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Induced neural stem cells (iNSCs) can be directly transdifferentiated from somatic cells. One potential clinical application of the iNSCs is for nerve regeneration. However, it is unknown whether iNSCs function in disease models. We produced transdifferentiated iNSCs by conditional overexpressing Oct4, Sox2, Klf4, c-Mycin mouse embryonic fibroblasts. They expanded readily in vitro and expressed NSC mRNA profile and protein markers. These iNSCs differentiated into mature astrocytes, neurons and oligodendrocytes in vitro. Importantly, they reduced lesion size, promoted the recovery of motor and sensory function as well as metabolism status in middle cerebral artery stroke rats. These iNSCs secreted nerve growth factors, which was associated with observed protection of neurons from apoptosis. Furthermore, iNSCs migrated to and passed through the lesion in the cerebral cortex, where Tuj1+ neurons were detected. These findings have revealed the function of transdifferentiated iNSCs in vivo, and thus provide experimental evidence to support the development of personalized regenerative therapy for CNS diseases by using genetically engineered autologous somatic cells. [ABSTRACT FROM AUTHOR]

Electrical signaling plays a crucial role in the cellular response to tissue injury in wound healing and an external electric field (EF) may expedite the healing process. Here, we have developed a standalone, wearable, and programmable electronic device to administer a well-controlled exogenous EF, aiming to accelerate wound healing in an in vivo mouse model to provide pre-clinical evidence. We monitored the healing process by assessing the re-epithelization rate and the ratio of M1/M2 macrophage phenotypes through histology staining. Following three days of treatment, the M1/M2 macrophage ratio decreased by 30.6% and the re-epithelization in the EF-treated wounds trended towards a non-statically significant 24.2% increase compared to the control. These findings provide point towards the effectiveness of the device in shortening the inflammatory phase by promoting reparative macrophages over inflammatory macrophages, and in speeding up re-epithelialization. Our wearable device supports the rationale for the application of programmed EFs for wound management in vivo and provides an exciting basis for further development of our technology based on the modulation of macrophages and inflammation to better wound healing. [ABSTRACT FROM AUTHOR]

Enhancing the robustness of complex networks is of great practical significance as it ensures the stable operation of infrastructure systems. We measure its robustness by examining the size of the largest connected component of the network after initial attacks. However, traditional research on network robustness enhancement has mainly focused on low-order networks, with little attention given to higher-order networks, particularly higher-low order coupling networks(the largest connected component of the network must exist in both higher-order and low-order networks). To address this issue, this paper proposes robust optimization methods for higher-low order coupled networks based on the greedy algorithm and the simulated annealing algorithm. By comparison, we found that the simulated annealing algorithm performs better. The proposed method optimizes the topology of the low-order network and the higher-order network by randomly reconnecting the edges, thereby enhancing the robustness of the higher-order and low-order coupled network. The experiments were conducted on multiple real networks to evaluate the change in the robustness coefficient before and after network optimization. The results demonstrate that the proposed method can effectively improve the robustness of both low-order and higher-order networks, ultimately enhancing the robustness of higher-low order coupled networks. [ABSTRACT FROM AUTHOR]

Diazoxide is the first-line drug for treating hyperinsulinism and the only pharmacological agent approved for hyperinsulinism by the Federal Drug Administration. This systemic review and meta-analysis aimed to investigate the efficacy and safety of diazoxide for treating hyperinsulinemic hypoglycemia (HH). The meta-analysis of the efficacy and safety of diazoxide in treating HH was performed by searching relevant studies in the PubMed, Embase, and Cochrane databases. The findings were summarized, and the pooled effect size and its 95% confidence interval (CI) were calculated. A total of 6 cohort studies, involving 1142 participants, met the inclusion criteria. Among the cohort studies, the pooled estimate of the response rate of diazoxide therapy was 71% (95% CI 50%–93%, Pheterogeneity< 0.001, I2 = 98.3%, Peffect< 0.001). The common side effects were hypertrichosis (45%), fluid retention (20%), gastrointestinal reaction (13%), edema (11%), and neutropenia (9%). Other adverse events included pulmonary hypertension (2%) and thrombocytopenia (2%). This meta-analysis suggested that diazoxide was potentially useful in HH management; however, it had some side effects, which needed careful monitoring. Furthermore, well-designed large-scale studies, such as randomized controlled trials, might be necessary in the future to obtain more evidence. [ABSTRACT FROM AUTHOR]

