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Abstract Background While depression is increasing worldwide, some patients are diagnosed as having Major Depressive Disorder (MDD), but others are diagnosed with minor depression, however, the potential neuro mechanism is unknown. Methods Sixty-two patients with minor depression, 44 adolescents with MDD and 54 healthy adolescents participated in this study. Functional near-infrared spectroscopy (fNIRS), both HAMD and HAMA data were collected from all of the participants. Results The result indicates the pervasively decreased activation of BA, 11, 21, 45 and 46 were observed in the MDD group and reduced activation of BA 45 was observed in the minor depression group. However, cortical activation was not observed between the minor depression or MDD groups. Cortical activation was also not correlated with the depressive/anxious score in the minor and MDD groups separately. Conclusions Cortical activation was pervasively decreased in the MDD group and slightly reduced in the minor depression group, which may be a potential neural mechanism. As reduced cortical activation in minor depression, interventions in the early stages of minor depression may help slow or even modify the development of the illness.

Abstract Background The positive effects of exposing corals to microorganisms have been reported though how the benefits are conferred are poorly understood. Here, we isolated an actinobacterial strain (SCSIO 13291) from Pocillopora damicornis with capabilities to synthesize antioxidants, vitamins, and antibacterial and antiviral compounds supported with phenotypic and/or genomic evidence. Strain SCSIO 13291 was labeled with 5 (and − 6)-carboxytetramethylrhodamine, succinimidyl ester and the labeled cell suspension directly inoculated onto the coral polyp tissues when nubbins were under thermal stress in a mesocosm experiment. We then visualized the labelled bacterial cells and analyzed the coral physiological, transcriptome and microbiome to elucidate the effect this strain conferred on the coral holobiont under thermal stress. Results Subsequent microscopic observations confirmed the presence of the bacterium attached to the coral polyps. Addition of the SCSIO 13291 strain reduced signs of bleaching in the corals subjected to heat stress. At the same time, alterations in gene expression, which were involved in reactive oxygen species and light damage mitigation, attenuated apoptosis and exocytosis in addition to metabolite utilization, were observed in the coral host and Symbiodiniaceae populations. In addition, the coral associated bacterial community altered with a more stable ecological network for samples inoculated with the bacterial strain. Conclusions Our results provide insights into the benefits of a putative actinobacterial probiotic strain that mitigate coral bleaching signs. This study suggests that the inoculation of bacteria can potentially directly benefit the coral holobiont through conferring metabolic activities or through indirect mechanisms of suppling additional nutrient sources.

Abstract Mesenchymal stem cells (MSCs) are widely used in cell therapy, tissue engineering, and regenerative medicine because of their self-renewal, pluripotency, and immunomodulatory properties. The microenvironment in which MSCs are located significantly affects their physiological functions. The microenvironment directly or indirectly affects cell behavior through biophysical, biochemical, or other means. Among them, the mechanical signals provided to MSCs by the microenvironment have a particularly pronounced effect on their physiological functions and can affect osteogenic differentiation, chondrogenic differentiation, and senescence in MSCs. Mechanosensitive ion channels such as Piezo1 and Piezo2 are important in transducing mechanical signals, and these channels are widely distributed in sites such as skin, bladder, kidney, lung, sensory neurons, and dorsal root ganglia. Although there have been numerous studies on Piezo channels in MSCs in recent years, the function of Piezo channels in MSCs is still not well understood, and there has been no summary of their relationship to illustrate which physiological functions of MSCs are affected by Piezo channels and the possible underlying mechanisms. Therefore, based on the members, structures, and functions of Piezo ion channels and the fundamental information of MSCs, this paper focused on summarizing the advances in Piezo channels in MSCs from various tissue sources to provide new ideas for future research and practical applications of Piezo channels and MSCs.

