Modulation Of Resistance Research Articles

A High Performance I/Q Zero-IF Mixer with IIP2 Calibration Technique in 45nm SOI CMOS

This paper presents a high performance I/Q zero intermediate frequency (IF) mixer with a second-order input intermodulation point (IIP2) calibration technique in 45nm SOI CMOS process. A behavioral model of the mixer is established to analyze the sources of the second-order intermodulation distortion (IMD2). Based on the analysis, a high accuracy load resistance modulation array is applied to achieve excellent IIP2 performance. The frequency of the local oscillator (LO) signal is 3.5GHz, while the RF input signal frequency range is 3.4GHz∼3.6GHz. Simulation results show that the proposed zero-IF mixer achieves a conversion gain of more than 9.2dB with the input 1dB compression point of -11.28dBm. Noise figure is about 16.9dB at 10kHz and lower than 11.6dB at the frequency above 1MHz. The IIP2 of the circuit is larger than 66dBm after the calibration, which increases more than 40dBm.

Exosomes: Emerging Modulators of Pancreatic Cancer Drug Resistance.

Pancreatic cancer (PaC) is one of the most lethal tumors worldwide, difficult to diagnose, and with inadequate therapeutical chances. The most used therapy is gemcitabine, alone or in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the multidrug FOLFIRINOX. Unfortunately, PaC develops resistance early, thus reducing the already poor life expectancy of patients. The mechanisms responsible for drug resistance are not fully elucidated, and exosomes seem to be actively involved in this phenomenon, thanks to their ability to transfer molecules regulating this process from drug-resistant to drug-sensitive PaC cells. These extracellular vesicles are released by both normal and cancer cells and seem to be essential mediators of intercellular communications, especially in cancer, where they are secreted at very high numbers. This review illustrates the role of exosomes in PaC drug resistance. This manuscript first provides an overview of the pharmacological approaches used in PaC and, in the last part, focuses on the mechanisms exploited by the exosomes released by cancer cells to induce drug resistance.

Modulating contact properties by molecular layers in organic thin‐film transistors

AbstractAdvanced organic devices and circuits demand both ultrahigh charge carrier mobilities and ultralow‐resistance contacts. However, due to a larger access resistance in staggered organic thin‐film transistors (OTFTs), the achievement of ultralow contact resistance () is still a challenge. The modulation of contact resistance by molecular layers near the interface has been rarely reported. Here, we demonstrate that few‐layer organic single crystals are grown on hafnium oxide (HfO2) by solution‐shearing epitaxy. We utilize these organic crystals to fabricate bottom‐gate staggered OTFTs with different contact processes. The results show that the contact properties of OTFTs are obviously modulated by crystal layers. The tri‐layer (3L) evaporated‐Au C10‐DNTT OTFTs exhibit optimal electrical performance, including ultralow of 5.6 Ω ∙ cm, recorded transfer length of 0.4 μm, field‐effect mobility over 14 , threshold voltage lower than 0.3 V, and long‐term air stability over 8 months. The main cause is that the metal atoms can penetrate into the charge transport layer, with damage‐free, in 3L evaporated‐Au OTFTs; nevertheless, it cannot be realized in other cases. Due to layer stacking of conjugated molecules and polymers, our strategy can efficiently modulate the contact resistance to aid the development of high‐performance organic devices and circuits.

Repositioning of HMG-CoA Reductase Inhibitors as Adjuvants in the Modulation of Efflux Pump-Mediated Bacterial and Tumor Resistance.