Allogrooming in primates has acquired an important social function beyond its original hygienic function and can be exchanged either for itself or used as a currency to obtain other benefits such as copulations, access to infants or agonistic support. We explore the strategic use of grooming as a social tool in semi-wild golden snub-nosed monkeys (Rhinopithecus roxellana) in central China, a species where two desirable resources, viz. reproductive males and infants, are restricted to the mating and birth season, respectively. We predict that females expend their grooming selectively to different individuals according to their “value”. Our results show that in the mating season, females devoted more grooming to the resident male than in the birth season, and this effect was particularly strong in non-mothers (females without newborn infants). Moreover, females were more likely to groom the resident male after copulation than during baseline social conditions. In the birth season, females devoted more grooming to other females than in the mating season, and mothers (females with newborn infants) were the most valuable grooming partners. The mean rate of contact by non-mothers toward infants of other females was significantly higher after grooming the mothers than in baseline social conditions. In conclusion, our findings lend credence to the notion that primate females use grooming as a strategic tool to obtain limited resources such as males and infants and vary preference for particular individuals depending on the seasonal availability of valuable resources. [ABSTRACT FROM AUTHOR]

Segmentation of retinal vessels is important for doctors to diagnose some diseases. The segmentation accuracy of retinal vessels can be effectively improved by using deep learning methods. However, most of the existing methods are incomplete for shallow feature extraction, and some superficial features are lost, resulting in blurred vessel boundaries and inaccurate segmentation of capillaries in the segmentation results. At the same time, the "layer-by-layer" information fusion between encoder and decoder makes the feature information extracted from the shallow layer of the network cannot be smoothly transferred to the deep layer of the network, resulting in noise in the segmentation features. In this paper, we propose the MFI-Net (Multi-resolution fusion input network) network model to alleviate the above problem to a certain extent. The multi-resolution input module in MFI-Net avoids the loss of coarse-grained feature information in the shallow layer by extracting local and global feature information in different resolutions. We have reconsidered the information fusion method between the encoder and the decoder, and used the information aggregation method to alleviate the information isolation between the shallow and deep layers of the network. MFI-Net is verified on three datasets, DRIVE, CHASE_DB1 and STARE. The experimental results show that our network is at a high level in several metrics, with F1 higher than U-Net by 2.42%, 2.46% and 1.61%, higher than R2U-Net by 1.47%, 2.22% and 0.08%, respectively. Finally, this paper proves the robustness of MFI-Net through experiments and discussions on the stability and generalization ability of MFI-Net. [ABSTRACT FROM AUTHOR]

