Increased lymphangiogenesis in joints of mice with inflammatory arthritis

Angiogenesis is involved in the pathogenesis of inflammatory arthritis, but little is known about the role of lymphangiogenesis in this setting. Here, we examined whether tumor necrosis factor (TNF) stimulates osteoclast precursors (OCPs) to produce the lymphatic growth factor, vascular endothelial growth factor-C (VEGF-C), and induce lymphangiogenesis. We used TNF-transgenic (Tg) mice and mice with serum-induced arthritis. OCPs were purified by fluorescence-activated cell sorting of CD11b+/Gr-1-/lo blood or bone marrow cells and subjected to microarray analysis or were generated from spleen or joint cells and treated with TNF. Expression of VEGFs was analyzed and examined by real-time reverse transcription-polymerase chain reaction and Western blotting. Immunostaining and magnetic resonance imaging were used to quantify lymphatic vessels and volumes of synovium and draining lymph nodes. TNF stimulated VEGF-C expression by OCPs and increased nuclear factor-kappa B (NF-κB) binding to an NF-κB sequence in the VEGF-C promoter. OCPs from joints of TNF-Tg mice express high levels of VEGF-C. Lymphatic vessel numbers and size were markedly increased in joint sections of TNF-Tg mice and mice with serum-induced arthritis. The severity of synovitis correlated with draining lymph node size. In summary, TNF induces OCPs to produce VEGF-C through NF-κB, leading to significantly increased lymphangiogenesis in joints of arthritic mice. The lymphatic system may play an important role in the pathogenesis of inflammatory arthritis

Quantification of hypsarrhythmia in infantile spasmatic EEG:a large cohort study

Infantile spasms (IS) is a neurological disorder causing mental and/or developmental retardation in many infants. Hypsarrhythmia is a typical symptom in the electroencephalography (EEG) signals with IS. Long-Term EEG/video monitoring is most frequently employed in clinical practice for IS diagnosis, from which manual screening of hypsarrhythmia is time consuming and lack of sufficient reliability. This study aims to identify potential biomarkers for automatic IS diagnosis by quantitative analysis of the EEG signals. A large cohort of 101 IS patients and 155 healthy controls (HC) were involved. Typical hypsarrhythmia and non-hypsarrhythmia EEG signals were annotated, and normal EEG were randomly picked from the HC. Root mean square (RMS), teager energy (TE), mean frequency, sample entropy (SamEn), multi-channel SamEn, multi-scale SamEn, and nonlinear correlation coefficient were computed in each sub-band of the three EEG signals, and then compared using either a one-way ANOVA or a Kruskal-Wallis test (based on their distribution) and the receiver operating characteristic (ROC) curves. The effects of infant age on these features were also investigated. For most of the employed features, significant ({p} &lt; {0}.{05} ) differences were observed between hypsarrhythmia EEG and non-hypsarrhythmia EEG or HC, which seem to increase with increased infant age. RMS and TE produce the best classification in the delta and theta bands, while entropy features yields the best performance in the gamma band. Our study suggests RMS and TE (delta and theta bands) and entropy features (gamma band) to be promising biomarkers for automatic detection of hypsarrhythmia in long-Term EEG monitoring. The findings of our study indicate the feasibility of automated IS diagnosis using artificial intelligence.</p

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. RESULTS: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. CONCLUSIONS: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease

Mendelian gene identification through mouse embryo viability screening.

BACKGROUND: The diagnostic rate of Mendelian disorders in sequencing studies continues to increase, along with the pace of novel disease gene discovery. However, variant interpretation in novel genes not currently associated with disease is particularly challenging and strategies combining gene functional evidence with approaches that evaluate the phenotypic similarities between patients and model organisms have proven successful. A full spectrum of intolerance to loss-of-function variation has been previously described, providing evidence that gene essentiality should not be considered as a simple and fixed binary property. METHODS: Here we further dissected this spectrum by assessing the embryonic stage at which homozygous loss-of-function results in lethality in mice from the International Mouse Phenotyping Consortium, classifying the set of lethal genes into one of three windows of lethality: early, mid, or late gestation lethal. We studied the correlation between these windows of lethality and various gene features including expression across development, paralogy and constraint metrics together with human disease phenotypes. We explored a gene similarity approach for novel gene discovery and investigated unsolved cases from the 100,000 Genomes Project. RESULTS: We found that genes in the early gestation lethal category have distinct characteristics and are enriched for genes linked with recessive forms of inherited metabolic disease. We identified several genes sharing multiple features with known biallelic forms of inborn errors of the metabolism and found signs of enrichment of biallelic predicted pathogenic variants among early gestation lethal genes in patients recruited under this disease category. We highlight two novel gene candidates with phenotypic overlap between the patients and the mouse knockouts. CONCLUSIONS: Information on the developmental period at which embryonic lethality occurs in the knockout mouse may be used for novel disease gene discovery that helps to prioritise variants in unsolved rare disease cases

