In this study, we present representative human contact networks among Chinese college students. Unlike schools in the US, human contacts within Chinese colleges are extremely clustered, partly due to the highly organized lifestyle of Chinese college students. Simulations of influenza spreading across real contact networks are in good accordance with real influenza records; however, epidemic simulations across idealized scale-free or small-world networks show considerable overestimation of disease prevalence, thus challenging the widely-applied idealized human contact models in epidemiology. Furthermore, the special contact pattern within Chinese colleges results in disease spreading patterns distinct from those of the US schools. Remarkably, class cancelation, though simple, shows a mitigating power equal to quarantine/vaccination applied on ~25% of college students, which quantitatively explains its success in Chinese colleges during the SARS period. Our findings greatly facilitate reliable prediction of epidemic prevalence, and thus should help establishing effective strategies for respiratory infectious diseases control.

The global epidemic of drug-resistant tuberculosis is a catastrophic example of how antimicrobial resistance is undermining the public health gains made possible by combination drug therapy. Recent evidence points to unappreciated bacterial factors that accelerate the emergence of drug resistance. In a genome-wide association study of Mycobacterium tuberculosis isolates from China, we find mutations in the gene encoding the transcription factor prpR enriched in drug-resistant strains. prpR mutations confer conditional drug tolerance to three of the most effective classes of antibiotics by altering propionyl-CoA metabolism. prpR-mediated drug tolerance is carbon-source dependent, and while readily detectable during infection of human macrophages, is not captured by standard susceptibility testing. These data define a previously unrecognized and clinically prevalent class of M. tuberculosis variants that undermine antibiotic efficacy and drive drug resistance.

The emergence and rapid spread of New Delhi Metallo-beta-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae strains has caused a great concern worldwide. To better understand the mechanisms underlying environmental adaptation of those highly drug-resistant K. pneumoniae strains, we took advantage of the China's Shenzhou 10 spacecraft mission to conduct comparative genomic and transcriptomic analysis of a NDM-1 K. pneumoniae strain (ATCC BAA-2146) being cultivated under different conditions. The samples were recovered from semisolid medium placed on the ground (D strain), in simulated space condition (M strain), or in Shenzhou 10 spacecraft (T strain) for analysis. Our data revealed multiple variations underlying pathogen adaptation into different environments in terms of changes in morphology, H2O2 tolerance and biofilm formation ability, genomic stability and regulation of metabolic pathways. Additionally, we found a few non-coding RNAs to be differentially regulated. The results are helpful for better understanding the adaptive mechanisms of drug-resistant bacterial pathogens.

The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.

Chronic low back pain has been observed to decrease movement coordination. However, it is unclear whether the existing alteration of inter-hemispheric synchrony of intrinsic activity in patients with chronic low back-related leg pain (cLBLP). The present study aims to investigate the alteration of homotopic connectivity and its clinical association with the cLBLP patients.

To investigate the functional connectivity (FC) and its variability in the primary somatosensory cortex (S1) of patients with low-back-related leg pain (LBLP) in the context of the persistent stimuli of pain and numbness.

The regulatory mechanisms enabling the intestinal epithelium to maintain a high degree of regenerative capacity during mucosal injury remain unclear. Ex vivo survival and clonogenicity of intestinal stem cells (ISCs) strictly required growth response mediated by cell division control 42 (Cdc42) and Cdc42-deficient enteroids to undergo rapid apoptosis. Mechanistically, Cdc42 engaging with EGFR was required for EGF-stimulated, receptor-mediated endocytosis and sufficient to promote MAPK signaling. Proteomics and kinase analysis revealed that a physiologically, but nonconventionally, spliced Cdc42 variant 2 (V2) exhibited stronger MAPK-activating capability. Human CDC42-V2 is transcriptionally elevated in some colon tumor tissues. Accordingly, mice engineered to overexpress Cdc42-V2 in intestinal epithelium showed elevated MAPK signaling, enhanced regeneration, and reduced mucosal damage in response to irradiation. Overproducing Cdc42-V2 specifically in mouse ISCs enhanced intestinal regeneration following injury. Thus, the intrinsic Cdc42-MAPK program is required for intestinal epithelial regeneration, and elevating this signaling cascade is capable of initiating protection from genotoxic injury.