Inactivating mutations in the ontrol f irulence two-component regulatory system (covRS) often account for the hypervirulent phenotype in severe, invasive group A streptococcal (GAS) infections. As CovR represses production of the anti-phagocytic hyaluronic acid capsule, high level capsule production is generally considered critical to the hypervirulent phenotype induced by CovRS inactivation. There have recently been large outbreaks of GAS strains lacking capsule, but there are currently no data on the virulence of covRS-mutated, acapsular strains in vivo. We investigated the impact of CovRS inactivation in acapsular serotype M4 strains using a wild-type (M4-SC-1) and a naturally-occurring CovS-inactivated strain (M4-LC-1) that contains an 11bp covS insertion. M4-LC-1 was significantly more virulent in a mouse bacteremia model but caused smaller lesions in a subcutaneous mouse model. Over 10% of the genome showed significantly different transcript levels in M4-LC-1 vs. M4-SC-1 strain. Notably, the Mga regulon and multiple cell surface protein-encoding genes were strongly upregulated–a finding not observed for CovS-inactivated, encapsulated M1 or M3 GAS strains. Consistent with the transcriptomic data, transmission electron microscopy revealed markedly altered cell surface morphology of M4-LC-1 compared to M4-SC-1. Insertional inactivation of covS in M4-SC-1 recapitulated the transcriptome and cell surface morphology. Analysis of the cell surface following CovS-inactivation revealed that the upregulated proteins were part of the Mga regulon. Inactivation of mga in M4-LC-1 reduced transcript levels of multiple cell surface proteins and reversed the cell surface alterations consistent with the effect of CovS inactivation on cell surface composition being mediated by Mga. CovRS-inactivating mutations were detected in 20% of current invasive serotype M4 strains in the United States. Thus, we discovered that hypervirulent M4 GAS strains with covRS mutations can arise in an acapsular background and that such hypervirulence is associated with profound alteration of the cell surface. [ABSTRACT FROM AUTHOR]

Hexanucleotide (GGGGCC) repeat expansion in C9ORF72 (HRE) causes frontotemporal lobar degeneration, frontotemporal dementia–amyotrophic lateral sclerosis, and amyotrophic lateral sclerosis. HRE was also seen in the genomes of patients suffering from several other degenerative diseases. However, whether it is present in the treatment-resistant schizophrenia patients remains unknown. Genotyping 386 patients suffering from treatment-resistant schizophrenia using the method of Repeat-Primed PCR, we reported here that no HRE was detected in the patients of Chinese Han. [ABSTRACT FROM AUTHOR]

The pathogenesis of the Brucella-induced inflammatory response in the bovine placenta is not completely understood. In this study we evaluated the role of the B. abortus Type IV secretion system and the anti-inflammatory factor BtpB in early interactions with bovine placental tissues. Transcription profiles of chorioallantoic membrane (CAM) explants inoculated with wild type (strain 2308), ΔvirB2 or ΔbtpB Brucella abortus were compared by microarray analysis at 4 hours post infection. Transcripts with significant variation (>2 fold change; P<0.05) were functionally classified, and transcripts related to defense and inflammation were assessed by quantitative real time RT-PCR. Infection with wild type B. abortus resulted in slightly more genes with decreased than increased transcription levels. Conversely, infection of trophoblastic cells with the ΔvirB2 or the ΔbtpB mutant strains, that lack a functional T4SS or that has impaired inhibition of TLR signaling, respectively, induced more upregulated than downregulated genes. Wild type Brucella abortus impaired transcription of host genes related to immune response when compared to ΔvirB and ΔbtpB mutants. Our findings suggest that proinflammatory genes are negatively modulated in bovine trophoblastic cells at early stages of infection. The virB operon and btpB are directly or indirectly related to modulation of these host genes. These results shed light on the early interactions between B. abortus and placental tissue that ultimately culminate in inflammatory pathology and abortion. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is believed to arise from leukemic stem-like cells (LSC) making understanding the biological differences between LSC and normal stem cells (HSC) or common myeloid progenitors (CMP) crucial to understanding AML biology. To determine if protein expression patterns were different in LSC compared to other AML and CD34+ populations, we measured the expression of 121 proteins by Reverse Phase Protein Arrays (RPPA) in 5 purified fractions from AML marrow and blood samples: Bulk (CD3/CD19 depleted), CD34-, CD34+(CMP), CD34+CD38+ and CD34+CD38-(LSC). LSC protein expression differed markedly from Bulk (n=31 cases, 93/121 proteins) and CD34+ cells (n= 30 cases, 88/121 proteins) with 54 proteins being significantly different (31 higher, 23 lower) in LSC than in either Bulk or CD34+ cells. Sixty-seven proteins differed significantly between CD34+ and Bulk blasts (n=69 cases). Protein expression patterns in LSC and CD34+ differed markedly from normal CD34+ cells. LSC were distinct from CD34+ and Bulk cells by principal component and by protein signaling network analysis which confirmed individual protein analysis. Potential targetable submodules in LSC included the proteins PU.1(SP1), P27, Mcl1, HIF1α, cMET, P53, Yap, and phospho-Stats 1, 5 and 6. Protein expression and activation in LSC differs markedly from other blast populations suggesting that studies of AML biology should be performed in LSC. [ABSTRACT FROM AUTHOR]

