Intrinsic Resistance Research Articles

The gene MAB_2362 is responsible for intrinsic resistance to various drugs and virulence in Mycobacterium abscessus by regulating cell division.

Mycobacterium abscessus exhibits intrinsic resistance to most antibiotics, hence leading to infections that are difficult to treat. To address this issue, the identification of new molecular targets is essential for the development or repositioning of therapeutic agents. This study demonstrated that the MAB_2362-knockout strain, MabΔ2362, became significantly susceptible to a range of antibiotics, not only in vitro but also exhibited susceptibility to rifabutin, bedaquiline, and linezolid in vivo. While the bacterial burden of the wild-type M. abscessus (MabWt) increased by over 1 log10 CFU/lung in a murine infection model 16 days post-infection, that of MabΔ2362 strain decreased by more than 1 log10 CFU/lung, which suggests that the disruption leads to attenuation. Bioinformatics analysis revealed that MAB_2362 shares the highest similarity (41.35%) with SteA, a protein known to influence cell division in Corynebacterium glutamicum, suggesting that MAB_2362 might be involved in cell division. MabΔ2362 cells exhibited a median length of 2.62 µm, which was substantially longer than the 1.44 µm recorded for MabWt cells. Additionally, multiple cell division septa were observed in 42% of MabΔ2362 cells, whereas none were seen in MabWt cells. An ethidium bromide uptake assay further suggested a higher cell envelope permeability in MabΔ2362 compared to MabWt. Collectively, these findings underscore the role of MAB_2362 in intrinsic resistance and virulence of M. abscessus possibly through the regulation of cell division. Thus, MAB_2362 emerges as a promising candidate for targeted interventions in the pursuit of novel antimicrobials against M. abscessus.

Radiotherapy-resistant prostate cancer cells escape immune checkpoint blockade through the senescence-related ataxia telangiectasia and Rad3-related protein.

The majority of patients with prostate cancer (PCa) exhibit intrinsic resistance to immune checkpoint blockade (ICB) following radiotherapy (RT). This resistance is generally attributed to the limited antigen presentation of heterogeneous cells within tumors. Here, we aimed to isolate and characterize these diverse subgroups of tumor post-RT to understand the molecular mechanisms of their resistance to ICB. Single-cell RNA-sequencing (scRNA-seq) was used to profile senescent cancer cell clusters induced by RT in LNCaP cells. The expression and phosphorylation levels of ataxia telangiectasia and Rad3-related protein (ATR) were assessed by immunohistochemistry in clinical samples from patients with or without RT. Co-immunoprecipitation, mutagenesis, and Western blotting were used to measure the interactions between proteins. Xenograft experiments were performed to assess the tumor immune response in the mice. We identified a subset of PCa cells that exhibited resistance to RT, characterized by a reduced antigen presentation capability, which enhanced their ability to evade immune detection and resist cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. scRNA-seq revealed that the senescent state was a transient phase of PCa cells post-RT, particularly in CTLA-4 blockade treatment-resistant cells. This state was marked by increased cytosolic ATR level. Cytosolic ATR phosphorylated CD86 in its cytosolic domain and enhanced the interaction between CD86 and its E3 ligase MARCH1 through electrostatic attraction. Depletion or inhibition of Atr increased the sensitivity to immune attack and improved responses to anti-Ctla-4 antibody treatment in a mouse model. Our findings indicate that the activation of cytosolic ATR, which is associated with cellular senescence, impedes the effectiveness of combined RT and ICB treatments. This discovery may provide valuable insights for improving the efficacy of combined RT and ICB therapies in PCa.

Understanding Bacterial Resistance to Heavy Metals and Nanoparticles: Mechanisms, Implications, and Challenges.

