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The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT and mTOR protein expression and exhibits robust cytotoxicity towards TNBC cells but not nontumorigenic normal breast epithelial cells. Mechanically, long noncoding RNA (lncRNA) AL354740.1-204 (also named as NUDT3-AS4) acts as a microRNA sponge to compete with AKT1/mTOR mRNAs for binding to miR-99s, leading to decrease in degradation of AKT1/mTOR mRNAs and subsequent increase in AKT1/mTOR protein expression. Inhibition of lncRNA-NUDT3-AS4 and suppression of the NUDT3-AS4/miR-99s association contribute to Comp34-affected biologic pathways. In addition, Comp34 alone is effective in cells with secondary resistance to rapamycin, the best-known inhibitor of mTOR, and displays a greater in vivo antitumor efficacy and lower toxicity than rapamycin in TNBC xenografted models. In conclusion, NUDT3-AS4 may play a proproliferative role in TNBC and be considered a relevant therapeutic target, and Comp34 presents promising activity as a single agent to inhibit TNBC through regulation of NUDT3-AS4 and miR-99s.

ABSTRACT The monothiol glutaredoxin GrxD plays an essential role in the biosynthesis of the antibiotic 2,4-diacetylphloroglucinol (2,4-DAPG) and the biocontrol capacity of the soil bacterium Pseudomonas fluorescens 2P24. However, the detailed mechanism underlying GrxD-mediated activation of the production of 2,4-DAPG remains unclear. Here, we found that GrxD directly interacted with IbaG, a BolA protein family member. The mutation of ibaG significantly decreased 2,4-DAPG production. Furthermore, expressing ibaG restored the production of 2,4-DAPG in the grxD ibaG double mutant to wild-type levels in the presence of dithiothreitol, suggesting that IbaG was required for GrxD-mediated regulation of 2,4-DAPG production. Transcriptome sequencing analyses revealed that IbaG plays a global role in gene regulation by affecting the expression of numerous genes throughout the genome. We also demonstrated that IbaG is an important regulator of several cellular processes, including swarming motility, biofilm formation, siderophore production, and acid resistance. Altogether, our data suggest that IbaG has an essential role in 2,4-DAPG production, motility, and biofilm formation. We also propose a regulatory mechanism linking GrxD to 2,4-DAPG production via IbaG. IMPORTANCE The production of 2,4-diacetylphloroglucinol (2,4-DAPG) is positively influenced by the monothiol glutaredoxin GrxD in Pseudomonas fluorescens 2P24. However, the regulatory mechanism underlying GrxD-mediated regulation of 2,4-DAPG biosynthesis is mostly uncharacterized. Here, we show the function of the BolA-like protein IbaG in 2,4-DAPG biosynthesis. We also demonstrate that GrxD directly interacts with IbaG and influences the redox state of IbaG. Altogether, this work provides new insights into the role of the highly conserved IbaG protein in regulating 2,4-DAPG synthesis, biofilm formation, and other biocontrol traits of P. fluorescens.

Abstract While stroke survivors with moderate or mild impairment are typically able to open their hand at will, those with severe impairment cannot. Abnormal synergies govern the arm and hand in stoke survivors with severe impairment, so hand opening, which is required to overcome the working synergy, is an extremely difficult task for them to achieve. It is universally accepted that alternative tracts including the cortico-reticulospinal tract (CRST), employed in the case that the corticospinal tract (CST) is damaged by stroke, brings about such abnormal synergies. Here we note that hand closing is enabled by alternative tracts as well as the CST, and a research question arises: Does motor characteristics while closing the hand depend on the integrity of the CST? In this study, we evaluate the abilities of 17 stroke survivors to flex and relax the metacarpophalangeal (MCP) joints and investigate whether motor characteristics can be distinguished based on CST integrity which is estimated using upper-extremity Fugl-Meyer (UEFM) scores. UEFM scores have been perceived as an indirect indicator of CST integrity. We found that participants with the UEFM score above a certain value, who are assumed to use the CST, moves the MCP joints more smoothly (P

