactors.

Feasibility of sewage sludge and food waste aerobic co-composting: Physicochemical properties, microbial community structures, and contradiction between microbial metabolic activity and safety risks.

Co-composting of sludge and food waste eliminates the disadvantages of composting these waste products separately. Specifically, co-composing neutralizes the pollutants and improves the organic matter that occur in sewage sludge, and solves the problem of the low pH values and high moisture content of food waste. However, little is known about the functional microorganisms, microbial metabolic capacity, and biosecurity risks involved in sewage sludge and food waste co-composting. Therefore, this study established four lab-scale composting reactors [T1 (separate composting of food waste), T2 (separate composting of sewage sludge), T3 (sewage sludge and food waste co-composting at a C/N ratio of 25), and T4 (equal proportions composting of sewage sludge and food waste)] to assess the feasibility of sewage sludge and food waste aerobic co-composting. Our findings indicated that polysaccharides and proteins in T3 could be effectively degraded, and the total nutrient levels in T3 were higher than those in the other groups. After composting, the microbial diversity and richness of T3 were higher than that of T1. In later composting stages, the functional microorganisms in T1 maintained higher metabolic activity, however, it also had a higher biosecurity risk than T3 due to the presence of pathogenic bacteria such as Enterococcus_faecalis and Bacillus_circulan. Although the product of T3 could not be used as a microbial fertilizer, its biosecurity risk was lower than that of T1 and could therefore be used as an organic fertilizer. Redundancy analysis (RDA) results indicated that changing the microbial community structure by adjusting key environmental factors could improve composting quality and reduce microbial safety risks. Collectively, our results provide a theoretical basis for the development of co-composting strategies for the biodegradation of perishable solid organic waste, in addition to proposing the risk of pathogenic bacteria exposure that could endanger human and animal health.

Diamondoids and thiadiamondoids generated from hydrothermal pyrolysis of crude oil and TSR experiments.

Diamondoid compounds are widely used to reflect thermal maturation of high mature source rocks or oils and oil cracking extents. However, diamondoids and thiadiamondoids were demonstrated to have newly been generated and decomposed in our hydrothermal pyrolysis of crude oil and TSR experiments. Our results show that adamantanes and diamantanes are generated primarily within the maturity range 0.48-2.1% and 1.2-3.0% EasyRo, respectively. Their formation is enhanced and the decomposition of diamantanes obviously lags at elevated temperatures compared with anhydrous experiments. MDI, EAI, DMAI-1, DMDI-2 may serve as reliable maturity proxies at > ca.1.0% EasyRo, and other isomerization indices (TMAI-1, TMAI-2 and DMAI-2) are effective for the highly mature organic matter at EasyRo > 2.0%. The extent of oil cracking (EOC) calculated from the broadly used (3- + 4-) MD method (Dahl et al. in Nature 399:54-56, 1999) is proven to overestimate, especially for highly cracked samples due to the new generation of (3- + 4-) MD. Still, it can be corrected using a new formula at < 3.0% EasyRo. Other diamondoid-related indices (e.g., EAI, DMDI-2, As/Ds, MAs/MDs, DMAs/DMDs, and DMAs/MDs) can also be used to estimate EOC. However, these indices cannot be applied to TSR-altered petroleum. TSR is experimentally confirmed to generate diamantanes and thiaadmantanes at 1.81% EasyRo likely via direct reactions of reduced S species with hydrocarbons and accelerate the decomposition of diamantanes at > 2.62% EasyRo compared with thermal chemical alteration (TCA). More studies are needed to assess specific mechanisms for the formation of thiadiamondoids under natural conditions.

Significant fluctuation in the global sulfate reservoir and oceanic redox state during the Late Devonian event.

Ocean sulfate concentration might have fluctuated greatly throughout the Earth's history and may serve as a window into perturbations in the ocean-atmosphere system. Coupling high-resolution experimental results with an inverse modeling approach, we, here, show an unprecedented dynamic in the global sulfate reservoir during the Frasnian-Famennian (F-F) boundary event, as one of the "Big five" Phanerozoic biotic crises. Notably, our results indicate that, in a relatively short-time scale (∼200 thousand years), seawater sulfate concentration would have dropped from several mM before the Upper Kellwasser Horizon (UKH) to an average of 235 ± 172 µM at the end of the UKH (more than 100 times lower than the modern level) as the result of evaporite deposition and euxinia, and returned to around mM range after the event. Our findings indicate that the instability in the global sulfate reservoir and nutrient-poor oceans may have played a major role in driving the Phanerozoic biological crises.