Antimicrobial resistance is a global health problem as it contributes to high mortality rates in several infectious diseases. To address this issue, engineered nanoparticles/nano-formulations of antibiotics have emerged as a promising strategy. Nanoparticles are typically defined as materials with dimensions up to 100nm and are made of different materials such as inorganic particles, lipids, polymers, etc. They are widely dispersed in the environment through various consumer products, and their clinical applications are diverse, ranging from contrast agents in imaging to carriers for gene and drug delivery. Nanoparticles can also act as antimicrobial agents either on their own or in combination with traditional antibiotics to produce synergistic effects, earning them the label of "next-generation therapeutics." They have also shown great effectiveness against multidrug-resistant pathogens responsible for nosocomial infections. However, overexposure or prolonged exposure to sublethal doses of nanoparticles can promote the development of resistance in human pathogens. The resistance can arise from various factors such as genetic mutation, horizontal gene transfer, production of reactive oxygen species, changes in the outer membrane of bacteria, efflux-induced resistance, cross-resistance from intrinsic antibiotic resistance determinants, plasmid-mediated resistance, and many more. Continuous exposure to nanoparticles can also transform an antibiotic-susceptible bacterial pathogen into multidrug resistance. Considering all these, the current review focuses on the mode of action of different heavy metals and nanoparticles and possible mechanisms through which bacteria attain resistance towards these heavy metals and nanoparticles.

Natural killer cell-mediated cytotoxicity shapes the clonal evolution of B cell leukaemia.

The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA barcoded mouse BCR/ABLp185+ B-cell acute lymphoblastic leukaemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Although most tumour cell clones were efficiently eliminated by NK cells, a certain fraction of tumour cells harboured an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumour cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell-mediated cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumour cell clones, which were characterised by an IFN-γ signature. Besides well-known regulators of immune evasion, our analysis of NK cell-resistant tumour cells revealed the upregulation of genes, including Ly6a, which we found to promote leukaemic-cell resistance to NK cells. Translation of our findings to the human system showed that high expression of LY6E on tumour cells impaired their physical interaction with NK cells and led to worse prognosis in leukaemia patients. Our results demonstrate that tumour cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.

Advancing electrochemical water desalination: Machine learning-driven prediction and RSM optimization of activated carbon electrodes

This study presents an innovative and sustainable approach for synthesizing porous carbon electrodes from palm kernel shells (PKS) using a single-step physicochemical activation process. The study investigates the effect of carbon dioxide and zinc chloride on electrochemical features such as surface morphology and functional chemistry, intrinsic resistance and electrical conductivity. The best electrode developed from palm kernel shell derived activated carbon (PKSAC) using ZnCl2 and N2/CO2 (PKSAC_N2/CO2_ZnCl2) exhibited a superior specific capacitance, electrosorption capacity, and average salt adsorption rate of 365.4 F/g, 22.5 mg/g and 0.372 mg/g/min under optimized CDI conditions, such as applied voltage, feed flow rate, and initial NaCl concentration of 1.2 V, 7.5 ml/min, and 750 mg/L, respectively. Comparatively, electrodes developed with either N2 activation (PKSAC_N2) or N2/ZnCl2 activation (PKSAC_N2_ZnCl2) demonstrated electrosorption capacities of 12.55 and 19.74 mg/g, respectively. Response surface methodology (RSM) was applied to optimize the CDI parameters for electrochemical water desalination, ensuring process efficiency and scalability. Further, the machine learning extreme gradient boosting (XGB) regressor model predicted the performance of the developed electrodes and aligned well with the experimental data. The article provides key insights into activated carbon synthesis and its role in electrochemical water desalination, offering a sustainable solution to water scarcity that aligns with the UN's sustainability goals.

Titanate nanorod/reduced graphene oxide-filled poly (vinylidene fluoride) fibers as piezoelectric nanogenerators

