Application of Human Acellular Dermal Matrix with Skin Graft for Lacunar Soft-Tissue Defect of Lateral Heel after Calcaneal Fracture.

OBJECTIVE: To investigate the clinical effect of human acellular dermal matrix (HADM) combined with split-thickness skin graft in repairing lacunar soft tissue defects of the lateral heel after calcaneal fracture. METHODS: From June 2018 to October 2020, providers repaired 11 cases of lacunar soft tissue defects at the lateral part of the heel using HADM combined with split-thickness skin graft. After thorough debridement, the HADM was trimmed and filled into the lacunar defect area. Once the wound was covered, a split-thickness skin graft and negative-pressure wound therapy were applied. Providers evaluated the appearance, scar, ductility of the skin graft site, appearance of the donor site, healing time, and any reoperation at follow-up. RESULTS: Of the 11 cases, 8 patients achieved successful wound healing by primary intention. Three patients showed partial necrosis in the edge of the skin graft, but the wound healed after standard wound care. Evaluation at 6 and 12 months after surgery showed that all patients had wound healing and mild local scarring; there was no obvious pigmentation or scar formation in the donor skin area. The average healing time was 37.5 days (range, 24-43 days). CONCLUSIONS: The HADM combined with split-thickness skin graft is a simple and effective reconstruction method for lacunar soft tissue defect of the lateral heel after calcaneal fracture. In this small sample, the combination demonstrated few infections, minor scar formation, few donor site complications, and relatively short hospital stays.

A simulation of acetate consumption and electricity generation in a single microbial fuel cell considering the diversity of nonelectrogenic bacteria.

To simulate acetate consumption and electricity generation in a cycle of a microbial fuel cell (MFC) treating synthetic acetate-based wastewater with low concentration, nonelectrogenic bacteria (NEB), which had no contribution in electricity generation, was incorporated with methanogen's kinetic parameters into a previous biofilm model proposed by Marcus et al. (Biotechnol Bioeng 98:1171-1182, 2007). However, the Coulombic efficiency was estimated to be 40.1%, whereas the experiment showed 13.6%, as the presence of NEB was obviously underestimated. Thus, the maximum NEB reaction rate (qmaxC) was temporarily calibrated, and a sensitivity analysis was then conducted. As a result, the growth parameters of NEB, the growth of the exoelectrogenic bacteria, and the biofilm detachment were identified as influential parameters. qmaxC and a half rate constant of NEB (KsC) were selected as potential calibration parameters. The two sets of calibrated parameters (0.342 mmol-acetate (Ac)/mg-volatile solids (VS)/d of qmaxC and 33.8 mg-carbon (C)/L of KsC; 0.274 mmol-Ac/mg-VS/d of qmaxC and 16.9 mg-C/L of KsC) showed a good agreement with the experimental results at 100 mg-C/L of initial acetate. However, the calibrated parameter values obviously differed from those in previous models. The calibrated model also showed good agreement with the experimental results at 50 and 200 mg-C/L of the initial acetate. In view of the different values of qmaxC and KsC from those of methanogenic bacteria in previous models and the previous findings on anode microbial community, which showed that NEB are not only methanogenic bacteria, we concluded that the diversity of NEB should be considered to simulate performances in a cycle of MFC treating low organic matter concentrations.

Continuous Hidden Markov Model Based Spectrum Sensing with Estimated SNR for Cognitive UAV Networks.

In this paper, to enhance the spectrum utilization in cognitive unmanned aerial vehicle networks (CUAVNs), we propose a cooperative spectrum sensing scheme based on a continuous hidden Markov model (CHMM) with a novel signal-to-noise ratio (SNR) estimation method. First, to exploit the Markov property in the spectrum state, we model the spectrum states and the corresponding fusion values as a hidden Markov model. A spectrum prediction is obtained by combining the parameters of CHMM and a preliminary sensing result (obtained from a clustered heterogeneous two-stage-fusion scheme), and this prediction can further guide the sensing detection procedure. Then, we analyze the detection performance of the proposed scheme by deriving its closed-formed expressions. Furthermore, considering imperfect SNR estimation in practical applications, we design a novel SNR estimation scheme which is inspired by the reconstruction of the signal on graphs to enhance the proposed CHMM-based sensing scheme with practical SNR estimation. Simulation results demonstrate the proposed CHMM-based cooperative spectrum sensing scheme outperforms the ones without CHMM, and the CHMM-based sensing scheme with the proposed SNR estimator can outperform the existing algorithm considerably.

