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Cefiderocol is a novel siderophore cephalosporin that displays activity against Gram-negative bacteria. To establish cefiderocol susceptibility levels of Acinetobacter baumannii strains from China, we performed susceptibility testing and genomic analyses on 131 clinical isolates. Cefiderocol shows high activity against the strains. The production of PER-1 is the key mechanism of cefiderocol resistance. In silico studies predicted that avibactam and durlobactam could inhibit cefiderocol hydrolysis by PER-1, which was confirmed by determining cefiderocol MICs in combination with inhibitors.

In geothermal development, induced earthquakes can be problematic side effects. To research the effect of fault distribution on induced earthquakes by hydraulic fracturing, a series of hydraulic fracturing tests were carried out on granite samples. We compared the performance of intact rock and prefabricated fault rock in the process of hydraulic fracturing, and an acoustic emission (AE) system was used to monitor acoustic emission events in the fracturing process. The test results revealed that fracture pressure increases with the increase of injection rate, and the acoustic emission cumulative energy of the prefabricated fault rock sample was higher than that of the intact rock sample. Also, in the process of fracturing, shear fracture accounted for more than 70% of all fractures for the prefabricated fault rock sample. However, for the intact rock sample, shear fracture only accounted for about 50% of all fractures. Our results support the conclusion that the existence of prefabricated faults could lead to an increase in shear fractures and fracture energy.

OXA-23 is the predominant carbapenemase in carbapenem-resistant

CD40 agonistic antibody is emerging as a front-line immunotherapy for patients with cancer. However, despite its remarkable curative effects, serious immune-related adverse reactions limit the clinical application of CD40 agonists. Crosslinking-dependent activation is one of the promising approaches to diminish the adverse effects of CD40 agonists. Agonistic CD40 stimulation on antigen presenting cells (APCs) not only promotes activation of T cells, but also results in PD-L1 upregulation on APCs, thus creating a negative feedback loop to dampen the anti-tumor immune response. Therefore, we hypothesized that the combination of CD40 agonist and blockade of PD-1/PD-L1 interaction may further induce a synergistic effect on T cell activation and anti-tumor activity. Here, we report a novel PD-L1xCD40 Bispecific Antibody (BsAb) designed to have synergistic curative effects as well as improved safety profiles. The PD-L1/CD40 BsAb was generated using the Harbour HBICE࣪® platform. It exhibited superior binding activities to both PD-L1 and CD40, respectively. CD40 activation was fully relied on the PD-L1 crosslinking. The PD-L1xCD40 BsAb showed potent tumor growth inhibition in preclinical efficacy models. Meanwhile, it showed much improved safety profile compared to a reference anti-CD40 agonistic antibody in the preclinical tox models. Overall, the PD-L1xCD40 BsAb demonstrated remarkable in vivo anti-tumor efficacy and improved safety profiles in preclinical models, which presents it as a promising candidate for the development of next-generation cancer immune therapeutics. Citation Format: Haishan luo, Zihong Meng, Jimmy Rong, Yuandong Wang, Yunxing Yang, Fei Chen, Youhong Wang, Victor Chen, Gang Deng, Yebo He, Xin Gan, Yiping Rong. Development of a novel PD-L1xCD40 bispecific antibody with excellent efficacy and safety profile for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5559.

In this paper, a new type of filter based on symmetry matching between the defect and waveguide modes in a square lattice photonic crystal for 1.31 μ m wavelength is designed and evaluated. The filter consists of one elliptical defect and three wire defect waveguides with two single-mode waveguides and one dual-mode waveguide. Because the point defect state has four different resonant frequencies and four corresponding types of mode field symmetries, the proposed filter uses the match or mismatch between the defect and waveguide modes to realize two resonant frequency filtering outputs through a dual channel. To evaluate the device, the transmission characteristics of the electromagnetic waves in the device are simulated using the finite element method. The quality factor and transmission coefficient of the filter is 2,017 and 0.84 at the frequency of 0.4034 c/ α (corresponding to 1.31 μ m wavelength). This device can be applied to wave division multiplexing, filtering, and has the potential for applications in optical integrated chip and optical communications.