To investigate the influence of nanorod ceramic powders MTiO3 (M: Mg, Co, Ni) as fillers on the electrical performance, piezoelectric nanogenerators (PENG) device, were constructed using the electrospinning method with polyvinylidene fluoride (PVDF), reduced graphene oxide (RGO), and ceramic powders. The composite nanofibers were characterized using SEM, EDX, ATR-FTIR, EDS-mapping analysis, and XRD. Sensing capacity of the PVDF-RGO-MTiO3 nanofiber-based PENG were compared. Utilizing CoTiO3 (CT) in the PENG resulted in a voltage output of 17.03, which exhibited the best piezoelectric response. Observations revealed that mechanical stimulation could charge different capacitors, suggesting a viable platform for removing the requirement of an external power source for operating portable devices. With varying resistances in the circuit, the resistance of 104 Ω produced the maximum power density of 1.40 mW/cm2. When comparing the P-RGO-CT composite to pure PVDF, the differential scanning calorimetric analysis revealed that the thermal stability and crystallinity percentage increased. Tensile testing was used to evaluate the mechanical characteristics of P-RGO-CT PENG. The maximum stress and breaking strain that the nanofiber film can tolerate are 50 kPa and 33.9%, respectively. EIS investigations obtained that the real intrinsic internal resistance of the P-RGO-CT PENG electrode is lower than PVDF, demonstrating the good conductivity of the synthesized PENG electrode. The impedance spectrum of the PENG electrode is almost parallel to the Zim axis, demonstrating good capacitance performance.

CAR T-cell therapy for B-cell lymphomas: outcomes and resistance mechanisms.

Chimeric antigen receptor (CAR) T cells are an exciting curative intent approach to the treatment of non-Hodgkin lymphomas (NHLs). Several products have received FDA approval for 2nd or 3rd line indications, and studies are underway for their use earlier in the disease course. These CAR T cells are ex vivo manufactured autologous cell products that specifically target tumor antigens to optimize tumor specificity and minimize off-tumor side effects-in NHLs, this is typically achieved by targeting B-cell antigens. Engagement of the CAR and corresponding antigen is designed to result in T-cell activation and subsequent tumor clearance. While curative for many NHL patients, too many patients fail to respond to or relapse following CAR T-cell treatment, and salvage options post CAR T-cell therapy are limited. Treatment failures occur because of myriad resistance mechanisms including CAR T-cell dysfunction, generalized immune dysregulation, and intrinsic tumor resistance. Focusing on patients with NHL, we review the clinical outcomes of CAR T-cell therapy and the major resistance mechanisms that lead to poor outcomes. We also review the many innovative and encouraging strategies that are being developed to improve CAR T-cell therapy for NHL.

Distribution and Antimicrobial Susceptibility Profiles of Pathogens in Patients With Esophageal Cancer From 2013 to 2022: A Retrospective Study.

Pathogenic microbial infections are closely related to the development and prognosis of esophageal cancer. The distribution and resistance of pathogens in different diseases are regional and gradually change over time. This study aimed to determine the distribution and drug resistance of pathogens isolated from patients with esophageal cancer and provide a reference for the rational use of antibiotics. The results of strain identification and antimicrobial susceptibility testing of pathogens in patients with esophageal cancer from January 2013 to December 2022 at our hospital were retrospectively analyzed. SPSS Statistics 26.0 (IBM) and R software 4.3.1 were used for data analysis. In total, 2322 non-repetitive pathogens were isolated from 14,037 samples. Of all strains, 1713 (73.77%) were Gram-negative bacteria, 483 (20.80%) were Gram-positive bacteria, and 126 (5.43%) were fungi. The top 10 pathogens were Pseudomonas aeruginosa (19.81%), Stenotrophomonas maltophilia (12.88%), A. baumannii (9.91%), Klebsiella pneumoniae (9.82%), Staphylococcus aureus (7.54%), Candida albicans (3.92%), Staphylococcus epidermidis (3.19%), Escherichia coli (3.14%), Enterococcus faecalis (2.97%), and Serratia marcescens (2.15%). The isolation rate of S. maltophilia showed an upward trend (p < 0.05). The resistance rates of P. aeruginosa, S. maltophilia, A. baumannii, and Enterobacteriaceae bacteria to some common antibiotics showed a tendency to change (p < 0.05), and 2019 became a turning point to some extent. All common Gram-positive pathogens were sensitive to vancomycin, except for three Enterococcus spp. isolates that showed intrinsic resistance. The prevalence of MRSA was 65.14% (114/175) in this study. In addition, the resistance rates of MRSA and MSSA to moxifloxacin, ciprofloxacin, levofloxacin, erythromycin, clindamycin, and penicillin were significantly different (p < 0.001). Pathogens are diverse in patients with esophageal cancer, with the most common being P. aeruginosa, followed by S. maltophilia. The pathogens exhibited different patterns of resistance. Antibiotics should be used rationally according to pathogen resistance patterns.