Genotype-phenotype correlations of heterozygous HTRA1-related cerebral small vessel disease: case report and systematic review.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is caused by biallelic HTRA1 pathogenic variants. Recent studies have shown that heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease (CSVD). However, large studies evaluating heterozygous HTRA1 carriers are lacking and the genotype-phenotype correlation is unknown. This study aimed to describe these mutations to clarify factors playing a role in the clinical phenotype amongst these patients. We reported two unrelated families and performed a systematic review of all published cases of heterozygous HTRA1-related CSVD. The clinical phenotype severity was independently related to the pathogenicity score (CADD score; p < 0.05) and mutation in the loop 3/loop D domains (p = 0.05); the pathogenicity score was also associated with exon distribution. More importantly, patients with mutations in exon 4 (p = 0.0001) or vascular risk factors (p < 0.05) presented with more severe clinical symptoms. Thus, clinical phenotype severity is influenced by the mutation domain and vascular risk factors. Applying the pathogenicity score to predict clinical outcomes and adopting preventive measures against cerebral vascular risk factors is advantageous.

SOX4-induced upregulation of ARHGAP9 promotes the progression of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common acute leukemia. Rho GTPase activating protein 9 (ARHGAP9) has been reported to be positively correlated with overall survival of AML patients, but the specific molecular function remains unclear. This study aims to further explore the functional role and the molecular mechanism of ARHGAP9 in AML cells. The expression level of ARHGAP9 in AML cells was measured using quantitative real-time PCR (qRT-PCR) and western blot. Cell transfection was performed to interfere ARHGAP9. CCK-8, flow cytometry and TUNEL assays were conducted to detect cell viability, cell cycle distribution and apoptosis, respectively. The binding relationship between SOX4 and ARHGAP9 promoter was verified using luciferase reporter assay and chromatin immunoprecipitation. The results showed that ARHGAP9 was upregulated in AML cells. Interference of ARHGAP9 greatly reduced cell viability and induced cell cycle arrest in G1 phase, accompanied with the reduction of Ki67, PCNA, cyclin D1, cyclin E1, CDK4 and CDK6. In addition, Interference of ARHGAP9 greatly promoted cell apoptosis, accompanied with the decreased protein expression of Bcl-2 and the increased protein expression of Bax, cleaved caspase 3 and cleaved caspase 9. Furthermore, SOX4 directly bound to ARHGAP9 promoter and regulated ARHGAP9 expression. In conclusion, this study suggested that ARHGAP9 interference exerted an anti-tumor effect through inhibiting cell proliferation, blocking cell cycle progression, and promoting cell apoptosis in AML cells. ARHGAP9 may serve as a novel therapeutic target for AML.

DNA metabarcoding for dietary analysis of Holland's carp (Spinibarbus hollandi) to evaluate the threat to native fishes in Taiwan.

DNA metabarcoding analysis for gut contents has been shown to compensate the disadvantage of traditionally morphological identification and offer higher resolution of prey items in an efficient way. Holland's carp (Spinibarbus hollandi) is a freshwater fish native to southern and eastern Taiwan. In the past two decades, this species has been introduced as a sport fish into the river basins of northern and western Taiwan. The large body size and active predation make it a potential threat for native fishes, but which native species are preyed by Holland's carp remains unknown. In this study, the diet from the gut contents of Holland's carp from the Zhonggang River, an invaded basin, was examined using DNA metabarcoding from 51 individuals and by morphological examinations on 140 samples. Detritus of plants were found in 83.6% samples (117 individuals). Twenty fish species of seven families were identified by DNA metabarcoding, including species of all water layers. Taiwan torrent carp (Acrossocheilus paradoxus) and Rhinogobius spp. are the most common prey items. Based on the results of this study, Holland's carp is considered an opportunistic omnivore because of its diverse diet items, which is an important trait for successful invasive fish species. The population decline of Opsariichthys pachycephalus may not result from the invasion of Holland's carps. Nonetheless, the time lag between successful invasion and the samplings of this study may be a concern because the population size of O. pachycephalus may have declined and become difficult to prey. The Holland's carps consumed the least species in winter; nonetheless, the occurrence frequencies of preys among seasons were not significantly different probably because of limited temperature fluctuation. The smallest Holland's carps consumed the least prey species compared to other size categories, similar to the relationship of prey species number to size of invasive largemouth bass (Micropterus salmoides).