Klebsiella pneumoniae strains carrying OXA-48-like carbapenemases are increasingly prevalent across the globe. There is thus an urgent need to better understand the mechanisms that underpin the dissemination of bla OXA-48-like carbapenemases. To this end, four ertapenem-resistant K. pneumoniae isolates producing OXA-48-like carbapenemases were isolated from two patients. Genome sequencing revealed that one sequence type (ST) 17 isolate carried bla OXA-181, whilst three isolates from a single patient, two ST76 and one ST15, carried bla OXA-232. The 50514 bp bla OXA-181-harbouring plasmid, pOXA-181_YML0508, was X3-type with a conjugation frequency to Escherichia coli of 1.94×10−4 transconjugants per donor. The bla OXA-232 gene was located on a 6141 bp ColKP3-type plasmid, pOXA-232_WSD, that was identical in the ST76 and ST15 K. pneumoniae isolates. This plasmid could be transferred from K. pneumoniae to E. coli at low frequency, 8.13×10−6 transconjugants per donor. Comparative analysis revealed that the X3 plasmid acquired the bla OXA-48-like gene via IS3000-mediated co-integration of the ColKP3-type plasmid. Our study highlights how plasmid integration and rearrangements can contribute to the spread of bla OXA-48-like genes, which provides important clues for clinical prevention of the dissemination of K. pneumoniae strains carrying bla OXA-48-like carbapenemases.

Background CCR8-expressing CD4 and Foxp3 positive Treg (CCR8+ Treg) has been demonstrated to be a major driver for immunosuppression in solid tumors1 Superscript. Clinical studies have shown that CCR8 is selectively up-regulated by tumor resident Tregs in several tumor types including clear cell renal cell carcinoma (ccRCC)2 Superscript and breast cancer3 Superscript. In these tumor types, CCR8 exhibit strong expression on tumor resident Tregs while it is rarely observed on Tregs in peripheral blood mononuclear cells (PBMCs). High expression of the CCR8 in tumor-infiltrating lymphocytes-Treg cells (TIL-Tregs) was associated with poor prognosis in breast cancer patients. These results suggest CCR8 as a promising therapeutic target; and anti-CCR8 mAbs could selectively inhibit a subpopulation of tumor resident Tregs in the tumor microenvironment (TME), to augment antitumor immunity. Methods In vitro assay:HBM1022 binding on human, cynomolgus CCR8 and TIL-Tregs are evaluated via flow cytometry. Blocking and ADCC functional assay are all based on CCR8 overexpressing cell lines.In vivo efficacy study:HBM1022 anti-CCR8 antibody was administered after implantation (≈ 100 mm3 Superscript tumor volume) alone and in combination with anti−PD-1. Results Anti-CCR8 antibody HBM1022 specifically binds to cell lines that over-express human or cynomolgus CCR8, as well as TIL-Tregs in multiple cancer types with the high affinity. HBM1022 potently blocks CCL1 binding to both human and cynomolgus CCR8. HBM1022 inhibits CCL1-induced migration and related GPCR signaling pathways. Furthermore, with enhanced antibody-dependent cell-mediated cytotoxicity (eADCC) activity, HBM1022 exhibits potent in vitro killing activity on CCR8-expressing cells. HBM1022 shows tumor growth inhibition as monotherapy in preclinical mouse syngeneic and humanized models. Moreover, HBM1022 shows enhanced antitumor activity with the combination of Keytruda® in preclinical efficacy models. Conclusions Our finding reveals HBM1022 as an innovative immunotherapy targeting intra-tumoral suppressive Treg cells to change suppressive tumor to hot tumor. HBM1022 presents its great potential as exciting mono or combo anti-tumor therapies. References Yiftah B, Gizi W, Eran L, et al. CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A 2017;114 (23):6086–6091. Tetsuya Y, Yujiro K, Mitsunobu M, et al. Method of treating cancer with an anti-CCR8 having antibody-dependent cell-mediated cytotoxicity (ADCC) activity against cells expressing CCR8. US10550191B2. 2020. George P, Catherine K, Kenmin W, et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 2016;45:1122–1134.