Genomic heterogeneity and ploidy identify patients with intrinsic resistance to PD-1 blockade in metastatic melanoma.

The introduction of immune checkpoint blockade (ICB) has markedly improved outcomes for advanced melanoma. However, many patients develop resistance through unknown mechanisms. While combination ICB has improved response rate and progression-free survival, it substantially increases toxicity. Biomarkers to distinguish patients who would benefit from combination therapy versus aPD-1 remain elusive. We analyzed whole-exome sequencing of pretreatment tumors from four cohorts (n = 140) of ICB-naïve patients treated with aPD-1. High genomic heterogeneity and low ploidy robustly identified patients intrinsically resistant to aPD-1. To establish clinically actionable predictions, we optimized and validated a predictive model using ploidy and heterogeneity to confidently identify (90% PPV) patients with intrinsic resistance to and worse survival on aPD-1. We further observed that three of seven (43%) patients predicted to be intrinsically resistant to single-agent PD-1 ICB responded to combination ICB, suggesting that these patients may benefit disproportionately from combination ICB. These findings highlight the importance of heterogeneity and ploidy, nominating an approach toward clinical actionability.

Toll-Like receptor 3-mediated interferon-β production is suppressed by oncostatin m and a broader epithelial-mesenchymal transition program

BackgroundPatients with Triple Negative Breast Cancer (TNBC) currently lack targeted therapies, and consequently face higher mortality rates when compared to patients with other breast cancer subtypes. The tumor microenvironment (TME) cytokine Oncostatin M (OSM) reprograms TNBC cells to a more stem-like/mesenchymal state, conferring aggressive cancer cell properties such as enhanced migration and invasion, increased tumor-initiating capacity, and intrinsic resistance to the current standards of care. In contrast to OSM, Interferon-β (IFN-β) promotes a more differentiated, epithelial cell phenotype in addition to its role as an activator of anti-tumor immunity. Importantly, OSM suppresses the production of IFN-β, although the mechanism of IFN-β suppression has not yet been elucidated.MethodsIFN-β production and downstream autocrine signaling were assessed via quantitative real-time PCR (qRT-PCR) and Western blotting in TNBC cells following exposure to OSM. RNA-sequencing (RNA-seq) was used to assess an IFN-β metagene signature, and to assess the expression of innate immune sensors, which are upstream activators of IFN-β. Cell migration was assessed using an in vitro chemotaxis assay. Additionally, TNBC cells were exposed to TGF-β1, Snail, and Zeb1, and IFN-β production and downstream autocrine signaling were assessed via RNA-seq, qRT-PCR, and Western blotting.ResultsHere, we identify the repression of Toll-like Receptor 3 (TLR3), an innate immune sensor, as the key molecular event linking OSM signaling and the repression of IFN-β transcription, production, and autocrine IFN signaling. Moreover, we demonstrate that additional epithelial-mesenchymal transition-inducing factors, such as TGF-β1, Snail, and Zeb1, similarly suppress TLR3-mediated IFN-β production and signaling.ConclusionsOur findings provide a novel insight into the regulation of TLR3 and IFN-β production in TNBC cells, which are known indicators of treatment responses to DNA-damaging therapies. Furthermore, strategies to stimulate TLR3 in order to increase IFN-β within the TME may be ineffective in stem-like/mesenchymal cells, as TLR3 is strongly repressed. Rather, we propose that therapies targeting OSM or OSM receptor would reverse the stem-like/mesenchymal program and restore TLR3-mediated IFN-β production within the TME, facilitating improved responses to current therapies.