TRIM59 inhibits PPM1A through ubiquitination and activates TGF-ß/Smad signaling to promote the invasion of ectopic endometrial stromal cells in endometriosis.

This study was conducted to define the underlying molecular mechanism of tripartite motif (TRIM) 59-induced invasion of ectopic endometrial stromal cells in endometriosis. Primary endometriosis ectopic endometrial stromal cells and normal endometrial cells were isolated and purified. Western blot was used to detect the expression of TRIM59, protein phosphatase Mg2+/Mn2+-dependent 1A (PPM1A), smad2/3, and phosphorylated (p)-smad2/3. Lentiviral vector-mediated TRIM59 interference and overexpression were established. Cell Counting Kit-8 assay was used to detect cell proliferation, and the Transwell migration assay was used to detect cell invasion. Matrix metalloproteinase (MMP-2), MMP9, smad2/3, and p-smad2/3 expressions were also detected using Western blot analysis; degradation of PPM1A was verified to be through ubiquitination. We found that TRIM59 expression levels in the endometriosis group was significantly higher compared with the normal group (P < 0.05), whereas the expression levels of PPM1A in the endometriosis group were significantly lower (P < 0.05). Endometriosis did not alter smad2/3 (P > 0.05) expression. However, after activating smad2/3 by phosphorylation, the expression of p-smad2/3 in the endometriosis group was significantly higher compared with the normal group (P < 0.05). The content of PPM1A in the TRIM59 overexpression group was significantly lower than that in the control group (P < 0.001), whereas the content of PPM1A in the siTRIM59 group was significantly higher than that in the control group (P < 0.001). In addition, there were no significant differences in the mRNA levels of PPM1A among the five groups, indicating that TRIM59 affects the expression of PPM1A at the posttranslational level (P < 0.05). Overexpression of TRIM59 significantly promoted the ubiquitination of PPM1A. We conclude that TRIM59 inhibits PPM1A through ubiquitination and activates the transforming growth factor-ß/Smad pathway to promote the invasion of ectopic endometrial stromal cells in endometriosis.

The Cone Opsin Repertoire of Osteoglossomorph Fishes: Gene Loss in Mormyrid Electric Fish and a Long Wavelength-Sensitive Cone Opsin That Survived 3R.

Vertebrates have four classes of cone opsin genes derived from two rounds of genome duplication. These are short wavelength sensitive 1(SWS1), short wavelength sensitive 2(SWS2), medium wavelength sensitive (RH2), and long wavelength sensitive (LWS). Teleosts had another genome duplication at their origin and it is believed that only one of each cone opsin survived the ancestral teleost duplication event. We tested this by examining the retinal cones of a basal teleost group, the osteoglossomorphs. Surprisingly, this lineage has lost the typical vertebrate green-sensitive RH2 opsin gene and, instead, has a duplicate of the LWS opsin that is green sensitive. This parallels the situation in mammalian evolution in which the RH2 opsin gene was lost in basal mammals and a green-sensitive opsin re-evolved in Old World, and independently in some New World, primates from an LWS opsin gene. Another group of fish, the characins, possess green-sensitive LWS cones. Phylogenetic analysis shows that the evolution of green-sensitive LWS opsins in these two teleost groups derives from a common ancestral LWS opsin that acquired green sensitivity. Additionally, the nocturnally active African weakly electric fish (Mormyroideae), which are osteoglossomorphs, show a loss of the SWS1 opsin gene. In comparison with the independently evolved nocturnally active South American weakly electric fish (Gymnotiformes) with a functionally monochromatic LWS opsin cone retina, the presence of SWS2, LWS, and LWS2 cone opsins in mormyrids suggests the possibility of color vision.