Background: Selaginellaceae is a family of nonseed plants with special evolutionary significance. Plants of the family Selaginellaceae are similarly shaped and easily confused, complicating identification via traditional methods. This study explored, for the first time, the use of the DNA barcode ITS2 to identify medicinal plants of the Selaginellaceae family. Methodology/Principal Findings: In our study, 103 samples were collected from the main distribution areas in China; these samples represented 34 species and contained almost all of the medicinal plants of Selaginellaceae. The ITS2 region of the genome was amplified from these samples and sequenced using universal primers and reaction conditions. The success rates of the PCR amplification and sequencing were 100%. There was significant divergence between the interspecific and intraspecific genetic distances of the ITS2 regions, while the presence of a barcoding gap was obvious. Using the BLAST1 and nearest distance methods, our results proved that the ITS2 regions could successfully identify the species of all Selaginellaceae samples examined. In addition, the secondary structures of ITS2 in the helical regions displayed clear differences in stem loop number, size, position, and screw angle among the medicinal plants of Selaginellaceae. Furthermore, cluster analysis using the ITS2 barcode supported the relationship between the species of Selaginellaceae established by traditional morphological methods. Conclusion: The ITS2 barcode can effectively identify medicinal plants of Selaginellaceae. The results provide a scientific basis for the precise identification of plants of the family Selaginellaceae and the reasonable development of these resources. This study may broaden the application of DNA barcoding in the medicinal plant field and benefit phylogenetic investigations. [ABSTRACT FROM AUTHOR]

Salvia miltiorrhiza is an important medicinal plant with great economic and medicinal value. The complete chloroplast (cp) genome sequence of Salvia miltiorrhiza, the first sequenced member of the Lamiaceae family, is reported here. The genome is 151,328 bp in length and exhibits a typical quadripartite structure of the large (LSC, 82,695 bp) and small (SSC, 17,555 bp) single-copy regions, separated by a pair of inverted repeats (IRs, 25,539 bp). It contains 114 unique genes, including 80 protein-coding genes, 30 tRNAs and four rRNAs. The genome structure, gene order, GC content and codon usage are similar to the typical angiosperm cp genomes. Four forward, three inverted and seven tandem repeats were detected in the Salvia miltiorrhiza cp genome. Simple sequence repeat (SSR) analysis among the 30 asterid cp genomes revealed that most SSRs are AT-rich, which contribute to the overall AT richness of these cp genomes. Additionally, fewer SSRs are distributed in the protein-coding sequences compared to the non-coding regions, indicating an uneven distribution of SSRs within the cp genomes. Entire cp genome comparison of Salvia miltiorrhiza and three other Lamiales cp genomes showed a high degree of sequence similarity and a relatively high divergence of intergenic spacers. Sequence divergence analysis discovered the ten most divergent and ten most conserved genes as well as their length variation, which will be helpful for phylogenetic studies in asterids. Our analysis also supports that both regional and functional constraints affect gene sequence evolution. Further, phylogenetic analysis demonstrated a sister relationship between Salvia miltiorrhiza and Sesamum indicum. The complete cp genome sequence of Salvia miltiorrhiza reported in this paper will facilitate population, phylogenetic and cp genetic engineering studies of this medicinal plant. [ABSTRACT FROM AUTHOR]