Substrate Reduction Therapy Reverses Mitochondrial, mTOR, and Autophagy Alterations in a Cell Model of Gaucher Disease.

Substrate reduction therapy (SRT) in clinic adequately manages the visceral manifestations in Gaucher disease (GD) but has no direct effect on brain disease. To understand the molecular basis of SRT in GD treatment, we evaluated the efficacy and underlying mechanism of SRT in an immortalized neuronal cell line derived from a Gba knockout (Gba-/-) mouse model. Gba-/- neurons accumulated substrates, glucosylceramide, and glucosylsphingosine. Reduced cell proliferation was associated with altered lysosomes and autophagy, decreased mitochondrial function, and activation of the mTORC1 pathway. Treatment of the Gba-/- neurons with venglustat analogue GZ452, a central nervous system-accessible SRT, normalized glucosylceramide levels in these neurons and their isolated mitochondria. Enlarged lysosomes were reduced in the treated Gba-/- neurons, accompanied by decreased autophagic vacuoles. GZ452 treatment improved mitochondrial membrane potential and oxygen consumption rate. Furthermore, GZ452 diminished hyperactivity of selected proteins in the mTORC1 pathway and improved cell proliferation of Gba-/- neurons. These findings reinforce the detrimental effects of substrate accumulation on mitochondria, autophagy, and mTOR in neurons. A novel rescuing mechanism of SRT was revealed on the function of mitochondrial and autophagy-lysosomal pathways in GD. These results point to mitochondria and the mTORC1 complex as potential therapeutic targets for treatment of GD.

The efficacy of probiotic preparations on inflammatory cytokines in patients with chronic kidney disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Probiotics supplementation has emerged as adjuvant therapy for chronic kidney disease (CKD) in recent years. However, the effects of probiotic preparations on serum inflammatory cytokine levels are still highly controversial and poorly documented. Therefore, we performed the protocol for systematic review and meta-analysis to further clarify the effects of probiotic preparations in CKD patients. METHODS: This review will develop following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines. We searched literature published until May, 2021 thoroughly in PUBMED, Scopus, EMBASE, Web of Science, and Cochrane Library databases on May, 2021. The risk of bias of included studies was estimated by taking into consideration the characteristics including random sequence generation, allocation concealment, blinding of patients, blinding of outcome assessment, completeness of outcome data, selective reporting, and other bias by Cochrane Collaboration's tool for assessing the risk of bias. Data synthesis and analyses were performed using Stata version 10.0 software. RESULTS: The results of this systematic review and meta-analysis will be published in a peer-reviewed journal. CONCLUSION: We hypothesized that probiotic preparations may decrease the serum levels of inflammatory cytokines and protect the intestinal epithelial barrier of patients with CKD.

Effects of antibiotics on hydrolase activity and structure of microbial community during aerobic co-composting of food waste with sewage sludge.

This study aimed to investigate the effects of antibiotics on environmental factors, hydrolase activity, and microbial community during aerobic co-composting of food waste and sewage sludge. The results showed that 5 mg/kg of antibiotics decreased cellulase activity and increased lipase and proteinase activity, while 20 mg/kg of antibiotics also decreased cellulase activity and increased the contents of Zn, Cu, and Hg. The dominant bacterial genera of the four treatment groups were Enterococcus, Pseudomonas, Idiomarina, Lactobacillus, and Bacillus. The addition of antibiotics affected the succession of microbial community structure. Microbial communities treated with 5 mg/kg antibiotics had the highest in diversity, while those treated with 20 mg/kg antibiotics had the lowest in richness. Redundancy analysis (RDA) revealed that the pH and temperature were the most important environmental factors that affected microbial community succession, followed by total nitrogen and moisture content during co-composting of food waste and sewage sludge.

Changes in aerobic fermentation and microbial community structure in food waste derived from different dietary regimes.

