Phase separation provides a mechanism to drive phenotype switching.

Phenotypic switching plays a crucial role in cell fate determination across various organisms. Recent experimental findings highlight the significance of protein compartmentalization via liquid-liquid phase separation in influencing such decisions. However, the precise mechanism through which phase separation regulates phenotypic switching remains elusive. To investigate this, we established a mathematical model that couples a phase separation process and a gene expression process with feedback. We used the chemical master equation theory and mean-field approximation to study the effects of phase separation on the gene expression products. We found that phase separation can cause bistability and bimodality. Furthermore, phase separation can control the bistable properties of the system, such as bifurcation points and bistable ranges. On the other hand, in stochastic dynamics, the droplet phase exhibits double peaks within a more extensive phase separation threshold range than the dilute phase, indicating the pivotal role of the droplet phase in cell fate decisions. These findings propose an alternative mechanism that influences cell fate decisions through the phase separation process. As phase separation is increasingly discovered in gene regulatory networks, related modeling research can help build biomolecular systems with desired properties and offer insights into explaining cell fate decisions.

Glycoprotein non-metastatic melanoma protein B (GPNMB): An attractive target in atherosclerosis.

Atherosclerosis (AS), the leading cause of cardiovascular diseases, is heavily influenced by inflammation, lipid accumulation, autophagy, and aging. The expression of glycoprotein non-metastatic melanoma B (GPNMB) has been observed to correlate with lipid content, inflammation, and aging, progressively increasing as atherosclerosis advances through its various stages, from baseline to early and advanced phases. However, the interaction between GPNMB and AS is controversial. Knockout of GPNMB has been shown to increase atherosclerotic plaque burden in mice. Conversely, targeted elimination of GPNMB-positive cells reduced atherosclerotic burden. These seemingly contradictory findings underscore the complexity of the issue and highlight the need for further research to reconcile these discrepancies and to elucidate the precise role of GPNMB in the pathogenesis of AS.

Exogenous Nucleotides Improve the Skin Aging of SAMP8 Mice by Modulating Autophagy through MAPKs and AMPK Pathways.

The skin, serving as the body's primary defense against external elements, plays a crucial role in protecting the body from infections and injuries, as well as maintaining overall homeostasis. Skin aging, a common manifestation of the aging process, involves the gradual deterioration of its normal structure and repair mechanisms. Addressing the issue of skin aging is increasingly imperative. Multiple pieces of evidence indicate the potential anti-aging effects of exogenous nucleotides (NTs) through their ability to inhibit oxidative stress and inflammation. This study aims to investigate whether exogenous NTs can slow down skin aging and elucidate the underlying mechanisms. To achieve this objective, senescence-accelerated mouse prone-8 (SAMP8) mice were utilized and randomly allocated into Aging, NTs-low, NTs-middle, and NTs-high groups, while senescence-accelerated mouse resistant 1 (SAMR1) mice were employed as the control group. After 9 months of NT intervention, dorsal skin samples were collected to analyze the pathology and assess the presence and expression of substances related to the aging process. The findings indicated that a high-dose NT treatment led to a significant increase in the thickness of the epithelium and dermal layers, as well as Hyp content (p < 0.05). Additionally, it was observed that low-dose NT intervention resulted in improved aging, as evidenced by a significant decrease in p16 expression (p < 0.05). Importantly, the administration of high doses of NTs could improve, in some ways, mitochondrial function, which is known to reduce oxidative stress and promote ATP and NAD+ production significantly. These observed effects may be linked to NT-induced autophagy, as evidenced by the decreased expression of p62 and increased expression of LC3BI/II in the intervention groups. Furthermore, NTs were found to upregulate pAMPK and PGC-1α expression while inhibiting the phosphorylation of p38MAPK, JNK, and ERK, suggesting that autophagy may be regulated through the AMPK and MAPK pathways. Therefore, the potential induction of autophagy by NTs may offer benefits in addressing skin aging through the activation of the AMPK pathway and the inhibition of the MAPK pathway.

The deubiquitinase cofactor UAF1 interacts with USP1 and plays an essential role in spermiogenesis.

Spermiogenesis defines the final phase of male germ cell differentiation. While multiple deubiquitinating enzymes have been linked to spermiogenesis, the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis. We selectively deleted Uaf1 in premeiotic germ cells using the Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. Further, UAF1 interacts and colocalizes with USP1 in the testes. Conditional knockout of Uaf1 in testes results in disturbed protein levels and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. Using tandem mass tag-based proteomics, we identified that conditional knockout of Uaf1 in the testes results in reduced levels of proteins that are essential for spermiogenesis. Thus, we conclude that the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.