Efflux pump (EP)-mediated multidrug resistance (MDR) seems ubiquitous in bacterial infections and neoplastic diseases. The diversity and lack of specificity of these efflux mechanisms raise a great obstacle in developing drugs that modulate efflux pumps. Since developing novel chemotherapeutic drugs requires large investments, drug repurposing offers a new approach that can provide alternatives as adjuvants in treating resistant microbial infections and progressive cancerous diseases. Hydroxy-methyl-glutaryl coenzyme-A (HMG-CoA) reductase inhibitors, also known as statins, are promising agents in this respect. Originally, statins were used in the therapy of dyslipidemia and for the prevention of cardiovascular diseases; however, extensive research has recently been performed to elucidate the functions of statins in bacterial infections and cancers. The mevalonate pathway is essential in the posttranslational modification of proteins related to vital eukaryotic cell functions. In this article, a comparative review is given about the possible role of HMG-CoA reductase inhibitors in managing diseases of bacterial and neoplastic origin. Molecular research and clinical studies have proven the justification of statins in this field. Further well-designed clinical trials are urged to clarify the significance of the contribution of statins to the lower risk of disease progression in bacterial infections and cancerous diseases.

Irisin deficiency exacerbates diet-induced insulin resistance and cardiac dysfunction in type II diabetes in mice.

Irisin is involved in the regulation of a variety of physiological conditions, metabolism, and survival. We and others have demonstrated that irisin contributes critically to modulation of insulin resistance and the improvement of cardiac function. However, whether the deletion of irisin will regulate cardiac function and insulin sensitivity in type II diabetes remains unclear. We utilized the CRISPR/Cas-9 genome-editing system to delete irisin globally in mice and high-fat diet (HFD)-induced type II diabetes model. We found that irisin deficiency did not result in developmental abnormality during the adult stage, which illustrates normal cardiac function and insulin sensitivity assessed by glucose tolerance test in the absence of stress. The ultrastructural analysis of the transmission electronic microscope (TEM) indicated that deletion of irisin did not change the morphology of mitochondria in myocardium. Gene expression profiling showed that several key signaling pathways related to integrin signaling, extracellular matrix, and insulin-like growth factors signaling were coordinately downregulated by deletion of irisin. However, when mice were fed a high-fat diet and chow food for 16 wk, ablation of irisin in mice exposed to HFD resulted in much more severe insulin resistance, metabolic derangements, profound cardiac dysfunction, and hypertrophic response and remodeling as compared with wild-type control mice. Taken together, our results indicate that the loss of irisin exacerbates insulin resistance, metabolic disorders, and cardiac dysfunction in response to HFD and promotes myocardial remodeling and hypertrophic response. This evidence reveals the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.NEW & NOTEWORTHY By utilizing the CRISPR/Cas-9 genome-editing system and high-fat diet (HFD)-induced type II diabetes model, our results provide direct evidence showing that the loss of irisin exacerbates cardiac dysfunction and insulin resistance while promoting myocardial remodeling and a hypertrophic response in HFD-induced diabetes. This study provides new insight into understanding the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.

One Step Back from Bedside to the Bench-How Do Different Arterial Stiffness Parameters Behave in Relation to Peripheral Resistance?

The investigation of arterial stiffening is a promising approach to estimating cardiovascular risk. Despite the widespread use of different methods, the dynamic nature of measured and calculated stiffness parameters is marginally investigated. We aimed to determine the stability of large artery elasticity parameters assessed via commonly used, ultrasound-based and oscillometric methods in relation to peripheral resistance modulation. A human experimental environment was composed, and fifteen young males were investigated at rest after extremity heating and external compression. Functional vascular parameters were monitored in each session, and several arterial stiffness parameters were analysed. The distensibility coefficient (DC) did not show significant changes during heat provocation and extremity compression, while DC's stability seemed to be acceptable. The same stability of carotid-femoral pulse wave velocity (PWV) was detected with ultrasound measurement (5.43 ± 0.79, 5.32 ± 0.86 and 5.28 ± 0.77, with p = 0.38, p = 0.27 and p = 0.76, respectively) with excellent intersession variability (intraclass correlation coefficient of 0.90, 0.88 and 0.91, respectively). However, the oscillometric PWV (oPWV) did change significantly between the heating and outer compression phase of the study (7.46 ± 1.37, 7.10 ± 1.18 and 7.60 ± 1.21, with p = 0.05, p = 0.68 and p < 0.001, respectively), the alteration of which is closely related to wave reflection, represented by the changes in reflection time. Our results indicate the good stability of directly measured elastic parameters such as DC and PWV, despite the extreme modulation of peripheral resistance. However, the oscillometric, indirectly detected PWV might be altered by physical interventions, which depend on wave reflection. The effective modulation of wave reflection was characterized by changes in the augmentation index, detected using both oscillometry and applanation tonometry. Thus, the environment during oscillometric measurement should be rigorously standardized. Furthermore, our results suggest the dynamic nature of the reflection point, rather than being a fixed anatomical point, proposed previously as aortic bifurcation.