Multi-stage stimulation using alternative injection has been successfully applied in low mobility hydrocarbon production. However, fracture initiation and growth induced by different injection schemes have been inadequately studied for hot dry rock (HDR) geothermal reservoirs. Here, the impact of injection schemes on hydraulic fracture (HF) propagation regimes was determined with PFC2D software. The results show that the propagation of natural fractures (NFs) created by cyclic injection are dominated by the mode of shear activation and direct penetration. However, cyclic injection with frequent starting and stopping can produce non-uniform stress and fatigue, resulting in crack initiation and more branched fractures growth. The stepped injection can activate NFs effectively, and the HF propagation are featured by a style of turning at the tip of NFs. However, the stepped injection often produces a single main fracture with few branches. Different injection methods can lead to different propagation regimes and ultimately result in variation of the fracture network. A numerical model of the FORGE site that contains relevant geological structure and a fracture network was established with 3DEC software, and the impact of NFs on the HF network formation was investigated systematically. Compared with cyclic injection, the fracture network formed by stepped injection is more susceptible to the distribution of the NFs. The value of stepped injection is about 1.31 times in surface area and 1.17 times in aperture than the cyclic injection. Cyclic injection is conducive to creating fractures in the matrix, while stepped injection is more inclined to activate the preexisting NFs. The method presented here can be adopted to other geologic settings to optimize the fracture growth regime and provide a scientific basis for Enhanced Geothermal System (EGS) multi-stage fracturing design.

Acinetobacter baumannii is an important Gram-negative pathogen in hospital-related infections. However, treatment options for A. baumannii infections have become limited due to multidrug resistance. Bacterial virulence is often associated with capsule genes found in the K locus, many of which are essential for biosynthesis of the bacterial envelope. However, the roles of other genes in the K locus remain largely unknown. From an in vitro evolution experiment, we obtained an isolate of the virulent and multidrug-resistant A. baumannii strain MDR-ZJ06, called MDR-ZJ06M, which has an insertion by the ISAba16 transposon in gnaA (encoding UDP-N-acetylglucosamine C-6 dehydrogenase), a gene found in the K locus. The isolate showed an increased resistance toward tigecycline, whereas the MIC decreased in the case of carbapenems, cephalosporins, colistin, and minocycline. By using knockout and complementation experiments, we demonstrated that gnaA is important for the synthesis of lipooligosaccharide and capsular polysaccharide and that disruption of the gene affects the morphology, drug susceptibility, and virulence of the pathogen.

Acinetobacter baumannii is an important pathogen and presents a major burden in healthcare as strains frequently cause hospital associated opportunistic infections with high mortality rates. Due to increasing numbers of drug resistant A. baumannii strains, newly developed antibiotics are being used to treat infections caused by such strains. One novel synthetic antibiotic of the tetracycline class with activity against A. baumannii is eravacycline. To investigate possible mechanisms of eravacycline resistance, we performed an in vitro evolution experiment to select for an eravacycline resistant strain, with the clinical isolate MDR-ZJ06 as parental strain. We obtained a strain designated MDR-ZJ06-E6 that was able to grow in 64-fold MIC. Genomic mutations were identified by whole genome sequencing, where we found a deletion mutation in the gene adeS. Using complementation experiments, including growth rate determination and antibiotics susceptibility testing, we could confirm that this mutation was responsible for eravacycline resistance of strain MDR-ZJ06-E6. As a mechanism of resistance, we identified a significant overexpression of the efflux pump AdeABC which seems to be regulated by the mutation in adeS in A. baumannii.

Acinetobacter baumannii is an important Gram-negative pathogen in hospital-related infections. However, treatment options for A. baumannii infections have become limited due to multidrug resistance. Bacterial virulence is often associated with capsule genes found in the K locus, many of which are essential for biosynthesis of the bacterial envelope. However, the roles of other genes in the K locus remain largely unknown. From an in vitro evolution experiment, we obtained an isolate of the virulent and multidrug-resistant A. baumannii strain MDR-ZJ06, called MDR-ZJ06(M), which has an insertion by the ISAba16 transposon in gnaA (encoding UDP-N-acetylglucosamine C-6 dehydrogenase), a gene found in the K locus. The isolate showed an increased resistance toward tigecycline, whereas the MIC decreased in the case of carbapenems, cephalosporins, colistin, and minocycline. By using knockout and complementation experiments, we demonstrated that gnaA is important for the synthesis of lipooligosaccharide and capsular polysaccharide and that disruption of the gene affects the morphology, drug susceptibility, and virulence of the pathogen.

Acinetobacter baumannii, a non-fermenting gram-negative coccobacillus, is a major pathogen responsible for a variety of healthcare-associated infections, including pneumonia, urinary tract and bloodstream infections. Moreover, A. baumannii is associated with alarming increases in drug resistance rates to almost all available antibiotics leaving limited treatment options. Here, we characterize the biological functions of a novel gene, abrp, which encodes a peptidase C13 family. We demonstrate that the abrp is associated with decreased susceptibility to tetracycline, minocycline, doxycycline, tigecycline, chloramphenicol and fosfomycin. Deletion of abrp was able to increase cell membrane permeability and display slower cell growth rate. Results from the present study show that abrp plays an important role in conferring reduced susceptibility to different classes of antibiotics and cell growth in A. baumannii. The change of antibiotic sensitivities may result from modifications to the cell membrane permeability of A. baumannii.