Transcriptome-Wide Identification and Integrated Analysis of a UGT Gene Involved in Ginsenoside Ro Biosynthesis in Panax ginseng.

Panax ginseng as a traditional medicinal plant with a long history of medicinal use. Ginsenoside Ro is the only oleanane-type ginsenoside in ginseng, and has various pharmacological activities, including anti-inflammatory, detoxification, and antithrombotic activities. UDP-dependent glycosyltransferase (UGT) plays a key role in the synthesis of ginsenoside, and the excavation of UGT genes involved in the biosynthesis of ginsenoside Ro has great significance in enriching ginsenoside genetic resources and further revealing the synthesis mechanism of ginsenoside. In this work, ginsenoside-Ro-synthesis-related genes were mined using the P. ginseng reference-free transcriptome database. Fourteen hub transcripts were identified by differential expression analysis and weighted gene co-expression network analysis. Phylogenetic and synteny block analyses of PgUGAT252645, a UGT transcript among the hub transcripts, showed that PgUGAT252645 belonged to the UGT73 subfamily and was relatively conserved in ginseng plants. Functional analysis showed that PgUGAT252645 encodes a glucuronosyltransferase that catalyzes the glucuronide modification of the C3 position of oleanolic acid using uridine diphosphate glucuronide as the substrate. Furthermore, the mutation at 622 bp of its open reading frame resulted in amino acid substitutions that may significantly affect the catalytic activity of the enzyme, and, as a consequence, affect the biosynthesis of ginsenoside Ro. Results of the in vitro enzyme activity assay of the heterologous expression product in E. coli of PgUGAT252645 verified the above analyses. The function of PgUGAT252645 was further verified by the result that its overexpression in ginseng adventitious roots significantly increased the content of ginsenoside Ro. The present work identified a new UGT gene involved in the biosynthesis of ginsenoside Ro, which not only enriches the functional genes in the ginsenoside synthesis pathway, but also provides the technical basis and theoretical basis for the in-depth excavation of ginsenoside-synthesis-related genes.

Evaluation of flavor substances of rice bran kvass based on electronic nose and gas chromatography-mass spectrometry.

In this paper, the electronic nose (E-nose) and headspace-solid phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS) were used to analyze the volatiles of rice bran kvass (RBK) with the reference of Qiulin kvass (QLK). Meanwhile, the flavor amino acids of RBK before and after fermentation were determined. The results showed that the kinds of kvass remained consistent in terms of the overall category of volatiles while there were differences in content between them (p < 0.05). A total of 35 volatile compounds, mainly including esters, alcohols, phenols, aldehydes, and acids, were identified by GC-MS in the two kinds of kvass. In addition, the total essential amino acid content and the total sweet amino acid content of RBK increased significantly (p < 0.05) after fermentation. RBK contains both the main flavor of kvass and its own unique characteristics, making it a new member of the Kvass family.

Trimethylamine N-oxide promotes oxidative stress and lipid accumulation in macrophage foam cells via the Nrf2/ABCA1 pathway

Recently, trimethylamine N-oxide (TMAO) has been considered a risk factor for cardiovascular disease and has a proatherogenic effect. Many studies have found that TMAO is involved in plaque oxidative stress and lipid metabolism, but the specific mechanism is still unclear. In our study, meta-analysis and bioinformatic analysis were firstly conducted in the database, and found that the effect of high plasma TMAO levels on promoting atherosclerotic plaque may be related to the expression of key antioxidant genes nuclear factor erytheroid-derived-2-like 2 (NFE2L2/Nrf2) decreased. Next, we assessed the role of Nrf2-mediated signaling pathway in TMAO-treated foam cells. Our results showed that TMAO can inhibit the expression of Nrf2 and its downstream antioxidant response element such as heme oxygenase-1 (HO-1) and glutathione peroxidase4 (GPX4), resulting in increased production of reactive oxygen species and decreased activity of superoxide dismutase, promoting oxidative stress. And TMAO can also promote lipid accumulation in foam cells by inhibiting cholesterol efflux protein expression. In addition, upregulation of Nrf2 expression partially rescues TMAO-induced oxidative stress and reduces ATP-binding cassette A1 (ABCA1)–mediated lipid accumulation. Therefore, TMAO promotes oxidative stress and lipid accumulation in macrophage foam cells through the Nrf2/ABCA1 pathway, which may provide a potential mechanism for the proatherogenic effect of TMAO. (AU)