4-1BBL-Armed Oncolytic Herpes Simplex Virus Exerts Antitumor Effects in Pancreatic Ductal Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a notably poor response to therapy due to its immunosuppressive tumor microenvironment (TME) and intrinsic drug resistance. The oncolytic virus (OV) represents a promising therapeutic strategy capable of transforming the “cold” immunological profile of PDAC tumors to a “hot” one by reshaping the TME. 4-1BB (CD137), a crucial member of the tumor necrosis factor receptor superfamily, plays a significant role in T-cell activation and function. Methods: In this study, we constructed an oncolytic herpes simplex virus armed with 4-1BBL (oHSV-4-1BBL), the ligand for the 4-1BB receptor, and investigated its therapeutic effects in two mouse models of pancreatic cancer, Pan02_HVEM and KPC. Results: We found that oHSV-4-1BBL remarkably inhibited tumor growth and extended the median survival time in both models. To amplify the therapeutic effect, we further combined oHSV-4-1BBL with PD-1 antibody. This combination therapy not only further suppressed tumor growth but also extended the median survival time by an additional 11 days compared to oHSV (armed with GFP as a control) combined with PD-1 antibody treatment, with some mice achieving complete tumor regression. Conclusions: Our findings confirm the potential of combining oncolytic viral therapy with 4-1BB targeting in enhancing the treatment of pancreatic cancer.

Fe-coordinated carbon dots with single atom nanozyme catalytic activity for synergistic catalytic/chemo-therapy in breast cancer

Single atom nanozyme (SAzyme) based on carbon dots (CDs) has showed great potential in oncotherapy via ultrasmall size-reinforced atomically dispersed catalytic sites. However, its curative effect is still unsatisfactory due to complex tumor microenvironment and intrinsic resistance. Herein, a coordinated carbon dots (CCDs)-integrated ZIF-8 nanoassembly (Ru/CCDs-PTX@ZIF) was constructed by loading paclitaxel and coating with rutin for synergistic catalytic/chemotherapy. Benefiting from inherited metal-polyphenol coordination, the CCDs exhibited superior peroxidase-like (POD) activity and served as a SAzyme to produce large amounts of hydroxyl radical, resulting in radical-dependent cell cycle arrest. With the assistance of GLUT receptor-mediated endocytosis, the Ru/CCDs-PTX@ZIF triggered the tumor-targeted killing and migration inhibition to suppress tumor progression. This study highlights a promising avenue to broaden the design and applications of CDs-based SAzyme in tumor treatment.

Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms.

Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer's intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway. However, despite initial success, the efficacy of PARPis is often compromised by the development of resistance mechanisms, including HRR restoration, stabilisation of replication forks, reduced PARP1 trapping, and drug efflux. This review explores latest breakthroughs in overcoming PARPi resistance through combination therapies. These strategies include the integration of PARPis with chemotherapy, immunotherapy, antibody-drug conjugates, and PI3K/AKT pathway inhibitors. These combinations aim to enhance the therapeutic efficacy of PARPis by targeting multiple cancer progression pathways. The review also discusses the evolving role of PARPis within the broader treatment paradigm for BRCA-mutated TNBC, emphasising the need for ongoing research and clinical trials to optimise combination strategies. By tackling the challenges associated with PARPi resistance and exploring novel combination therapies, this review sheds light on the future possibilities for improving outcomes for patients with BRCA-mutated TNBC.

Anisotropy in fracture toughness and toughening mechanism of Ti-22Al-25Nb alloy related to texture and grain boundary damage

