No abstract

Schizophrenia is thought as a self-disorder with dysfunctional brain connectivity. This self-disorder is often attributed to high-order cognitive impairment. Yet due to the frequent report of sensorial and perceptual deficits, it has been hypothesized that self-disorder in schizophrenia is dysfunctional communication between sensory and cognitive processes. To further verify this assumption, the present study comprehensively examined dynamic reconfigurations of resting-state functional connectivity (rsFC) in schizophrenia at voxel level, region level, and network levels (102 patients vs. 124 controls). We found patients who show consistently increased rsFC variability in sensory and perceptual system, including visual network, sensorimotor network, attention network, and thalamus at all the three levels. However, decreased variability in high-order networks, such as default mode network and frontal–parietal network were only consistently observed at region and network levels. Taken together, these findings highlighted the rudimentary role of elevated instability of information communication in sensory and perceptual system and attenuated whole-brain integration of high-order network in schizophrenia, which provided novel neural evidence to support the hypothesis of disrupted perceptual and cognitive function in schizophrenia. The foci of effects also highlighted that targeting perceptual deficits can be regarded as the key to enhance our understanding of pathophysiology in schizophrenia and promote new treatment intervention.

Hydrogen therapy is an emerging and highly promising strategy for the treatment of inflammation-related diseases. However, nonpolarity and low solubility of hydrogen under the physiological conditions results in a limited therapeutic effect. Herein, we develop a biocompatible magnesium micromotor coated with hyaluronic acid as a hydrogen generator for precise rheumatoid arthritis management. The hydrogen bubbles generated locally not only function as a propellant for the motion but also function as the active ingredient for reactive oxygen species (ROS) and inflammation scavenging. Under ultrasound guidance, the micromotors are injected intra-articularly, and the dynamics of the micromotors can be visualized. By scavenging ROS and inflammation via active hydrogen, the oxidative stress is relieved and the levels of inflammation cytokines are reduced by our micromotors, showing prominent therapeutic efficacy in ameliorating joint damage and suppressing the overall arthritis severity toward a collagen-induced arthritis rat model. Therefore, our micromotors show great potential for the therapy of rheumatoid arthritis and further clinical transformation.

c Mycobacterium tuberculosis can acquire resistance to rifampin (RIF) through mutations in the rpoB gene. This is usually accompanied by a fitness cost, which, however, can be mitigated by secondary mutations in the rpoA or rpoC gene. This study aimed to identify rpoA and rpoC mutations in clinical M. tuberculosis isolates in northern China in order to clarify their role in the transmission of drug-resistant tuberculosis (TB). The study collection included 332 RIF-resistant and 178 RIF-susceptible isolates. The majority of isolates belonged to the Beijing genotype (95.3%, 486/510 isolates), and no mutation was found in rpoA or rpoC of the non-Beijing genotype strains. Among the Beijing genotype strains, 27.8% (89/320) of RIF-resistant isolates harbored nonsynonymous mutations in the rpoA (n ‫؍‬ 6) or rpoC (n ‫؍‬ 83) gene. The proportion of rpoC mutations was significantly higher in new cases (P ‫؍‬ 0.023) and in strains with the rpoB S531L mutation (P < 0.001). In addition, multidrug-resistant (MDR) strains with rpoC mutations were significantly associated with 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem-repeat clustering (P ‫؍‬ 0.016). In summary, we believe that these findings indirectly suggest an epistatic interaction of particular mutations related to RIF resistance and strain fitness and, consequently, the role of such mutations in the spread of MDR M. tuberculosis strains.

In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX) via hydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generated via avidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor region via αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of folate receptor (FR) after US exposure. In vitro experiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected using in vivo fluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their therapeutic applications in vivo.

Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10-11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population.

Mycobacterium tuberculosis Beijing genotype originated in China and has undergone a dramatic population growth and global spread in the last century. Here, a collection of M. tuberculosis Beijing family isolates from different provinces across all China was genotyped by high-resolution (24-MIRU-VNTR) and lowresolution, high-rank (modern and ancient sublineages) markers. The molecular profiles and global and local phylogenies were compared to the strain phenotype and patient data. The phylogeographic patterns observed in the studied collection demonstrate that large-scale (but not middle/small-scale) distance remains one of the decisive factors of the genetic divergence of M. tuberculosis populations. Analysis of diversity and network topology of the local collections appears to corroborate a recent intriguing hypothesis about Beijing genotype originating in South China. Placing our results within the Eurasian context suggested that important Russian B0/W148 and Asian/Russian A0/94-32 epidemic clones of the Beijing genotype could trace their origins to the northeastern and northwestern regions of China, respectively. The higher clustering of the modern isolates in children and lack of increased MDR rate in any sublineage suggest that not association with drug resistance but other (e.g., speculatively, virulencerelated) properties underlie an enhanced dissemination of the evolutionarily recent, modern sublineage of the Beijing genotype in China.The advent of next-generation sequencing technologies for whole genome analysis of bacterial pathogens opened a new perspective to the more robust and more meaningful reconstructions. Nonetheless, a new technology is not a magic wand in itself since bioinformatics tools and algorithms do not always permit to achieve an unambiguous interpretation 1 . In the field of molecular evolution and phylogenetics of Mycobacterium tuberculosis, a consensus view on many issues is yet to be reached. Perhaps, the most controversial topics with contrasting opinions concern the location and dating of the origin of M. tuberculosis species and its lineages and reasons underlying the evolutionary success of certain strains [2][3][4] .M. tuberculosis is a clonal species and its different lineages are marked with clearly different "curricula vitae", some having declined even in the areas of their origin (M. africanum in West Africa being the most remarkable example), others having undergone a dramatic increase in effective population size and global dispersal. The latter may be exemplified by the Beijing family and its particular sublineages and clonal clusters.

Purpose: To examine diagnostic performance of qualitative shear wave elastography (SWE) for evaluation of status of axillary lymph nodes (ALN) in comparison with conventional ultrasonograghy (US) and quantitative SWE parameters. Methods: A total of 118 patients were enrolled, who were all scheduled for breast cancer surgery and core needle biopsy. Conventional US and SWE were performed before biopsy. Based on qualitative evaluation of each ALN, the SWE images were classified into four color patterns: Color Pattern 1: homogeneous; Color Pattern 2: filling defect within lymph node (LN); Color Pattern 3: homogeneous within LN with a localized colored area at the margin; and Color Pattern 4: filling defect within LN with a localized colored area at the margin. The diagnostic performances of the three methods were compared. Results: There were 60 metastatic nodes and 61 benign nodes in the 121 ALNs. Benign ALNs were presented as Color Pattern 1 while metastatic ALNs usually were presented as Color Pattern 2 to 4 ( p < 0.05). The AUC of qualitative SWE classification was 0.983, higher than that of quantitative SWE parameters and conventional US ( p <0.05). The highest diagnostic performance, with AUC of 0.998, could be achieved if both conventional US and qualitative SWE were applied. Conclusion: The qualitative SWE classification of ALNs proposed in our study exhibited better diagnostic performance than quantitative SWE parameters and conventional US, especially for differentiating metastatic ALNs from benign reactive ALNs. More accurate diagnosis could be reached with this new method and unnecessary biopsy might be avoided in the meantime.