This study aimed to analyze the relationship between food components and food waste aerobic fermentation efficiency. Different food wastes were designed to be reflective of different dietary regimes, including formulated (R1), high oil/fat and salt (R2), high oil/fat and sugar (R3), and vegetarian (R4) diets, after which the physicochemical properties, enzyme activity, and structural characteristics of food waste microbial communities were examined to explore the potential mechanisms of food waste degradation under different dietary regimes. The main results of this study demonstrated that the physicochemical properties and hydrolase activity of different food waste were significantly different. The species richness in R2 and R3 food waste was higher than that of R1 and R4, whereas the community diversity of R1 and R4 food waste was higher than that of R2 and R3. At the genus level, the dominant bacteria in the four food waste types were Bacillus, Thermoactinomyces, Paenibacillus, and Cohnella.

Integrated analysis of the molecular pathogenesis of FDXR-associated disease.

The mitochondrial flavoprotein ferredoxin reductase (FDXR) is required for biogenesis of iron-sulfur clusters and for steroidogenesis. Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, and an increasing number of disorders are associated with disruptions in the synthesis of Fe-S clusters. Our previous studies have demonstrated that hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans and mice, attributed in part to reduced function of the electron transport chain (ETC) as well as elevated production of reactive oxygen species (ROS). Inflammation and peripheral neuropathy are also hallmarks of this disease. In this paper, we demonstrate that FDXR mutation leads to significant optic transport defects that are likely to underlie optic atrophy, a major clinical presentation in FDXR patients, as well as a neurodegenerative loss of cells in the central nervous system (CNS). Molecular analysis indicates that FDXR mutation also leads to mitochondrial iron overload and an associated depolarization of the mitochondrial membrane, further supporting the hypothesis that FDXR mutations cause neurodegeneration by affecting FDXR's critical role in iron homeostasis.

Systemic enzyme delivery by blood-brain barrier-penetrating SapC-DOPS nanovesicles for treatment of neuronopathic Gaucher disease.

BACKGROUND: Enzyme replacement therapy (ERT) can positively affect the visceral manifestations of lysosomal storage diseases (LSDs). However, the exclusion of the intravenous ERT agents from the central nervous system (CNS) prevents direct therapeutic effects. METHODS: Using a neuronopathic Gaucher disease (nGD) mouse model, CNS-ERT was created using a systemic, non-invasive, and CNS-selective delivery system based on nanovesicles of saposin C (SapC) and dioleoylphosphatidylserine (DOPS) to deliver to CNS cells and tissues the corrective, functional acid ß-glucosidase (GCase). FINDINGS: Compared to free GCase, human GCase formulated with SapC-DOPS nanovesicles (SapC-DOPS-GCase) was more stable in serum, taken up into cells, mostly by a mannose receptor-independent pathway, and resulted in higher activity in GCase-deficient cells. In contrast to free GCase, SapC-DOPS-GCase nanovesicles penetrated through the blood-brain barrier into the CNS. The CNS targeting was mediated by surface phosphatidylserine (PS) of blood vessel and brain cells. Increased GCase activity and reduced GCase substrate levels were found in the CNS of SapC-DOPS-GCase-treated nGD mice, which showed profound improvement in brain inflammation and neurological phenotypes. INTERPRETATION: This first-in-class CNS-ERT approach provides considerable promise of therapeutic benefits for neurodegenerative diseases. FUNDING: This study was supported by the National Institutes of Health grants R21NS 095047 to XQ and YS, R01NS 086134 and UH2NS092981 in part to YS; Cincinnati Children's Hospital Medical Center Research Innovation/Pilot award to YS and XQ; Gardner Neuroscience Institute/Neurobiology Research Center Pilot award to XQ and YS, Hematology-Oncology Programmatic Support from University of Cincinnati and New Drug State Key Project grant 009ZX09102-205 to XQ.

[Clinical and genetic analysis of a patient with Hb Ottawa in conjunction with ß -thalassemia].

OBJECTIVE: To analyze the hematological characteristics of a patient with Hb Ottawa in conjunction with ß -thalassemia. METHODS: Peripheral blood samples from the proband and her parents were collected and subjected to red blood cell analysis and hemoglobin electrophoresis. Genotypes of α - and ß -globin genes were also analyzed. RESULTS: The proband and her mother were both heterozygotes for Hb Ottawa and ß -thalassemia variant IVS II-654, and presented with typical ß -thalassemia trait featuring hypochromic microcytic anemia. An abnormal hemoglobin band was detected upon electrophoresis. CONCLUSION: Co-existence of Hb Ottawa and ß -thalassemia may not aggravate the phenotype.