Trimethylamine N-oxide promotes oxidative stress and lipid accumulation in macrophage foam cells via the Nrf2/ABCA1 pathway

Recently, trimethylamine N-oxide (TMAO) has been considered a risk factor for cardiovascular disease and has a proatherogenic effect. Many studies have found that TMAO is involved in plaque oxidative stress and lipid metabolism, but the specific mechanism is still unclear. In our study, meta-analysis and bioinformatic analysis were firstly conducted in the database, and found that the effect of high plasma TMAO levels on promoting atherosclerotic plaque may be related to the expression of key antioxidant genes nuclear factor erytheroid-derived-2-like 2 (NFE2L2/Nrf2) decreased. Next, we assessed the role of Nrf2-mediated signaling pathway in TMAO-treated foam cells. Our results showed that TMAO can inhibit the expression of Nrf2 and its downstream antioxidant response element such as heme oxygenase-1 (HO-1) and glutathione peroxidase4 (GPX4), resulting in increased production of reactive oxygen species and decreased activity of superoxide dismutase, promoting oxidative stress. And TMAO can also promote lipid accumulation in foam cells by inhibiting cholesterol efflux protein expression. In addition, upregulation of Nrf2 expression partially rescues TMAO-induced oxidative stress and reduces ATP-binding cassette A1 (ABCA1)–mediated lipid accumulation. Therefore, TMAO promotes oxidative stress and lipid accumulation in macrophage foam cells through the Nrf2/ABCA1 pathway, which may provide a potential mechanism for the proatherogenic effect of TMAO. (AU)

Atomistically informed hierarchical modeling for revisiting the constituent structures from heredity and nano-micro mechanics of sheath-core carbon fiber.

To better understand the heterogeneous anisotropic nanocomposite features and provide reliable underlying constitutive parameters of carbon fiber for continuum-level simulations, hierarchical modeling approaches combining quantum chemistry, molecular dynamics, numerical and analytical micromechanics are employed for studying the structure-performance relationships of the precursor-inherited sheath-core carbon fiber layers. A robust debonding force field is derived from energy matching protocols, including bond dissociation enthalpy calculations and rigid-constraint potential energy surface scan. Logistic long range bond stretching curves with exponential parameters and shifted force vdW curves are designed to diminish energy perturbations. The pseudo-crystalline microstructure is proposed and validated using virtual wide angle X-ray diffraction patterns and bond-orientational order parameters. The distribution or alignment features of the nanocomposite microstructures are collected from quantum chemical topology analysis and normal vector extractions. Non-equilibrium tensile loading simulation predicts the decomposed strain energy contributions, principal-axis modulus, strength limit, localized stress, and fracture morphologies of the model. Finally, an atomistically-informed stiffness prediction model combining numerical homogenization and analytical self-consistent Eshelby-Mori-Tanaka-type effective mean field micromechanics theory is proposed, giving a successful estimation of the overall stiffness matrix of the sheath-core carbon fiber system. The hierarchical models in combination with the carbonization reaction template will help in providing efficient and feasible schemes for the synergistic process-performance control of distinct types of carbon fiber.

Trimethylamine N-oxide promotes oxidative stress and lipid accumulation in macrophage foam cells via the Nrf2/ABCA1 pathway.

Recently, trimethylamine N-oxide (TMAO) has been considered a risk factor for cardiovascular disease and has a proatherogenic effect. Many studies have found that TMAO is involved in plaque oxidative stress and lipid metabolism, but the specific mechanism is still unclear. In our study, meta-analysis and bioinformatic analysis were firstly conducted in the database, and found that the effect of high plasma TMAO levels on promoting atherosclerotic plaque may be related to the expression of key antioxidant genes nuclear factor erytheroid-derived-2-like 2 (NFE2L2/Nrf2) decreased. Next, we assessed the role of Nrf2-mediated signaling pathway in TMAO-treated foam cells. Our results showed that TMAO can inhibit the expression of Nrf2 and its downstream antioxidant response element such as heme oxygenase-1 (HO-1) and glutathione peroxidase4 (GPX4), resulting in increased production of reactive oxygen species and decreased activity of superoxide dismutase, promoting oxidative stress. And TMAO can also promote lipid accumulation in foam cells by inhibiting cholesterol efflux protein expression. In addition, upregulation of Nrf2 expression partially rescues TMAO-induced oxidative stress and reduces ATP-binding cassette A1 (ABCA1)-mediated lipid accumulation. Therefore, TMAO promotes oxidative stress and lipid accumulation in macrophage foam cells through the Nrf2/ABCA1 pathway, which may provide a potential mechanism for the proatherogenic effect of TMAO.