CARM1 is heterogeneous in mouse four-cell embryo and important to blastocyst development.

Coactivator-associated arginine methyltransferase 1 (CARM1) is a type I arginine methyltransferase that methylates the arginine residues of histone and nonhistone. Carm1 regulates various cellular processes, including transcriptional regulation, mRNA processing, cellular proliferation, and differentiation. Blastomeres with high Carm1 expression levels show cleavage tendency to inner cell mass (ICM) in mouse embryos. However, details about the factors for CARM1 distribution in mouse early embryos and the role of Carm1 in blastocyst development remain unclear. Here, the endonuclear distribution of CARM1 protein was heterogeneous between blastomeres from the late four-cell stage to the blastocyst stage. The heterogeneity of CARM1 distribution in blastomeres at the late four-cell stage was randomly obtained from two-cell stage embryos. From the four-cell stage to morula, CARM1 in individual blastomere remained heterogeneous. In the blastocyst stage, CARM1 protein level in ICM was much higher than that in trophoblast. We found that microRNA (miRNA) miR-181a is an important regulator for Carm1 distribution at the late four-cell stage. The ratio of heterogeneous embryos was reduced in all the embryos when miR-181a was inhibited. CARM1 inhibition reduced the level of symmetrical histone H3 arginine-26 dimethylation and impaired blastocyst development. Silencing Carm1 reduced cell number and increased cell apoptosis at the blastocyst stage. These results show a CARM1 heterogeneous distribution from the four-cell embryos to the blastocysts. miR-181a regulates the control of CARM1 heterogeneous distribution in the four-cell-stage embryos, and CARM1 is an important protein in regulating blastocyst development.

MicroRNA-27b Modulates Inflammatory Response and Apoptosis during Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis poses a significant global health threat. MicroRNAs play an important role in regulating host anti-mycobacterial defense; however, their role in apoptosis-mediated mycobacterial elimination and inflammatory response remains unclear. In this study, we explored the role of microRNA-27b (miR-27b) in murine macrophage responses to M. tuberculosis infection. We uncovered that the TLR-2/MyD88/NF-κB signaling pathway induced the expression of miR-27b and miR-27b suppressed the production of proinflammatory factors and the activity of NF-κB, thereby avoiding an excessive inflammation during M. tuberculosis infection. Luciferase reporter assay and Western blotting showed that miR-27b directly targeted Bcl-2-associated athanogene 2 (Bag2) in macrophages. Overexpression of Bag2 reversed miR-27b-mediated inhibition of the production of proinflammatory factors. In addition, miR-27b increased p53-dependent cell apoptosis and the production of reactive oxygen species and decreased the bacterial burden. We also showed that Bag2 interacts with p53 and negatively regulates its activity, thereby controlling cell apoptosis and facilitating bacterial survival. In summary, we revealed a novel role of the miR-27b/Bag2 axis in the regulation of inflammatory response and apoptosis and provide a potential molecular host defense mechanism against mycobacteria.

Methionine adenosyltransferase 2A regulates mouse zygotic genome activation and morula to blastocyst transition†.

Methionine adenosyltransferase II (MAT2A) is essential to the synthesis of S-adenosylmethionine, a major methyl donor, from L-methionine and ATP. Upon fertilization, zygotic genome activation (ZGA) marks the period that transforms the genome from transcriptional quiescence to robust transcriptional activity. During this period, embryonic epigenome undergoes extensive modifications, including histone methylation changes. However, whether MAT2A participates in histone methylation at the ZGA stage is unknown. Herein, we identified that MAT2A is a pivotal factor for ZGA in mouse embryos. Mat2a knockdown exhibited 2-cell embryo arrest and reduced transcriptional activity but did not affect H3K4me2/3 and H3K9me2/3. When the cycloleucine, a selective inhibitor of MAT2A catalytic activity, was added to a culture medium, embryos were arrested at the morula stage in the same manner as the embryos cultured in an L-methionine-deficient medium. Under these two culture conditions, H3K4me3 levels of morula and blastocyst were much lower than those cultured under normal medium. Furthermore, cycloleucine treatment or methionine starvation apparently reduced the developmental potential of blastocysts. Thus, Mat2a is indispensable for ZGA and morula-to-blastocyst transition.