Mycobacterium kansasii can cause serious pulmonary disease. It belongs to a group of closely-related species of non-tuberculous mycobacteria known as the M. kansasii complex (MKC). Here, we report a population genomics analysis of 358 MKC isolates from worldwide water and clinical sources. We find that recombination, likely mediated by distributive conjugative transfer, has contributed to speciation and on-going diversification of the MKC. Our analyses support municipal water as a main source of MKC infections. Furthermore, nearly 80% of the MKC infections are due to closely-related M. kansasii strains, forming a main cluster that apparently originated in the 1900s and subsequently expanded globally. Bioinformatic analyses indicate that several genes involved in metabolism (e.g., maintenance of the methylcitrate cycle), ESX-I secretion, metal ion homeostasis and cell surface remodelling may have contributed to M. kansasii's success and its ongoing adaptation to the human host.

Pyrazinamide still may be a useful drug for treatment of rifampin-resistant (RR-TB) or multidrug-resistant tuberculosis (MDR-TB) in China while awaiting scale up of new drugs and regimens including bedaquiline and linezolid. The level of pyrazinamide resistance among MDR-TB patients in China is not well established. Therefore, we assessed pyrazinamide resistance in a representative sample and explored determinants and patterns of pncA mutations.

Using Kendall's coefficient of concordance (KCC-) and Coherence (Cohe-) regional homogeneity (ReHo) to explore the alterations of brain local functional connectivity in acute and remitting relapsing-remitting multiple sclerosis (RRMS), and its clinical relevance.18 acute RRMS, 26 remitting RRMS and 20 healthy controls received resting-state functional magnetic resonance imaging scanning. After data preprocessing and ReHo (KCC-ReHo and Cohe-ReHo) calculation, analysis of variance and followed post hoc analysis was used to compare the KCC-ReHo or Cohe ReHo maps across groups.After analysis of variance analysis, regions with significant among-group differences detected by the 2 ReHo analysis were overlapped, these overlapped regions located in the left superior frontal gyrus (SFG), right SFG, left cuneus and right middle occipital gyrus (P < .01, Gaussian random field theory correction). Followed post hoc tests showed that, compared with healthy controls,Both acute and remitting RRMS patients has disease-related brain dysfunction, interestingly, relative to remitting RRMS, the acute RRMS patients mobilized more brain regions involving visual information processing in an attempt to maintain functional stability. In addition, our results also provide a methodological consideration for future ReHo analysis.

The growth and productivity of Casuarina equisetifolia is negatively impacted by planting sickness under long-term monoculture regimes. In this study, Illumina MiSeq sequencing targeting nifH genes was used to assess variations in the rhizospheric soil diazotrophic community under long-term monoculture rotations. Principal component analysis and unweighted pair-group method with arithmetic means (UPGMA) clustering demonstrated distinct differences in diazotrophic community structure between uncultivated soil (CK), the first rotation plantation (FCP), the second rotation plantation (SCP), and the third rotation plantation (TCP). Taxonomic analysis showed that the phyla Proteobacteria increased while Verrucomicrobia decreased under the consecutive monoculture (SCP and TCP). The relative abundance of Paraburkholderia, Rhodopseudomonas, Bradyrhizobium, Geobacter, Pseudodesulfovibrio, and Frankia increased significantly while Burkholderia, Rubrivivax, and Chlorobaculum declined significantly at the genus level under consecutive monoculture (SCP and TCP). Redundancy analysis (RDA) showed that Burkholderia, Rubrivivax, and Chlorobaculum were positively correlated with total nitrogen and available nitrogen. In conclusion, continuous C. equisetifolia monoculture could change the structure of diazotrophic microbes in the rhizosphere, resulting in the imbalance of the diazotrophic bacteria population, which might be a crucial factor related to replanting disease in this cultivated tree species.

Tuberculosis (TB) remains a severe public health problem globally, and it is essential to comprehend the transmission pattern to control tuberculosis. Herein, we evaluated the drug-resistant characteristics, recent transmission, and associated risk factors of TB in Golmud, Qinghai, China.

Monoclonal antibodies (mAbs) to CD137 (a.k.a. 4-1BB) have anti-tumor efficacy in several animal models and have entered clinical trials in patients with advanced cancer. Importantly, anti-CD137 mAbs can also ameliorate autoimmunity in preclinical models. As an approach to better understand the action of agonistic and antagonistic anti-CD137 mAbs we have mapped the binding region of the CD137 ligand (CD137L) to human and mouse CD137. By investigating the binding of CD137L to cysteine rich domain II (CRDII )and CRDIII of CD137, we found that the binding interface was limited and differed between the two species in that mouse CD137L mainly combined with CRDII and human CD137L mainly combined with CRDIII.