Exogenous Nucleotides Ameliorate Age-Related Decline in Testosterone in Male Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice by Modulating the Local Renin-Angiotensin System Antioxidant Pathway.

In older men, an age-related decline in testosterone is closely associated with various adverse health outcomes. With the progression of aging, hyperactivation of the local renin-angiotensin system (RAS) and oxidative stress increase in the testis. The regulation of RAS antioxidants may be a target to delay testicular aging and maintain testosterone levels. Exogenous nucleotides (NTs) have anti-aging potential in several systems, but there are no studies of their effects on the reproductive system. In our study, we examined the effects of exogenous NTs on testosterone synthesis and explored possible mechanisms of action. Therefore, senescence-accelerated mouse prone-8 (SAMP8) mice and senescence-accelerated mouse resistant 1 (SAMR1) were used in the experiment, and they were randomly divided into an NTs free group (NTs-F), a normal control group (control), a low-dose NTs group (NTs-L), a middle-dose NTs (NTs-M), a high-dose NTs group (NTs-H) and SAMR1 groups, and the testis of the mice were collected for testing after 9 months of intervention. The results showed that exogenous NTs could increase the testicular organ index in mice during aging, and delayed the age-associated decline in testosterone levels in SAMP8 male mice, possibly by modulating the local RAS antioxidant pathway and reducing oxidative stress to protect the testis. The present study provides new research clues for the development of preventive and therapeutic strategies for related diseases.

Enhanced chemoimmunotherapy of breast cancer in mice by apolipoprotein A1-modified doxorubicin liposomes combined with interleukin-21.

Backgroud: Breast cancer is a prevalent malignancy among women, with triple-negative breast cancer (TNBC) comprising approximately 15-20% of all cases, possessing high invasiveness, drug resistance and poor prognosis. Chemotherapy, the main treatment for TNBC, is limited by toxicity and drug resistance. Apolipoprotein A1 modified doxorubicin liposome (ApoA1-lip/Dox) was constructed in our previous study, with promising anti-tumour effect and improved safety been proved. However, during long-term administration, the problem of cumulative toxicity and insufficient tumour inhibition is still inevitable. Interleukin-21 is a small molecule protein secreted by T cells with various immune regulatory functions. IL-21 has significantly curative effects in numerous solid tumours, but it has the disadvantages of low response rate and short half-life. The combination of chemotherapy and immunotherapy has received increasing attention.Purpose: In this study, ApoA1 drug loading system and long-acting IL-21 are innovatively combined for tumour treatment.Methods: We combined ApoA1-lip/Dox and IL-21 for treatment and evaluated their impact on tumor-infiltrating lymphocytes and CD8+ T and NK cell cytotoxicity.Results: Combined administration significantly improved the tumour-infiltrating lymphocytes and enhanced the cytotoxicity of CD8+ T and NK cells. The combination of ApoA1-lip/Dox and IL-21 exhibits significantly enhanced anti-tumour efficacy with lower toxicity of ApoA1-lip/Dox, providing a new strategy for TNBC treatment with enhanced anti-tumour response and reduced toxicity.

Exogenous Nucleotides Ameliorate Ageing-Related Intestinal Inflammation in Senescence-Accelerated Mouse Prone-8 (SAMP8) Mice.

As one of the most important barriers in the body, the intestinal barrier is a key factor in maintaining human health. Ageing of the intestine is a degenerative process that is closely associated with a variety of poor health conditions in the elderly. Inflammation and the immune system are anti-ageing targets that can regulate the function of the intestine. Nucleotides (NTs) are involved in important physiological and biochemical reactions in the body, but there are few studies about their effect on the ageing intestine. This paper examines the role of exogenous NTs in the ageing intestine. For this purpose, we used senescence-accelerated mouse prone-8 (SAMP8) mice and senescence-accelerated mouse resistant 1 (SAMR1) mice for the experiment, and randomly divided the mice into NTs-free, Normal Control, NTs-low, NTs-medium, NTs-high, and SAMR1 groups. After 9 months of intervention, we collected the colon tissue of mice for testing. In our study, exogenous NTs could increase bodyweight of mice during ageing and improve the morphological structure of the intestine, and we found that NTs could promote the secretion of intestinal protective factors, such as TFF3 and TE. Furthermore, supplementation with NTs suppressed intestinal inflammation and improved intestinal immunity, possibly by activating the p38 signaling pathway. These results suggest that exogenous NTs are able to maintain the health condition of the ageing intestine.