Combining the intrinsic (crack tip plasticity) and extrinsic (crack deflection) toughening mechanism, the anisotropy of fracture toughness for Ti-22Al-25Nb alloy obtain by B2 phase region isothermal forging process is discussed. The results show that the sequence of fracture toughness from high to low is RD (radial direction), OD (45° to RD) and AD (axial direction). Intrinsically, it is found that the damage of lamellar O phase ahead of the crack tip dominates crack propagation. Compared with grain interior, continuous lamellar O phase on grain boundary can more easily promote the nucleation and propagation of crack, reducing the intrinsic resistance of crack propagation. Consequently, AD sample with intergranular fracture has the smallest crack tip plastic zone than RD and OD samples with transgranular fracture. Due to the activation of prism <a> slip for O phase, the texture of RD sample has a higher Schmid factor than that of OD sample, resulting in better crack tip plasticity. Extrinsically, it can be concluded that grain boundaries have a significant effect on crack deflection due to the pancake shaped B2 morphology. For RD sample, the grain boundary is perpendicular to the initial crack plane, so the stress intensity factor (KI) required for cleavage fracture is less than that for intergranular fracture. The deflection of the cleavage facets results in the highest crack propagation tortuosity. Also, the crack propagation near grain boundary of OD sample leads to significant deflection because the grain boundary is located in the direction of maximum shear stress. Compared with RD and OD samples, the KI required for intergranular fracture of AD sample is minimum, results in a flat fracture path.

Temporal control of Staphylococcus aureus intracellular pH by sodium and potassium.

Adaptation to environmental change during both colonization and infection is essential to the pathogenesis of Staphylococcus aureus. Like other bacterial pathogens that require potassium to fulfill nutritional and chemiosmotic requirements, S. aureus has been shown to utilize potassium transport to modulate virulence gene expression, antimicrobial resistance, and osmotic tolerance. Recent studies examining the role for potassium uptake in mediating S. aureus physiology have also described its contribution in mediating carbon flux within central metabolism and generation of a proton motive force. Here, we utilize a pH-sensitive green fluorescent protein to examine the temporal regulation of S. aureus intracellular pH by potassium and sodium under various environmental conditions, including extracellular pH and antibiotic stress. Our results distinguish unique conditions and transport mechanisms that utilize these ions to modulate cytoplasmic pH homeostasis, and they identify these processes as a novel mechanism of intrinsic ampicillin resistance in S. aureus.

Emergence of polymyxin-resistant Yersinia enterocolitica strains in natural aquatic environments

Aquatic environments serve as ideal reservoirs for antibiotic-resistant bacteria and resistance genes. However, the presence of polymyxin-resistant Yersinia enterocolitica, the pathogen responsible for human yersiniosis, in aquatic environments remains poorly understood. Herein, we isolated polymyxin-resistant Y. enterocolitica strains from natural water for the first time. In addition to intrinsic resistance to ampicillin and cefazolin, the strains demonstrated high resistance to polymyxin B and polymyxin E. All isolates were capable of biofilm production and exerted high virulent effects in Galleria mellonella, with 90% mortality occurring within 48 h post-infection. Furthermore, whole genome sequencing identified 26 antibiotic resistance genes, including polymyxin resistance determinants (arnA and PmrF), beta-lactam resistance determinants (vatF and blaA), and 60 virulence genes such as yaxA and yaxB in Y. enterocolitica isolates. Notably, phylogenetic analysis revealed that Y. enterocolitica involved multilocus sequence types ST937 and ST631, which were clustered with strains isolated from a human in the United States or swine in China. The close relatedness to clinical isolates suggests that polymyxin-resistant Y. enterocolitica may pose considerable health risk to humans. Our findings provide evidence of the presence of polymyxin-resistant Y. enterocolitica in aquatic environments and raise concerns about health risks due to their potential high virulence.

Comparison of mode II delamination behaviours in multidirectional and unidirectional composite laminates

Multidirectional (MD) composite laminates are extensively employed in structural applications owing to their superior mechanical characteristics. Nevertheless, the evaluation of the fracture toughness of composite laminates primarily relies on tests using unidirectional (UD) specimens. This study evaluates the reliability of characterizing mode II delamination behaviour in MD laminates by using UD specimens. The quantification of delamination area through Digital Image Correlation (DIC) analysis is integrated with a physical Energy Release Rate (ERR) method to ascertain the fracture resistance, which is compared with the ERR derived via a modified J-integral method and the standardized compliance methods. Fractographic analysis reveals similar fracture mechanisms in specimens with identical interfaces. The physical ERR increases notably due to large-scale fibre bridging induced by fibre nesting at 0∘//0∘ interfaces. Conversely, in 0∘//90∘ interfaces, large-area matrix cracking enhances the intrinsic fracture resistance, excluding the extrinsic toughening provided by fibre bridging.