Research on the influence of bilateral oophorectomy on the BMD, body components and sex hormone of women during the perimenopause.

To investigate the effect of bilateral oophorectomy on bone mineral density, body composition and sex hormone of peri-menopause women. 33 cases of peri-menopause women patients performed bilateral oophorectomy were chosen from xxx gynaecology and obstetrics department of xxx hospital from January 1st,2014 to Dec31th, 2014. And the 33 cases were taken as ovariectomy group. 35 women who were the naturally postmenopausal after menopause collected in clinic and in the same period with the patients of ovariectomy group were taken in control group. American GE-Lunar-Prodigy dual energy X-ray absorptiometry and chemiluminescence method were employed to detect the bone mineral density, fat content, muscle content and sex hormone of the patients in both groups at the 6th and 12th month after menostasis. There was no statistical significance on the comparative difference of bone mineral density, fat content and muscle content at the 6th and 12th month after menostasis between both groups, P>0.05. At the 6th month after menostasis, the estradiol (E2) level in ovariectomy group was significantly lower than that of control group [(14.79±22.17)U/L vs (32.74±31.02U/L)], P<0.05; at the 12th month after menostasis, it had the statistical significance for the comparative difference between the level of E2 and and follicle-stimulating hormone (FSH) in ovariectomy group and that in control group, E2: (8.09±4.38)U/L vs (25.92±3.53)U/L; FSH: (64.88±18.39)U/L vs (40.69±31.63)U/L], P<0.05. the change of E2 and FSH were the main symptom of peri-menopausal women within 12 months after bilateral oophorectomy, the decrease of E2 level had no effect on bone mineral density, fat content and muscle content.

Association Between Single Nucleotide Polymorphisms in NFATC1 Signaling Pathway Genes and Susceptibility to Congenital Heart Disease in the Chinese Population.

The nuclear factor of activated T lymphocytes (NFATC1) signaling has been demonstrated to play important roles in cardiac valve and septal development. Genetic variants in genes involved in NFATC1 signaling may affect their expression and promote the formation of congenital heart disease (CHD). The goal of this study was to investigate the associations of single nucleotide polymorphism (SNP) in seven genes (NFATC1, VEGFR, VEGF, RANKL, FGFR1, BCL-6 and ZNRD1) with the risk of CHD. Twenty-nine polymorphisms were genotyped by using MassARRAY RS1000 platform in 277 CHD child patients and 293 controls from the Henan Province in China. Fours SNPs were excluded for the association analysis because of deviation from the Hardy-Weinberg equilibrium. Of the 25 SNPs, only two were found to be significantly associated with increased CHD risk after Bonferroni correction (RANKL, rs4531631: homozygous, AA vs. GG; OR 2.38, 95 % CI 1.40-4.07, p = 0.001; recessive, AA vs. AG + GG; OR 2.54, 95 % CI 1.53-4.22, p = 0.0003; FGFR1, rs13317: recessive, CC vs. CT + TT; OR 2.06, 95 % CI 1.30-3.25, p = 0.00196). Our findings suggest rs4531631 and rs13317 may be potential biomarkers for genetic diagnosis and treatment of CHD.

Association of DNMT1 Gene Polymorphisms with Congenital Heart Disease in Child Patients.