Whole-genome sequencing was used to analyze the profiles of isoniazid (INH) resistance-related mutations among 188 multidrug-resistant strains of Mycobacterium tuberculosis (MDR-TB) and mono-INH-resistant isolates collected in a recent Chinese national survey. Mutations were detected in 18 structural genes and two promoter regions in 96.8% of 188 resistant isolates. There were high mutation frequencies in katG, the inhA promoter, and ahpC-oxyR regulator regions in INH-resistant isolates with frequencies of 86.2%, 19.6%, and 18.6%, respectively. Moreover, a high diversity of mutations was identified as 102 mutants contained various types of single or combined gene mutations in the INH-resistant group of isolates. The cumulative frequencies of katG 315 or inhA-P/inhA mutations was 68.1% (128/188) for the INH-resistant isolates. Of these isolates, 46 isolates (24.5% of 188) exhibited a high level of resistance. A high level of resistance was also observed in 21 isolates (11.2% of 188) with single ahpC-oxyR mutations or a combination of ahpC-oxyR and katG non-315 mutations. The remaining 17 mutations occurred sporadically and emerged in isolates with combined katG mutations. Such development of INH resistance is likely due to an accumulation of mutations under the pressure of drug selection. Thus, these findings provided insights on the levels of INH resistance and its correlation with the combinatorial mutation effect resulting from less frequent genes (inhA and/or ahpC). Such knowledge of other genes (apart from katG) in high-level resistance will aid in developing better strategies for the diagnosis and management of TB.

Paneth cells are post-mitotic intestinal epithelial cells supporting the stem cell niche and mucosal immunity. Paneth cell pathologies are observed in various gastrointestinal diseases, but their plasticity and response to genomic and environmental challenges remain unclear. Using a knockin allele engineered at the mouse Lyz1 locus, we performed detailed Paneth cell-lineage tracing. Irradiation induced a subset of Paneth cells to proliferate and differentiate into villus epithelial cells. RNA sequencing (RNA-seq) revealed that Paneth cells sorted from irradiated mice acquired a stem cell-like transcriptome; when cultured in vitro, these individual Paneth cells formed organoids. Irradiation activated Notch signaling, and forced expression of Notch intracellular domain (NICD) in Paneth cells, but not Wnt/β-catenin pathway activation, induced their dedifferentiation. This study documents Paneth cell plasticity, particularly their ability to participate in epithelial replenishment following stem cell loss, adding to a growing body of knowledge detailing the molecular pathways controlling injury-induced regeneration.

Replanting disease caused by negative plant-soil feedback in continuous monoculture of Radix pseudostellariae is a critical factor restricting the development of this common and popular Chinese medicine, although wild R. pseudostellariae plants were shown to grow well without occurrence of disease in the same site for multiple years. Therefore, we aimed to identify the changes in microbial community composition in the rhizosphere soil of wild R. pseudostellariae thus providing a potential method for controlling soil-borne diseases. We analyzed differences in soil physicochemical properties, changes in soil microbial community structure, and root exudates of wild R. pseudostellariae under different biotopes. And then, simple sequence repeats amplification was used to isolate and collect significantly different formae speciales of Fusarium oxysporum. Finally, we analyzed the pathogenicity testing and influence of root exudates on the growth of F. oxysporum. We found that the different biotopes of R. pseudostellariae had significant effects on the soil microbial diversity. The soil fungal and bacterial abundances were significantly higher and the abundance of F. oxysporum was significantly lower under the rhizosphere environment of wild R. pseudostellariae than under consecutive monoculture. The relative abundances of most genera were Penicillium, Aspergillus, Fusarium, Nitrobacter, Nitrospira, Streptomyces, Actinoplanes, and Pseudomonas. Venn diagram and LEfSe analyses indicated numerously specific microbiome across all the samples, and the numbers of specific fungi were higher than the shared ones in the four biotopes. Eight types of phenolic acids were identified across all the rhizosphere soils. Mixed phenolic acids and most of the examined single phenolic acids had negative effects on the growth of isolated pathogenic F. oxysporum strains and promoted the growth of non-pathogenic strains. Similarly, correlation analysis suggested that most of the identified phenolic acids were positively associated with beneficial Pseudomonas, Nitrobacter, Nitrospira, Streptomyces, and Bacillus. This study suggested that wild R. pseudostellariae was able to resist or tolerate disease by increasing soil microbial diversity, and reducing the accumulation of soil-borne pathogens.