Tigecycline (TIG) resistance is a growing concern because this antibiotic is regarded as one of the last resorts to treat infections caused by multidrug-resistant and extensively drug-resistant (XDR) bacteria. Information regarding TIG-resistant Escherichia coli isolates is scarce. In this study, we report the emergence of high-level TIG resistance in a longitudinal series of XDR E. coli isolates collected during TIG treatment. Whole-genome sequencing was performed for six E. coli strains harbouring bla(NDM-5) and genomic comparison revealed two amino acid substitutions. Mutation in rpsJ could be a significant factor conferring TIG resistance in these isolates. The fitness cost of TIG resistance in resistant strains was evaluated by determining the relative growth rate, indicating that TIG resistance reduced fitness by ca. 7%. This study is the first report to demonstrate high-level TIG resistance in E. coli in vivo. In addition, we report the first treatment-emergent minimum inhibitory concentration (MIC) development of TIG from 1mg/L to 64 mg/L in E. coli. Clinicians should be aware of the risk of an increase in the MIC of TIG under therapy.

Geothermal energy has been widely proposed as a potential renewable energy to replace traditional fossil fuel energy. Deep buried geothermal reservoirs are usually called Hot Dry Rock (HDR) or Enhanced Geothermal Systems (EGS). Hot dry rock (HDR) reservoirs are the main geothermal energy resources, and usually consist of low-permeability hard granite without fluid. Developing HDR requires water cyclically flowing between injection and production wells to extract heat energy. Hydraulic fracturing, as a key reservoir stimulation technology, can create the path of fluid cyclically flowing. Although hydraulic fracturing in HDR formations has attracted more and more attention these years, large-size HDR formation environment is difficult to establish in laboratory and large granite samples are difficult to crack because of their high toughness and strength, the reservoir stimulation characteristics in this hard granite have not been thoroughly addressed by the researchers and the hydraulic induced fracture morphology has yet remained unnoticed. To advance this technology development, a true triaxial hydraulic fracturing apparatus with high temperature heated system has been developed by Jilin University to simulate the real HDR environment, and this paper investigated HDR geothermal reservoir stimulation characteristics in large-size granite under different injection flow rates, temperatures and confining stresses conditions. The granite samples were collected form Gonghe Basin where the Chinese first EGS field operation will be built. Results showed that these laboratorial conditions affected hydraulic fracturing characteristics, breakdown pressures increased with the increase of injection flow rate and confining stresses, decreased with the increase of temperatures. Numerical simulations were conducted to model the laboratory tests. These results can provide some reasonable advice for implementing reservoir stimulations on the application of field-scale HDR operation.

Sulbactam is a plausible option for treating Acinetobacter infections because of its intrinsic antibacterial activity against the members of the Acinetobacter genus, but the mechanisms of sulbactam resistance have not been fully studied in Acinetobacter baumannii . In this study, a total of 2,197 clinical A. baumannii isolates were collected from 27 provinces in China. Eighty-eight isolates with various MICs for sulbactam were selected on the basis of their diverse clonality and underwent multilocus sequence typing (MLST), antimicrobial susceptibility testing, and resistance gene screening. The copy number and relative expression of bla TEM-1D and ampC were measured via quantitative PCR and quantitative reverse transcription-PCR, respectively. The genetic structure of multicopy bla TEM-1D was determined using the whole-genome sequencing technology. The cefoperazone-sulbactam resistance rate of the 2,197 isolates was 39.7%. The rate of positivity for bla TEM-1D or IS Aba1-ampC in the sulbactam-nonsusceptible group (64.91% and 78.95%, respectively) was significantly higher than that in the sulbactam-susceptible group (0% and 0%, respectively; P < 0.001). The MIC of sulbactam ( P < 0.001) varied considerably between the groups expressing ampC with or without upstream IS Aba1 . Notably, the genetic structure of the multicopy bla TEM-1D gene in strain ZS3 revealed that bla TEM-1D was embedded within four tandem copies of the cassette IS 26-bla TEM-1D -Tn 3 -IS 26 . Therefore, bla TEM-1D and IS Aba1-ampC represent the prevalent mechanism underlying sulbactam resistance in clinical A. baumannii isolates in China. The structure of the four tandem copies of bla TEM-1D first identified may increase sulbactam resistance.