To reveal the association between DNMT1 polymorphisms and congenital heart disease (CHD) in child patients, a total of 224 CHD child patients as well as 199 healthy individuals were enrolled in the present study. The DNA was extracted from whole blood, and four SNPs including rs16999593, rs2228612, rs2288349 and rs10420321 were selected for the gene polymorphism investigation via ligase detection reaction (LDR) assay. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. rs16999593 was associated with the CHD under the heterozygous (CT vs TT: OR 0.62; 95 % CI 0.41-0.95; p = 0.03), dominant (CT + CC vs TT: OR 0.63; 95 % CI 0.42-0.95; p = 0.03), and allele models (C vs T: OR 0.07; 95 % CI 0.50-1.00; p = 0.05). rs2228612 was related with the CHD under the heterozygous (AG vs AA: OR 0.42; 95 % CI 0.27-0.65; p = 0.0001), homozygous (GG vs AA: OR 0.43; 95 % CI 0.240-0.77; p = 0.004), dominant (AG + GG vs AA: OR 0.42; 95 % CI 0.28-0.64; p < 0.0001), and allele models (G vs A: OR 0.62; 95 % CI 0.47-0.82; p = 0.0007). rs10420321 correlated with the CHD only under the recessive model (GG vs AG + AA: OR 0.61; 95 % CI 0.37-1.01, p = 0.05). However, no significant association between the rs2288349 polymorphisms and the risk of CHD was observed (p > 0.05). DNMT1 polymorphisms might contribute to the risk of CHD, especially rs16999593 and rs2228612.

Heterogeneous selectivity and morphological evolution of marine clades during the Permian-Triassic mass extinction.

Morphological disparity and taxonomic diversity are distinct measures of biodiversity, typically expected to evolve synergistically. However, evidence from mass extinctions indicates that they can be decoupled, and while mass extinctions lead to a drastic loss of diversity, their impact on disparity remains unclear. Here we evaluate the dynamics of morphological disparity and extinction selectivity across the Permian-Triassic mass extinction. We developed an automated approach, termed DeepMorph, for the extraction of morphological features from fossil images using a deep learning model and applied it to a high-resolution temporal dataset encompassing 599 genera across six marine clades. Ammonoids, brachiopods and ostracods experienced a selective loss of complex and ornamented forms, while bivalves, gastropods and conodonts did not experience morphologically selective extinctions. The presence and intensity of morphological selectivity probably reflect the variations in environmental tolerance thresholds among different clades. In clades affected by selective extinctions, the intensity of diversity loss promoted the loss of morphological disparity. Conversely, under non-selective extinctions, the magnitude of diversity loss had a negligible impact on disparity. Our results highlight that the Permian-Triassic mass extinction had heterogeneous morphological selective impacts across clades, offering new insights into how mass extinctions can reshape biodiversity and ecosystem structure.

The genomic evolution of visual opsin genes in amphibians.

Among tetrapod (terrestrial) vertebrates, amphibians remain more closely tied to an amphibious lifestyle than amniotes, and their visual opsin genes may be adapted to this lifestyle. Previous studies have discussed physiological, morphological, and molecular changes in the evolution of amphibian vision. We predicted the locations of the visual opsin genes, their neighboring genes, and the tuning sites of the visual opsins, in 39 amphibian genomes. We found that all of the examined genomes lacked the Rh2 gene. The caecilian genomes have further lost the SWS1 and SWS2 genes; only the Rh1 and LWS genes were retained. The loss of the SWS1 and SWS2 genes in caecilians may be correlated with their cryptic lifestyles. The opsin gene syntenies were predicted to be highly similar to those of other bony vertebrates. Moreover, dual syntenies were identified in allotetraploid Xenopus laevis and X. borealis. Tuning site analysis showed that only some Caudata species might have UV vision. In addition, the S164A that occurred several times in LWS evolution might either functionally compensate for the Rh2 gene loss or fine-tuning visual adaptation. Our study provides the first genomic evidence for a caecilian LWS gene and a genomic viewpoint of visual opsin genes by reviewing the gains and losses of visual opsin genes, the rearrangement of syntenies, and the alteration of spectral tuning in the course of amphibians' evolution.

Respiratory protein-driven selectivity during the Permian-Triassic mass extinction.