Abstract Background Peripheral atherosclerosis is a common macrovascular complication of diabetes, but the treatment is limited. Chinese herbal medicine is the complementary and alternative therapy to delay the progression of atherosclerosis and reduce blood glucose and lipids. Shen-Qi Xiao-Tan (SQXT) formula is one of the prescriptions commonly used to treat diabetic peripheral atherosclerosis, but there is still a lack of high-quality evidence-based evidence. Methods This is a randomized, double-blind, placebo-controlled add-on trial that is expected to enroll 114 diabetic patients with peripheral atherosclerosis. After a 2-week run-in period, participants will been randomly assigned in a 1:1 ratio and receive 12 weeks of usual treatment and SQXT formula (treatment group) or usual treatment and placebo (control group). The primary outcome is the change in carotid intima-media thickness from baseline to endpoint. The secondary outcomes are the structure and function of peripheral arteries, blood glucose and lipids, traditional Chinese medicine syndrome score, and quality of life, and safety and endpoint events are evaluated. To explore the therapeutic mechanism through oxidative stress, inflammation, and advanced glycation end products, and lipidomics will be used to screen for biomarkers for diagnosis and efficacy evaluation. Discussion The objective of this trial is to evaluate the efficacy, safety and therapeutic mechanism of SQXT formula in the treatment of diabetic peripheral atherosclerosis. It will obtain high-quality evidence-based evidence and promote the treatment of diabetic macroangiopathy and the research and development of new drugs. Trial registration This trial is registered on Chinese Clinical Trials.gov with number ChiCTR2100047189 on 10 Jun 2021, and has been approved by the Ethical Review Committee of Hospital of Chengdu University of Traditional Chinese Medicine with number 2020KL-080.

Abstract Background Although the genetic spectrum of human colorectal cancer (CRC) is mainly characterized by APC, KRAS and TP53 mutations, driver genes in tumor initiation have not been conclusively demonstrated. In this study, we aimed to identify novel markers for CRC. Methods We performed exome analysis of sporadic colorectal cancer (sCRC) coding regions to screen loss of function (LoF) mutation genes, and carried out systems-level approaches to confirm top rank gene in this study. Results We identified loss of BMP5 is an early event in CRC. Deep sequencing identified BMP5 was mutated in 7.7% (8/104) of sCRC samples, with 37.5% truncating mutation frequency. Notably, BMP5 negative expression and its prognostic value is uniquely significant in sCRC but not in other tumor types. Furthermore, BMP5 expression was positively correlated with E-cadherin in CRC patients and its dysregulation play a vital role in epithelial-mesenchymal transition (EMT), thus triggering tumor initiation and development. RNA sequencing identified, independent of BMP/Smads pathway, BMP5 signaled though Jak-Stat pathways to inhibit the activation of oncogene EPSTI1. Conclusions Our result support a novel concept that the importance of BMP5 in sCRC. The tumor suppressor role of BMP5 highlights its crucial role in CRC initiation and development.

Abstract Background Estimates of survival in the older can be of benefit in various facets, particularly in medical and individual decision-making. We aim to validate the value of a combination of nutrition status evaluation and comorbidity assessment in predicting long-term survival among community-dwelling older. Methods The Charlson Comorbidity Index (CCI) was applied for comprehensive evaluation of comorbidities. Participants were classified into CCI score ≤ 2 and ≥ 3 subgroups. Nutritional status was assessed by using Mini Nutritional Assessment-Short Form (MNA-SF) and Geriatric Nutritional Risk Index (GNRI) evaluations. Mortality rates and survival curves over a 5-year period were compared among subgroups classified by CCI and/or MNA-SF/GNRI evaluations. Results A total of 1033 elderly male participants were enrolled in this study, with an average age of 79.44 ± 8.61 years. 108 deceased participants (10.5%) were identified during a follow-up of 5 years. Cox proportional hazards regression analysis showed that age, CCI, MNA-SF and GNRI were independent predictors of 5-year all-cause death in this cohort. Compared to those with normal nutrition status and CCI ≤ 2, the subgroup at risk of malnutrition and CCI ≥ 3 had a significantly higher 5-year all-cause mortality rate (HR = 4.671; 95% CI:2.613–8.351 for MNA-SF and HR = 7.268; 95% CI:3.401–15.530 for GNRI; P

Abstract Background Envelope stress responses (ESRs) are critical for adaptive resistance of Gram-negative bacteria to envelope-targeting antimicrobial agents. However, ESRs are poorly defined in a large number of well-known plant and human pathogens. Dickeya oryzae can withstand a high level of self-produced envelope-targeting antimicrobial agents zeamines through a zeamine-stimulated RND efflux pump DesABC. Here, we unraveled the mechanism of D. oryzae response to zeamines and determined the distribution and function of this novel ESR in a variety of important plant and human pathogens. Results In this study, we documented that a two-component system regulator DzrR of D. oryzae EC1 mediates ESR in the presence of envelope-targeting antimicrobial agents. DzrR was found modulating bacterial response and resistance to zeamines through inducing the expression of RND efflux pump DesABC, which is likely independent on DzrR phosphorylation. In addition, DzrR could also mediate bacterial responses to structurally divergent envelope-targeting antimicrobial agents, including chlorhexidine and chlorpromazine. Significantly, the DzrR-mediated response was independent on the five canonical ESRs. We further presented evidence that the DzrR-mediated response is conserved in the bacterial species of Dickeya, Ralstonia, and Burkholderia, showing that a distantly located DzrR homolog is the previously undetermined regulator of RND-8 efflux pump for chlorhexidine resistance in B. cenocepacia. Conclusions Taken together, the findings from this study depict a new widely distributed Gram-negative ESR mechanism and present a valid target and useful clues to combat antimicrobial resistance.