Integrin ß6 mediates epithelial-mesenchymal transition in diabetic kidney disease.

The progression of diabetic kidney disease (DKD) is associated with increased fibronectin (FN) levels in proximal tubular epithelial cells. Bioinformatics analysis showed that integrin ß6 and cell adhesion function were significantly changed in the cortices of db/db mice. Remodelling of cell adhesion is one of the core changes during epithelial-mesenchymal transition (EMT) in DKD. Integrin is a family of transmembrane proteins that regulates cell adhesion and migration, and extracellular FN is the major ligand of integrin ß6. We found that the expression of integrin ß6 was elevated in the proximal tubules of db/db mice and FN-induced renal proximal tubule cells. The levels of EMT were also significantly increased in vivo and in vitro. In addition, FN treatment activated the Fak/Src pathway, increased the expression of p-YAP, and then upregulated the Notch1 pathway in diabetic proximal tubules. Knockdown of integrin ß6 or Notch1 reduced the EMT aggravation induced by FN. Furthermore, urinary integrin ß6 was significantly increased in DKD patients. Our findings reveal a critical role of integrin ß6 in regulating EMT in proximal tubular epithelial cells and identify a novel direction for the detection and treatment of DKD.

The Protective Effect of Walnut Oligopeptides against Indomethacin-Induced Gastric Ulcer in Rats.

The aim of this study was to investigate the potential protective effects of walnut oligopeptides (WOPs) on indomethacin-induced gastric ulcers in rats. The rats were divided into the following groups: normal group, model group, omeprazole group (0.02 g/kg), and WOPs groups (0.22, 0.44, and 0.88 g/kg, respectively). After receiving gavage once per day for 30 consecutive days, the rats were injected intraperitoneally with indomethacin 48 mg/kg to induce gastric ulcers. Then, the serum inflammatory cytokines and gastric prostaglandin E2 (PGE2), oxidative stress-related indicators, and the RNA expression of COX-1 and COX-2 were measured. The results revealed that WOPs confer significant gastroprotection on gastric ulcers caused by indomethacin, regulating inflammatory cytokines, oxidative stress, and prostaglandins synthesis, and enhancing the expression of COX-1 and COX-2 in gastric tissue, thus exerting its protective effect on gastric mucosa. The gastroprotective mechanism may be related to the involvement of the arachidonic acid metabolism and upregulation of tryptophan, phenylalanine, tyrosine, and alpha-Linolenic acid metabolism synthesis in vivo.

The Effects of Peanut Oligopeptides on Exercise-Induced Fatigue in Mice and Its Underlying Mechanism.

The aim of this study was to clarify the anti-fatigue effect of peanut oligopeptides (POPs) in mice and to investigate its possible underlying mechanism. A total of 150 male ICR mice were randomly assigned into five groups: control, whey protein (0.50 g/kg·bw), and three peanut peptide groups (0.25, 0.50, and 1.00 g/kg·bw). All the mice were treated with intra-gastric administration for 30 days. Following the intervention, a weight-loaded swimming test, blood lactate concentration, glycogen content, the activities of antioxidant factors and energy metabolism enzymes, and the function of mitochondria in the skeletal muscle were examined. The results show that POP intervention significantly prolonged the exhaustive swimming time, decreased blood lactate concentration levels, regulated the process of energy metabolism, and increased the level of antioxidant enzymes, muscle glycogen, and expressions of mtTFA and NRF-1 in the mitochondria of the gastrocnemius muscle. The results suggest that POPs produce an anti-fatigue effect in the animals, and they may exert this effect through the mechanism of improving the animals' antioxidant capacity to reduce oxidative damage levels and regulating the process of energy metabolism.

SPIDR is required for homologous recombination during mammalian meiosis.

Meiotic recombinases RAD51 and DMC1 mediate strand exchange in the repair of DNA double-strand breaks (DSBs) by homologous recombination. This is a landmark event of meiosis that ensures genetic diversity in sexually reproducing organisms. However, the regulatory mechanism of DMC1/RAD51-ssDNA nucleoprotein filaments during homologous recombination in mammals has remained largely elusive. Here, we show that SPIDR (scaffold protein involved in DNA repair) regulates the assembly or stability of RAD51/DMC1 on ssDNA. Knockout of Spidr in male mice causes complete meiotic arrest, accompanied by defects in synapsis and crossover formation, which leads to male infertility. In females, loss of Spidr leads to subfertility; some Spidr-/- oocytes are able to complete meiosis. Notably, fertility is rescued partially by ablation of the DNA damage checkpoint kinase CHK2 in Spidr-/- females but not in males. Thus, our study identifies SPIDR as an essential meiotic recombination factor in homologous recombination in mammals.