Extinction selectivity determines the direction of macroevolution, especially during mass extinction; however, its driving mechanisms remain poorly understood. By investigating the physiological selectivity of marine animals during the Permian-Triassic mass extinction, we found that marine clades with lower O2-carrying capacity hemerythrin proteins and those relying on O2 diffusion experienced significantly greater extinction intensity and body-size reduction than those with higher O2-carrying capacity hemoglobin or hemocyanin proteins. Our findings suggest that animals with high O2-carrying capacity obtained the necessary O2 even under hypoxia and compensated for the increased energy requirements caused by ocean acidification, which enabled their survival during the Permian-Triassic mass extinction. Thus, high O2-carrying capacity may have been crucial for the transition from the Paleozoic to the Modern Evolutionary Fauna.

Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer's Disease.

Familial Alzheimer's disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aß protein deposition. The cerebrospinal fluid amyloid protein test showed Aß42/Aß40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.

C-kit controls blood-brain barrier permeability by regulating caveolae-mediated transcytosis after chronic cerebral hypoperfusion.

Blood-brain barrier (BBB) dysfunction plays a pivotal role in the pathology of chronic cerebral hypoperfusion (CCH)-related neurodegenerative diseases. Continuous endothelial cells (EC) that line the blood vessels of the brain are important components of the BBB to strictly control the flow of substances and maintain the homeostatic environment of the brain. However, the molecular mechanisms from the perspective of EC-induced BBB dysfunction after CCH are largely unknown. In this study, the BBB function was assessed using immunostaining and transmission electron microscopy. The EC dysfunction profile was screened by using EC enrichment followed by RNA sequencing. After identified the key EC dysfunction factor, C-kit, we used the C-kit inhibition drug (imatinib) and C-kit down-regulation method (AAV-BR1-C-kit shRNA) to verify the role of C-kit on BBB integrity and EC transcytosis after CCH. Furthermore, we also activated C-kit with stem cell factor (SCF) to observe the effects of C-kit on BBB following CCH. We explored that macromolecular proteins entered the brain mainly through EC transcytosis after CCH and caused neuronal loss. Additionally, we identified receptor tyrosine kinase C-kit as a key EC dysfunction molecule. Furthermore, the pharmacological inhibition of C-kit with imatinib counteracted BBB leakage by reducing caveolae-mediated transcytosis. Moreover, treatment with AAV-BR1-C-kit shRNA, which targets brain EC to inhibit C-kit expression, also ameliorated BBB leakage by reducing caveolae-mediated transcytosis. Furthermore, the SCF increased the permeability of the BBB by actively increasing caveolae-mediated transcytosis. This study provides evidence that C-kit is a key BBB permeability regulator through caveolae-mediated transcytosis in EC after CCH.

Impact of regional accessibility on urban residents' income in China: A bidirectional-fixed panel model.

The income gap between regions and its expansion are the main manifestations of the imbalanced and inadequate economic development in China. High-speed railway (HSR) construction is regarded as an important method to drive domestic demand, drive the pulse of the economy, and promote the coordinated development of regions. Based on the opening of HSR and the acceleration of ordinary railways, we used the weighted average travel time model and accessibility coefficient to estimate the changes on accessibility in 286 cities at prefecture-level and above from 2000 to 2018. Then, the influence mechanisms of improving regional accessibility on urban residents' income were estimated by using the bidirectional-fixed effects panel model and the recursive model respectively. We found that: (1) The accessibility of urban areas has been greatly improved due to the opening of HSR and the acceleration of ordinary railway, among which the improvement of HSR cities is greater. (2) The improvement of regional accessibility significantly promoted the income growth of urban residents, and the increase of the regional accessibility coefficient by 1 unit led to an average increase of 2140 yuan in the per capita disposable income of urban residents. (3) There is regional heterogeneity in the impact of improving regional accessibility on urban residents' income, and it has a significant effect on the eastern and northeastern regions. It has a greater positive effect on improving the income of residents in central cities compared with peripheral cities. (4) Regional accessibility can promote urban income growth through regional employment and fixed asset investment. In the future, the transportation network should be further improved to facilitate the regional economic cycle, strengthen the coordination and complementarity of regional economies, and promote regional economic integration so as to promote the improvement of resident income level and the common prosperity of the people.