Abstract Background Although the extreme environmental adaptation of organisms is a hot topic in evolutionary biology, genetic adaptation to high-altitude environment remains poorly characterized in ectothermic animals. Squamates are among the most diverse terrestrial vertebrates, with tremendous ecological plasticity and karyotype diversity, and are a unique model system to investigate the genetic footprints of adaptation. Results We report the first chromosome-level assembly of the Mongolian racerunner (Eremias argus) and our comparative genomics analyses found that multiple chromosome fissions/fusions events are unique to lizards. We further sequenced the genomes of 61 Mongolian racerunner individuals that were collected from altitudes ranging from ~ 80 to ~ 2600 m above sea level (m.a.s.l.). Population genomic analyses revealed many novel genomic regions under strong selective sweeps in populations endemic to high altitudes. Genes embedded in those genomic regions are mainly associated with energy metabolism and DNA damage repair pathways. Moreover, we identified and validated two substitutions of PHF14 that may enhance the lizards’ tolerance to hypoxia at high altitudes. Conclusions Our study reveals the molecular mechanism of high-altitude adaptation in ectothermic animal using lizard as a research subject and provides a high-quality lizard genomic resource for future research.

Abstract The colonization of bacterial pathogens is a major concern in wound infection and becoming a public health issue. Herein, a core–shell structured Ag@MSN (silver core embedded with mesoporous silica, AM)-based nanoplatform was elaborately fabricated to co-load ciprofloxacin (CFL) and tumor necrosis factor-α (TNF-α) small interfering RNA (siTNF-α) (AMPC@siTNF-α) for treating the bacterial-infected wound. The growth of bacterial pathogens was mostly inhibited by released silver ions (Ag+) and CFL from AMPC@siTNF-α. Meanwhile, the loaded siTNF-α was internalized by macrophage cells, which silenced the expression of TNF-α (a pro-inflammatory cytokine) in macrophage cells and accelerated the wound healing process by reducing inflammation response. In the in vivo wound model, the Escherichia coli (E. coli)-infected wound in mice almost completely disappeared after treatment with AMPC@siTNF-α, and no suppuration symptom was observed during the course of the treatment. Importantly, this nanoplatform had negligible side effects both in vitro and in vivo. Taken together, this study strongly demonstrates the promising potential of AMPC@siTNF-α as a synergistic therapeutic agent for clinical wound infections. Graphical Abstract

Abstract Cancer is a leading public health problem worldwide. Its treatment remains a daunting challenge, although significant progress has been made in existing treatments in recent years. A large concern is the poor therapeutic effect due to lack of specificity and low bioavailability. Gene therapy has recently emerged as a powerful tool for cancer therapy. However, delivery methods limit its therapeutic effects. Exosomes, a subset of extracellular vesicles secreted by most cells, have the characteristics of good biocompatibility, low toxicity and immunogenicity, and great designability. In the past decades, as therapeutic carriers and diagnostic markers, they have caught extensive attention. This review introduced the characteristics of exosomes, and focused on their applications as delivery carriers in DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNA (siRNA), circular RNA (circRNA) and other nucleic acids. Meanwhile, their application in cancer therapy and exosome-based clinical trials were presented and discussed. Through systematic summarization and analysis, the recent advances and current challenges of exosome-mediated nucleic acid delivery for cancer therapy are introduced, which will provide a theoretical basis for the development of nucleic acid drugs. Graphical Abstract