Superior EMI Shielding and Thermal Management of Flexible, Fire‐Resistant SiBCNZr Nanofiber Fabrics Enhanced by Defect Engineering and Graphitization

AbstractGiven the critical threats to aviation safety induced by electromagnetic interference (EMI), fire hazards, and icing, high‐performance multifunctional materials integrating mechanical flexibility, EMI shielding, fire resistance, and thermal management capabilities are highly desired yet challenging. Herein, a synergistic strategy is developed involving defect engineering and graphitization to enhance EMI shielding and thermal management properties of SiBCNZr nanofiber fabrics. Initially, the SiBCNZr nanofiber fabrics demonstrate excellent mechanical flexibility and intrinsic ceramic fire resistance. Furthermore, after annealing at 1400 °C, t‐ZrO2 nanograins with various types of defects are precipitated from the amorphous matrix, accompanied by the formation of turbostratic graphite C. The synergistic effects of defect engineering of t‐ZrO2 nanograins and graphitization of turbostratic C enhance conductivity and polarization loss, leading to a specific shielding effectiveness (SSE/t) of 2718 dB cm2 g−1. Additionally, the fabrics also demonstrate remarkable electrothermal conversion capability with a rapid electrothermal response. This work provides valuable insights into designing multifunctional EMI shielding ceramic nanofiber fabrics for aviation safety.

Understanding tumour growth variability in breast cancer xenograft models identifies PARP inhibition resistance biomarkers.

Understanding the mechanisms of resistance to PARP inhibitors (PARPi) is a clinical priority, especially in breast cancer. We developed a novel mathematical framework accounting for intrinsic resistance to olaparib, identified by fitting the model to tumour growth metrics from breast cancer patient-derived xenograft (PDX) data. Pre-treatment transcriptomic profiles were used with the calculated resistance to identify baseline biomarkers of resistance, including potential combination targets. The model provided both a classification of responses, as well as a continuous description of resistance, allowing for more robust biomarker associations and capturing the observed variability. Thirty-six resistance gene markers were identified, including multiple homologous recombination repair (HRR) pathway genes. High WEE1 expression was also linked to resistance, highlighting an opportunity for combining PARP and WEE1 inhibitors. This framework facilitates a fully automated way of capturing intrinsic resistance, and accounts for the pharmacological response variability captured within PDX studies and hence provides a precision medicine approach.

Antibiotic Resistance in Mycobacterium Tuberculosis and Non-Tuberculous Mycobacteria

Mycobacterium tuberculosis (MTB) and non-tuberculous mycobacteria (NTM) antibiotic resistance presents an important challenge to the treatment of mycobacterial infections. The therapeutic approaches are complicated by the resistance of both MTB and NTM to a variety of antibiotics. Resistance to first-line drugs such as isoniazid, rifampicin, ethambutol, and streptomycin has been consistently increasing in MTB, underscoring the necessity of effective treatment strategies. Conversely, the necessity of species-specific treatment regimens is underscored by the high resistance rates of NTM species, such as Mycobacterium avium complex, M. kansasii, and M. abscessus complex, to commonly used anti-tuberculosis pharmaceuticals. A combination of intrinsic and acquired factors are involved in the mechanisms of antibiotic resistance in these mycobacteria. Features such as biofilm formation, thick cell walls, and reduced drug uptake are responsible for intrinsic resistance in NTM, whereas acquired resistance can develop as a result of protracted antibiotic exposure. Understanding these resistance mechanisms is essential for the development of new therapies and the prevention of the increasing prevalence of drug resistance in mycobacterial infections. The significance of continuous surveillance, species-specific treatment protocols, and the development of novel antimicrobial agents to effectively manage mycobacterial diseases is emphasized by the prevalence of antibiotic resistance in MTB and NTM. This review article focuses on the molecular mechanisms that have resulted in the development of resistance in both MTB and NTMs, as well as the extent to which various classes of antimycobacterial drugs act.