Bioinspired Young's Modulus-Hierarchical E-Skin with Decoupling Multimodality and Neuromorphic Encoding Outputs to Biosystems.

As key interfaces for the disabled, optimal prosthetics should elicit natural sensations of skin touch or proprioception, by unambiguously delivering the multimodal signals acquired by the prosthetics to the nervous system, which still remains challenging. Here, a bioinspired temperature-pressure electronic skin with decoupling capability (TPD e-skin), inspired by the high-low modulus hierarchical structure of human skin, is developed to restore such functionality. Due to the bionic dual-state amplifying microstructure and contact resistance modulation, the MXene TPD e-skin exhibits high sensitivity over a wide pressure range and excellent temperature insensitivity (91.2% reduction). Additionally, the high-low modulus structural configuration enables the pressure insensitivity of the thermistor. Furthermore, a neural model is proposed to neutrally code the temperature-pressure signals into three types of nerve-acceptable frequency signals, corresponding to thermoreceptors, slow-adapting receptors, and fast-adapting receptors. Four operational states in the time domain are also distinguished after the neural coding in the frequency domain. Besides, a brain-like machine learning-based fusion process for frequency signals is also constructed to analyze the frequency pattern and achieve object recognition with a high accuracy of 98.7%. The TPD neural system offers promising potential to enable advanced prosthetic devices with the capability of multimodality-decoupling sensing and deep neural integration.

Performance Enhancement and In Situ Observation of Resistive Switching and Magnetic Modulation by a Tunable Two‐Level System of Mn Dopants in a‐Gallium Oxide‐based Memristor

AbstractPurely gallium oxide‐based memristors (GOMRs) show great potentials in resistive random‐access‐memory (RRAM) due to their chemical stability and resistive switching characteristics with Roff/Ron ratios up to 102; indeed, GOMRs with higher Roff/Ron ratios and more functionalities are more expected. In this study, ferromagnetic amorphous gallium oxide (a‐GMO) films with a tunable two‐level system of Mn dopants, i.e., Mn2+ and Mn3+ ions, are prepared by scalable polymer assisted deposition. The Pt/a‐GMO/Pt memristors show a high Roff/Ron ratio of 103, at least one order of magnitude higher than those of previously reported purely GOMRs, thanks to the abundant oxygen vacancies (VOs)‐induced low resistance state and Mn2+‐enhanced high resistance state. Meanwhile, magnetic modulation (MM) is realized electrically in the a‐GOMRs during the RS, through the tuning of bound magnetopolarons (BMPs) by bias voltage‐induced VOs variations, which may be useful for quaternary information coding. Notably, the transition between Mn3+ and Mn2+ions is observed in the GOMRs, which is closely related to the variations of VO concentration and BMP amount, providing an in situ tool to probe the VO‐induced RS and BMP‐dependent MM. The results give insights to Mn‐doped GOMRs and may be useful for design, fabrication, and testing of multifunctional high‐performance RRAMs.

Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats.

Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes's impairment of spatial learning memory. Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines. Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide. Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.