Abstract Background As one of the largest transcription factor families in plants, the APETALA2/Ethylene-Responsive Factor (AP2/ERF) superfamily is involved in various biological processes and plays significant roles in plant growth, development and responses to various stresses. Although identification and characterization of AP2/ERF superfamily genes have been accomplished in many plant species, very little is known regarding the structure and function of AP2/ERF genes in maize. Results In this study, a total of 214 genes encoding ZmAP2/ERF proteins with complete AP2/ERF domain were eventually identified according to the AGPv4 version of the maize B73 genome. Based on the number of AP2/ERF domain and similarities of amino acid sequences among AP2/ERF proteins from Arabidopsis, rice and maize, all 214 putative ZmAP2/ERF proteins were categorized into three distinct families, including the AP2 family (44), the ERF family (166) and the RAV family (4), respectively. Among them, the ERF family was further subdivided into two diverse subfamilies, including the DREB and ERF subfamilies with 61 and 105 members, respectively. Further, based on phylogenetic analysis, the members of DREB and ERF subfamilies were subdivided into four (Group I-IV) and eight (Group V-XII) groups, respectively. The characteristics of exon-intron structure of these putative ZmAP2/ERF genes and conserved protein motifs of their encoded ZmAP2/ERF proteins were also presented respectively, which was in accordance with the results of group classification. Promoter analysis suggested that ZmAP2/ERF genes shared many stress- and hormone-related cis-regulatory elements. Gene duplication and synteny analysis revealed that tandem or segmental duplication and purifying selection might play significant roles in evolution and functional differentiation of AP2/ERF superfamily genes among three various gramineous species (maize, rice and sorghum). Using RNA-seq data, transcriptome analysis indicated that the majority of ZmAP2/ERF genes displayed differential expression patterns at different developmental stages of maize. In addition, the following analyses of co-expression network among ZmAP2/ERF genes and protein protein interaction between ZmAP2 and ZmERF proteins further enabled us to understand the regulatory relationship among members of the AP2/ERF superfamily in maize. Furthermore, by quantitative real-time PCR analysis, twenty-seven selected ZmAP2/ERF genes were further confirmed to respond to three different abiotic stresses, suggesting their potential roles in various abiotic stress responses. Collectively, these results revealed that these ZmAP2/ERF genes play essential roles in abiotic stress tolerance. Conclusions Taken together, the present study will serve to present an important theoretical basis for further exploring the function and regulatory mechanism of ZmAP2/ERF genes in the growth, development, and adaptation to abiotic stresses in maize.

Abstract Background Distance metastasis is the leading cause of death for breast cancer patients, and circulating tumor cells (CTCs) play a key role in cancer metastasis. There have been few studies on CTCs at the molecular level due to their rarity, and the heterogeneity of CTCs may provide special information for solid tumor analysis. Methods In this study, we used the gene expression and clinical information of single-cell RNA-seq data of CTCs of breast cancer and discovered a cluster of epithelial cells that had more aggressive characteristics. The differentially expressed genes (DEGs) between the identified epithelial cells cluster and others from single-CTCs were selected for further analysis in bulk sequence data of solid breast cancers. Results Eighteen genes closely related to the specific CTC epithelial phenotype and breast cancer patient prognosis were identified. Among these 18 genes, we selected the GARS gene, which has not been studied in breast cancer, for functional research and confirmed that it may be a potential oncogene in breast cancer. A risk score was established by the 18 genes, and a high-risk score was strongly associated with a high metastasis rate and poor survival prognosis in breast cancer. The high-risk score group was related to a defective immune infiltration environment in breast cancer, and the immune checkpoint therapy response rate was lower in this group. The drug-sensitive analysis shows that the high-risk score patients may be more sensitive to AKT-mTOR and the cyclin-dependent kinase (CDK) pathways drugs than low-risk score patients. Conclusions Our 18-gene risk score shows good prognostic and predictive values and might be a personalized prognostic marker or therapy guide marker in breast cancer patients.

Abstract Background The rapid identification of pathogenic bacteria is important for determining an appropriate antimicrobial therapy for pneumonia, but traditional bacterial culture is time-consuming and labourious. The aim of this study was to develop and evaluate a DNA microarray assay for the simultaneous detection of fifteen bacterial species directly from respiratory tract specimens in patients with pneumonia. These species included Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Mycoplasma pneumoniae, Enterococcus faecalis, Enterococcus faecium, Enterobacter cloacae, Stenotrophomonas maltophilia, Burkholderia cepacia, Legionella pneumophila and Chlamydia pneumoniae. The 16S rDNA genes and other specific genes of each pathogen were chosen as the amplification targets, amplified via multiplex polymerase chain reaction (PCR), and hybridized to oligonucleotide probes in a microarray. Results The DNA microarray detection limit was 103 copies/μL. Nineteen standard strains and 119 clinical isolates were correctly detected with our microarray, and 3 nontarget species from 4 clinical isolates were not detected. Additionally, bacterial pathogens were accurately identified when two or three bacterial targets were mixed together. Furthermore, the results for 99.4% (156/157) of clinical specimens were the same as those from a conventional assay. Conclusions We developed a DNA microarray that could simultaneously detect various bacterial pathogens in pneumonia. The method described here has the potential to provide considerable labour and time savings due to its ability to screen for 15 bacterial pathogens simultaneously.