Paneth cells are the primary source of C-type lysozyme, a β-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1-/- hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti- and pro-inflammatory responses, with implications for IBD.

Viruses are the most abundant living entities in marine ecosystems, playing critical roles in altering the structure and function of microbial communities and driving ocean biogeochemistry. Phages that infect Roseobacter clade-affiliated (RCA) cluster strains are an important component of marine viral communities. Here, we characterize the genome sequences of two new RCA phages, CRP-9 and CRP-13, which infect RCA strain FZCC0023. Genomic analysis reveals that CRP-9 and CRP-13 represent a novel evolutionary lineage of marine phages. They both have a DNA replication module most similar to those in Cobavirus group phages. In contrast, their morphogenesis and packaging modules are distinct from those in cobaviruses but homologous to those in HMO-2011-type phages. The genomic architecture of CRP-9 and CRP-13 suggests a genomic recombination event between distinct phage groups. Metagenomic data sets were examined for metagenome-assembled viral genomes (MAVGs) with similar recombinant genome architectures. Fifteen CRP-9-type MAVGs were identified from marine viromes. Additionally, 158 MAVGs were identified containing HMO-2011-type morphogenesis and packaging modules with other types of DNA replication genes, providing more evidence that recombination between different phage groups is a major driver of phage evolution. Altogether, this study significantly expands the understanding of diversity and evolution of marine roseophages. Meanwhile, the analysis of these novel RCA phages and MAVGs highlights the critical role of recombination in shaping phage diversity. These phage sequences are valuable resources for inferring the evolutionary connection of distinct phage groups. IMPORTANCE Diversity and evolution of phages that infect the relatively slow-growing but dominant Roseobacter lineages are largely unknown. In this study, RCA phages CRP-9 and CRP-13 have been isolated on a Roseobacter RCA strain and shown to have a unique genomic architecture, which appears to be the result of a recombination event. CRP-9 and CRP-13 have a DNA replication module most similar to those in Cobavirus group phages and morphogenesis and packaging modules most similar to those in HMO-2011-type phages. HMO-2011-type morphogenesis and packaging modules are found in combination with distinct types of DNA replication genes, suggesting compatibility with various DNA replication modules. Altogether, this study contributes toward a better understanding of marine viral diversity and evolution.

The marine roseobacter-clade affiliated cluster (RCA) represents one of the most abundant groups of bacterioplankton in the global oceans, particularly in temperate and sub-polar regions. They play a key role in the biogeochemical cycling of various elements and are important players in oceanic climate-active trace gas metabolism. In contrast to copiotrophic roseobacter counterparts such as Ruegeria pomeroyi DSS-3 and Phaeobacter sp. MED193, RCA bacteria are truly pelagic and have smaller genomes. We have previously shown that RCA bacteria do not appear to encode the PlcP-mediated lipid remodeling pathway, whereby marine heterotrophic bacteria remodel their membrane lipid composition in response to phosphorus (P) stress by substituting membrane glycerophospholipids with alternative glycolipids or betaine lipids. In this study, we report lipidomic analysis of six RCA isolates. In addition to the commonly found glycerophospholipids such as phosphatidylglycerol (PG) and phosphatidylethanolamine (PE), RCA bacteria synthesize a relatively uncommon phospholipid, acylphosphatidylglycerol, which is not found in copiotrophic roseobacters. Instead, like the abundant SAR11 clade, RCA bacteria upregulate ornithine lipid biosynthesis in response to P stress, suggesting a key role of this aminolipid in the adaptation of marine heterotrophs to oceanic nutrient limitation.

To explore the drug susceptibility of levofloxacin (LFX), moxifloxacin (MFX), bedaquiline (BDQ), linezolid (LZD), clofazimine (CFZ) and delamanid (DLM) against multidrug resistant tuberculosis (MDR-TB) isolates from drug resistance survey of southwest China, and to illustrate the genetic characteristics of MDR-TB isolates with acquired drug resistance.