In order to reduce data volume of carrier-free ultra-wideband (UWB) fuze's signal processing and improve fuze's instantaneity, a signal processing method for carrier-free UWB fuze based on wavelet transform is proposed in this study. Under least mean square error criterion, decompose the transmitted pulse and echo signal by wavelet transform firstly, then estimate the target's distance and velocity information on high level of wavelet decomposition, finally, generate detonator signal to drive the executive level. The simulation results show that this method can effectively estimate the distance and velocity of target, also it can reduce data volume of signal processing greatly without impacting the measurement which is good to the real-time processing and engineering applications.

In order to understand the relationship between sequences and biological functions of RGD-containing wild silkworm silk fibroin, it is important to purify the basic RGD-containing motif in large quantities. In this study, a gene monomer encoding RGD-contained motif GSGAGGRGDGGYGSGSS (-RGD-) derived from Antheraea pernyi (the same in Antheraea yamamai) was designed and cloned. (-RGD-)n in various degrees of polymerizations was obtained by gene monomer doubling-extension and expression. Two glutathione-S-transferase (GST)-tagged fusion proteins GST-(-RGD-)12 and GST-(-RGD-)24 were successfully expressed in Escherichia coli (E. coli) BL21. The fusion proteins were isolated and purified by GST affinity chromatography, and the polypeptides (-RGD-)12 and (-RGD-)24 were cleaved from GST fusion proteins by thrombin digestion. Two-dimensional electrophoresis and amino acid composition analysis were performed to confirm the identity of the engineered polypeptides. Results indicated that this technology reliably obtained expected polypeptides (-RGD-)n for future research on structure and functions.

In order to effectively improve the utilization rate and service turnover rate of highway service area, and make the traffic flow more smoothly, this paper studies the transportation organizations under special circumstances, such as extreme weather, natural disasters, holiday peak trips and other special situations. Traffic organization optimization countermeasures are proposed from three aspects: controlling the total amount of traffic, optimizing the internal organization and improving the departure rate. The result can provide reference for the construction and optimization of service area in the future.

When direct digital frequency synthesizer (DDS) is applied in frequency-hopping fuse, it could be restricted by circuit size and efficiency of signal. Wide-band VCO can be also employed in this fuse to realize the design of high-speed frequency hopping source. It loads an impedance circuit upon varactor which makes pseudo-code signal through impendence network without distortion and isolates the high-frequency signals. The result of simulation shows that, the time of frequency hopping is short, and signal is in high stable situation. The circuit is easily realized and the performance is excellent.

Clinical infections caused by Acinetobacter spp. have increasing public health concerns because of their global occurrence and ability to acquire multidrug resistance. Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex encompasses A. calcoaceticus, A. baumannii, A. pittii (formerly genomic species 3), and A nosocomial (formerly genomic species 13TU), which are predominantly responsible for clinical pathogenesis in the Acinetobacter genus. In our previous study, a putative novel species isolated from 385 non-A. baumannii spp. strains based on the rpoB gene phylogenetic tree was reported. Here, the putative novel species was identified as A. seifertii based on the whole-genome phylogenetic tree. A. seifertii was recognized as a novel member of the ACB complex and close to A. baumannii and A. nosocomials. Furthermore, we studied the characteristics of 10 A. seifertii isolates, which were distributed widely in 6 provinces in China and mainly caused infections in the elderly or children. To define the taxonomic status and characteristics, the biochemical reactions, antimicrobial susceptibility testing, pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and whole-genome sequence analysis were performed. The phenotypic characteristics failed to distinguish A. serfertii from other species in the ACB complex. Most of the A. seifertii isolates were susceptible to antibiotics commonly used for nosocomial Acinetobacter spp. infections, but one isolate (strain A362) was resistant to ampicillin/sulbactam, ceftazidime and amikacin. The different patterns of MLST and PFGE suggested that the 10 isolates were not identical and lacked clonal relatedness. Our study reported for the first time the molecular epidemiological and genomic features of widely disseminated A. seifertii in China. These observations could enrich the knowledge of infections caused by non-A. baumannii and may provide a scientific basis for future clinical treatment.