Many Bacillus species are essential antibacterial agents, but their antibiosis potential still needs to be elucidated to its full extent. Here, we isolated a soil bacterium, BP9, which has significant antibiosis activity against fungal and bacterial pathogens. BP9 improved the growth of wheat seedlings via active colonization and demonstrated effective biofilm and swarming activity. BP9 sequenced genome contains 4282 genes with a mean G-C content of 45.94% of the whole genome. A single copy concatenated 802 core genes of 28 genomes, and their calculated average nucleotide identity (ANI) discriminated the strain BP9 from Bacillus licheniformis and classified it as Bacillus paralicheniformis. Furthermore, a comparative pan-genome analysis of 40 B. paralicheniformis strains suggested that the genetic repertoire of BP9 belongs to open-type genome species. A comparative analysis of a pan-genome dataset using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cluster of Orthologous Gene groups (COG) revealed the diversity of secondary metabolic pathways, where BP9 distinguishes itself by exhibiting a greater prevalence of loci associated with the metabolism and transportation of organic and inorganic substances, carbohydrate and amino acid for effective inhabitation in diverse environments. The primary secondary metabolites and their genes involved in synthesizing bacillibactin, fencing, bacitracin, and lantibiotics were identified as acquired through a recent Horizontal gene transfer (HGT) event, which contributes to a significant part of the strain`s antimicrobial potential. Finally, we report some genes essential for plant-host interaction identified in BP9, which reduce spore germination and virulence of multiple fungal and bacterial species. The effective colonization, diverse predicted metabolic pathways and secondary metabolites (antibiotics) suggest testing the suitability of strain BP9 as a potential bio-preparation in agricultural fields.

Unified power flow controller (UPFC), static synchronous series compensator (SSSC), thyristor controlled series compensation (TCSC) and phase shifter (PST) can be able to adjust line parameters and flexibly control power flow. They have been applied in domestic and foreign power grids, and have played an important role in balancing power flow in transmission channels and improving power supply capacity. The theoretical research and engineering practice of UPFC, SSSC, TCSC and PST are summarized. Firstly, the basic structure and power flow control principle of four kinds of power flow control devices are analyzed, and projections of power flow control devices are introduced. Then, the key technologies of power flow control devices are summarized from five aspects: topology, converter technology, location and capacity, control strategy and fault protection. Finally, the typical application scenarios of power flow control devices in the future power grid are prospected, and the research direction of power flow control technology in the future is analyzed.

With the continuous development of artillery, the disadvantages of hydraulic recoil brakes gradually appear. At the same time, the appearance of high-performance NdFeB permanent magnet makes it possible to apply electromagnetic braking technology to recoil mechanism. In this paper, prototype tests of a certain artillery were carried out to verify the feasibility of the electromagnetic brake (EMB) and obtain the electromagnetic braking force. Due to the brittleness of NdFeB, in order to eliminate the worry about the safety of EMB, SHPB experiments of NdFeB were carried out. Then, based on the assumption of uniform crack distribution, the law of crack propagation and damage accumulation was described theoretically, and the damage constitutive model suitable for brittle materials was proposed by combining the Zhu-Wang-Tang (ZWT) equation. Finally, the numerical simulation model of the artillery prototype was established and through calculation, the dynamic mechanical characteristics of NdFeB in the prototype were analyzed. The calculation results show that the strength of NdFeB can meet the requirements of the use in the working process. From the perspective of damage factor, the damage value of the permanent magnet on the far right is larger, and the damage value of the inner ring gradually decreases to the outer ring.

Advanced nuclear reactors are currently moving toward longer fuel cycles and higher burnup levels. Besides, high burnup levels can improve fuel economy and reduce the total amount of spent fuel in reactors. The formation of high burnup fuel particle is closely related to the failure behavior of ceramic dispersion fuel, and it is of great significance to focus on the strength analysis and cracking behavior of high burnup fuel particle. The representative volume element of dispersion fuel was innovatively established in this paper, and the heterogeneity of pore size and position in high burnup fuel particle was considered, corresponding parametric modeling and mechanical simulation procedure of high burnup fuel particle was realized automatically. The impacts of mechanical property of matrix, distance between fuel particles, ambient hydrostatic pressure and damaged layer on the strength of the fuel particles were analyzed systematically. The results show that the distance between fuel particles increases, the less possibility of crack initiates from the fuel particle. The existence of damaged layer will increase the risk of cracking of the fuel particles slightly. Due to the stress interference of the heterogeneous pores, crack initiates from multiple sites within the fuel particle, and the danger zones are more possibility located at the outer space, which is consistent with the experimental observations. Besides, danger zones within the high burnup fuel particle were characterized by larger pores and pore strings. It can be inferred that the formation of larger pores is probably due to the continuous coalescence of small pores and their surrounding pores. The constraint pressure of matrix on the fuel particle is not a constant, specially, it fluctuates significantly, and its average value increases linearly with the ambient hydrostatic pressure. Increasing the elasticity modulus of the matrix will inhibit the cracking behavior of the fuel particle, which reveals that the matrix should be designed more stronger and tougher. The higher the ambient hydrostatic pressure, the less likely the fuel particle will crack. While shortening the distance between fuel particles, and the impact degree of ambient hydrostatic pressure reduces. This work realizes the accurate calculation of the internal stress field of high burnup fuel particle and establishes a high burnup fuel cracking strength evaluation model based on fine microstructure modeling. Besides, this paper provides an analytical method and numerical reference for the failure study and optimal design of dispersion fuel under high burnup conditions.