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Indoor Radio Map Construction Based on Position Adjustment and Equipment Calibration

The crowdsourcing-based wireless local area network (WLAN) indoor localization system has been widely promoted for the effective reduction of the workload from the offline phase data collection while constructing radio maps. Aiming at the problem of the diverse terminal devices and the inaccurate location annotation of the crowdsourced samples, which will result in the construction of the wrong radio map, an effective indoor radio map construction scheme (RMPAEC) is proposed based on position adjustment and equipment calibration. The RMPAEC consists of three main modules: terminal equipment calibration, pedestrian dead reckoning (PDR) estimated position adjustment, and fingerprint amendment. A position adjustment algorithm based on selective particle filtering is used by RMPAEC to reduce the cumulative error in PDR tracking. Moreover, an inter-device calibration algorithm is put forward based on receiver pattern analysis to obtain a device-independent grid fingerprint. The experimental results demonstrate that the proposed solution achieves higher localization accuracy than the peer schemes, and it possesses good effectiveness at the same time

Has “The Belt and Road” initiative promoted regional economic growth and economic innovation?

The article regards “The Belt and Road” initiative as a quasi-natural experiment. Based on the county panel data from 1999 to 2017, difference-in-differences model (DID) is used to examine the impact of the “The Belt and Road” initiative on regional economic growth and economic innovation. The study found that the “The Belt and Road” initiative can significantly increase the economic growth and innovation of the region. Through the placebo test and the robustness test, it shows good policy uniqueness characteristics. The article further analyzes the heterogeneity of the initiative. The study found that the initiative has more obvious economic growth and innovation in the central region

Efficient Protection Mechanism Based on Self-Adaptive Decision for Communication Networks of Autonomous Vehicles

The communication network of autonomous vehicles is composed of multiple sensors working together, and its dynamic topology makes it vulnerable to common attacks such as black hole attack, gray hole attack, rushing attack, and flooding attack, which pose a threat to the safety of passengers and vehicles; most of the existing safety detection mechanisms for a vehicle can only detect attacks but cannot intelligently defend against attacks. To this end, an efficient protection mechanism based on self-adaptive decision (SD-EPM) is proposed, which is divided into the offline phase and the online phase. The online phase consists of two parts: intrusion detection and efficient response. Attack detection and defense in the vehicular ad hoc networks (VANETs) are performed in terms of the attack credibility value (AC), the network performance attenuation value (NPA), and the list of self-adaptive decision. The simulation results show that the proposed mechanism can correctly identify the attack and respond effectively to different attack types. And, the negative impact on VANETs is small

Intestinal microbiota dysbiosis and liver metabolomic changes during brain death

Background: Whether a causative link exists between brain death (BD) and intestinal microbiota dysbiosis is unclear, and the distortion in liver metabolism associated with BD requires further exploration. Methods: A rat model of BD was constructed and sustained for 9 h (BD group, n=6). The sham group (n=6) underwent the same procedures, but the catheter was inserted into the epidural space without ballooning. Intestinal contents and portal vein plasma were collected for microbiota sequencing and microbial metabolite detection. Liver tissue was resected to investigate metabolic alterations, and the results were compared with those of a sham group. Results: α-diversity indexes showed that BD did not alter bacterial diversity. Microbiota dysbiosis occurred after 9 h of BD. At the family level, Peptostreptococcaceae and Bacteroidaceae were both decreased in the BD group. At the genus level, Romboutsia, Bacteroides, Erysipelotrichaceae_UCG_004, Faecalibacterium, and Barnesiella were enriched in the sham group, whereas Ruminococcaceae_UCG_007, Lachnospiraceae_ND3007_group, and Papillibacter were enriched in the BD group. Short-chain fatty acids, bile acids, and 132 other microbial metabolites remained unchanged in both the intestinal contents and portal vein plasma of the BD group. BD caused alterations in 65 metabolites in the liver, of which, carbohydrates, amino acids, and organic acids accounted for 64.6%. Additionally, 80.0% of the differential metabolites were decreased in the BD group livers. Galactose metabolism was the most significant metabolic pathway in the BD group. Conclusions: BD resulted in microbiota dysbiosis in rats; however, this dysbiosis did not alter microbial metabolites. Deterioration in liver metabolic function during extended periods of BD may reflect a continuous worsening in energy deficiency