CCIO: A Cross-Chain Interoperability Approach for Consortium Blockchains Based on Oracle.

Cross-chain interoperability can expand the ability of data interaction and value circulation between different blockchains, especially the value interaction and information sharing between industry consortium blockchains. However, some current public blockchain cross-chain technologies or data migration schemes between consortium blockchains need help to meet the consortium blockchain requirements for efficient two-way data interaction. The critical issue to solve in cross-chain technology is improving the efficiency of cross-chain exchange while ensuring the security of data transmission outside the consortium blockchain. In this article, we design a cross-chain architecture based on blockchain oracle technology. Then, we propose a bidirectional information cross-chain interaction approach (CCIO) based on the former architecture, we novelly improve three traditional blockchain oracle patterns, and we combine a mixture of symmetric and asymmetric keys to encrypt private information to ensure cross-chain data security. The experimental results demonstrate that the proposed CCIO approach can achieve efficient and secure two-way cross-chain data interactions and better meet the application needs of large-scale consortium blockchains.

Molecular Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae in a Tertiary Hospital in Northern China.

Background: In recent years, carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged rapidly in China with the abuse and overuse of antibiotics, and infections caused by CRKP pose a serious threat to global public health safety. The present study aimed to explore the epidemiological characteristics of CRKP isolates in Northern China and to elucidate their drug resistance mechanisms. Methods: 45 CRKP strains were consecutively collected at a teaching hospital from March 1st, 2018 to June 30th, 2018. Antimicrobial susceptibility was determined by the VITEK2 compact system and microbroth dilution method. Polymerase chain reaction (PCR) and sequencing were used to analyze multilocus sequence typing (MLST), drug resistance determinants, and plasmid types. The transfer of resistance genes was determined by conjugation. All statistical analysis was performed using SPSS 22.0 software. Results: All 45 isolates showed multidrug resistance (MDR). MLST analysis showed ST11 (48.9%, 22/45) was the most frequent type. All of the 45 CRKP isolates contained carbapenemase genes, extended-spectrum ß-lactamase (ESBL) genes, and plasmid-mediated quinolone resistance (PMQR) genes. For carbapenemase genes, KPC-2 (93.3%, 42/45) was the main genotype, and followed by GES (37.8%, 17/45) and NDM-1 (11.1%, 5/45). Plasmid typing analysis showed that IncFII and IncFIB were the most prevalent plasmids. The carbapenem resistance rate of K.pneumoniae was 11.4% and ICU was the main CRKP infection source. Conclusions: ST11 is the most frequent sequence type and KPC-2 is the predominant carbapenemase of CRKP strains in Northern China. KPC-2-ST11 are representative clonal lineages.

A maximum-type microbial differential abundance test with application to high-dimensional microbiome data analyses.

Background: High-throughput metagenomic sequencing technologies have shown prominent advantages over traditional pathogen detection methods, bringing great potential in clinical pathogen diagnosis and treatment of infectious diseases. Nevertheless, how to accurately detect the difference in microbiome profiles between treatment or disease conditions remains computationally challenging. Results: In this study, we propose a novel test for identifying the difference between two high-dimensional microbiome abundance data matrices based on the centered log-ratio transformation of the microbiome compositions. The test p-value can be calculated directly with a closed-form solution from the derived asymptotic null distribution. We also investigate the asymptotic statistical power against sparse alternatives that are typically encountered in microbiome studies. The proposed test is maximum-type equal-covariance-assumption-free (MECAF), making it widely applicable to studies that compare microbiome compositions between conditions. Our simulation studies demonstrated that the proposed MECAF test achieves more desirable power than competing methods while having the type I error rate well controlled under various scenarios. The usefulness of the proposed test is further illustrated with two real microbiome data analyses. The source code of the proposed method is freely available at https://github.com/Jiyuan-NYU-Langone/MECAF. Conclusions: MECAF is a flexible differential abundance test and achieves statistical efficiency in analyzing high-throughput microbiome data. The proposed new method will allow us to efficiently discover shifts in microbiome abundances between disease and treatment conditions, broadening our understanding of the disease and ultimately improving clinical diagnosis and treatment.