Lymphoma-associated hemophagocytic syndrome (LAHS) is a rare and life-threatening clinical syndrome with rapidly deteriorating health and high mortality. We retrospectively analyzed clinical features and prognostic factors from 117 patients diagnosed with LAHS. The cumulative incidence rate of LAHS was 4.0% (117/2906). Patients were classified into B-cell LAHS (B-LAHS, n = 22) and T/natural killer (NK)-cell LAHS (T/NK-LAHS, n = 95) groups. Patients with T/NK-LAHS were younger and had lower neutrophil counts and fibrinogen values, higher LDH and transaminase levels, and were more likely to develop hemophagocytic syndrome (HPS) during the clinical course than those with B-LAHS. The median survival time for the entire cohort was 57 days, and for the T/NK-LAHS and B-LAHS groups, it was 52 and 154 days, respectively, after the diagnosis of LAHS. Patients with B-LAHS had superior 1-year OS (p = 0.003, 36.4% versus 14.5%) compared with those with T/NK-LAHS. Prognostic factor analysis revealed that elevated LDH levels (LDH > 1000 IU/L) (p = 0.004), T/NK-cell lineage (p

We identified relapsing fever (RF) Borrelia in 1.45% (145/10426) of the ticks and 1.40% (40/2850) of the wild mammals in a field investigation in China. Three RF Borrelia species, including human-pathogenic Borrelia miyamotoi, Borrelia persica and unclassified Babesia sp. were determined. Main species determined from ticks was B. miyamotoi (44.14%), followed by the unclassified Borrelia sp. (42.76%), and Borrelia theileri (13.10%). In wild mammals, main species found was B. persica (57.50%), followed by the unclassified Borrelia sp. (40.00%), and B. miyamotoi (2.50%). We determined B. theileri and B. persica in China for the first time. The coexistence of RF Borrelia species in one tick species in a given region was observed, with the most frequent coexistence seen for B. miyamotoi and the unclassified Borrelia sp. in Dermacentor silvarum, Haemaphysalis japonica, Haemaphysalis longicornis, and Ixodes persulcatuss respectively. The wide distribution and high variety of RF Borrelia in China pose a potential threat to public health.

Lyme borreliosis, recognized as one of the most important tick-borne diseases worldwide, has been increasing in incidence and spatial extent. Currently, there are few geographic studies about the distribution of Lyme borreliosis risk across China. Here we established a nationwide database that involved Borrelia burgdorferi sensu lato (B. burgdorferi) detected in humans, vectors, and animals in China. The eco-environmental factors that shaped the spatial pattern of B. burgdorferi were identified by using a two-stage boosted regression tree model and the model-predicted risks were mapped. During 1986−2020, a total of 2,584 human confirmed cases were reported in 25 provinces. Borrelia burgdorferi was detected from 35 tick species with the highest positive rates in Ixodes granulatus, Hyalomma asiaticum, Ixodes persulcatus, and Haemaphysalis concinna ranging 20.1%−24.0%. Thirteen factors including woodland, NDVI, rainfed cropland, and livestock density were determined as important drivers for the probability of B. burgdorferi occurrence based on the stage 1 model. The stage 2 model identified ten factors including temperature seasonality, NDVI, and grasslands that were the main determinants used to distinguish areas at high or low-medium risk of B. burgdorferi, interpreted as potential occurrence areas within the area projected by the stage 1 model. The projected high-risk areas were not only concentrated in high latitude areas, but also were distributed in middle and low latitude areas. These high-resolution evidence-based risk maps of B. burgdorferi was first created in China and can help as a guide to future surveillance and control and help inform disease burden and infection risk estimates.

Glioblastoma multiforme (GBM) is the most aggressive and deadliest type of brain tumor with a > >th he most aggressive and deadliest type of brain tumor witnear-infrared fluorescent dye, but it is hard to directly target brain tumor. Therefore, our study aimed to develop a new carrier for ICG to accurately visualize cancer tissue during surgery. Exosomes were isolated from culture U-87 MG cells, then loaded with Indocyanine green (ICG) and conjugated with RGERPPR peptide (RGE) (R-exo-ICG). The parameters of R-exo-ICG were analyzed and injected into tumor-bearing nude mice to evaluate its anti-tumor effect. R-exo-ICGs were nano size, and completely released ICG within 24 h. RGE modification increased cell uptake of exosomes, and induced cell apoptosis through activating Caspase 3 signaling pathway after laser irradiation. Moreover, R-exo-ICG was largely accumulated in the brain tumor in vivo, and inhibited tumor growth in tumor-bearing mice. RGE-conjugated exosomes that loaded ICG could target brain tumor in mice and significantly inhibited tumor growth in mice, which suggested that R-exo-ICG might serve as a novel approach for GBM treatment.