Molecular surveillance of Plasmodium falciparum drug-resistance markers in Vietnam using multiplex amplicon sequencing (2000–2016)

Emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapies (ACT) is a major challenge for Greater Mekong Subregion countries in their goal to eliminate malaria by 2030. Tools to efficiently monitor drug resistance beyond resource-demanding therapeutic efficacy studies are necessary. A custom multiplex amplicon sequencing assay based on Illumina technology was designed to target the marker of partial resistance to artemisinin (K13), five candidate modulators of artemisinin resistance, the marker of resistance to chloroquine (crt), and four neutral microsatellite loci. The assay was used to genotype 635 P. falciparum-positive blood samples collected across seven provinces of Vietnam and one of Cambodia between 2000 and 2016. Markers of resistance to artemisinin partner-drugs piperaquine (copy number of plasmepsin-2) and mefloquine (copy number of multidrug-resistance 1) were determined by qPCR. Parasite population structure was further assessed using a 101-SNP barcode. Validated mutations of artemisinin partial resistance in K13 were found in 48.1% of samples, first detection was in 2000, and by 2015 prevalence overcame > 50% in Central Highlands and Binh Phuoc province. K13-C580Y variant became predominant country-wide, quickly replacing an outbreak of K13-I543T in Central Highlands. Mutations in candidate artemisinin resistance modulator genes paralleled the trends of K13 mutants, whereas resistance to piperaquine and mefloquine remained low (≈ 10%) by 2015–2016. Genomic tools applied to malaria surveillance generate comprehensive information on dynamics of drug resistance and population structure and reflect drug efficacy profiles from in vivo studies.

Baseline azithromycin resistance in the gut microbiota of preterm born infants

BackgroundMacrolides, including azithromycin, are increasingly used in preterm-born infants to treat Ureaplasma infections. The baseline carriage of macrolide resistance genes in the preterm stool microbiota is unknown.ObjectivesIdentify carriage of azithromycin resistant bacteria and the incidence of macrolide resistant genes.MethodsAzithromycin resistant bacteria were isolated from serial stool samples obtained from preterm infants (≤32 weeks’ gestation) by culturing aerobically/anaerobically, in the presence/absence of azithromycin. Using quantitative PCR, we targeted 6 common macrolide resistance genes (erm(A), erm(B), erm(C), erm(F), mef(A/E), msr(A)) in DNA extracted from selected bacteria resistant to azithromycin.ResultsFrom 89 stool samples from 37 preterm-born infants, 93.3% showed bacterial growth in aerobic or anaerobic conditions. From the 280 azithromycin resistant isolates that were identified, Staphylococcus (75%) and Enterococcus (15%) species dominated. Macrolide resistance genes were identified in 91% of resistant isolates: commonest were erm(C) (46% of isolates) and msr(A) (40%). Multiple macrolide resistance genes were identified in 18% of isolates.ConclusionMacrolide resistance is common in the gut microbiota of preterm-born infants early in life, most likely acquired from exposure to the maternal microbiota. It will be important to assess modulation of macrolide resistance, if macrolide treatment becomes routine in the management of preterm infants.Impact StatementAzithromycin resistance is present in the stool microbiota in the first month of life in preterm infants91% of azithromycin resistant bacteria carried at least one of 6 common macrolide resistant genesIncreasing use of macrolides in the preterm population makes this an important area of study

Study of silicon-oxide RRAM devices based on complex impedance spectroscopy

This work presents a study of Metal-Oxide-Semiconductor RRAM structures with highly doped Si substrates that exhibit the resistive switching effect. We use DC measurements to show the resistance modulation effect and small-signal measurements to investigate the resistive switching layer behavior. We show that by utilizing the results of impedance spectroscopy measurements, we can build an equivalent electrical circuit that can be used to investigate the properties of RRAM devices. Our model fits very well with the measurement data for investigated frequency and voltage values.

Impact of the COVID-19 Pandemic on Inpatient Antibiotic Use in the United States, January 2019 Through July 2022.

Antimicrobial use data reported to the National Healthcare Safety Network's Antimicrobial Use and Resistance Module between January 2019 and July 2022 were analyzed to assess the impact of the COVID-19 pandemic on inpatient antimicrobial use.

Noncoding RNAs: an emerging modulator of drug resistance in pancreatic cancer.

Pancreatic cancer is the eighth leading cause of cancer-related deaths worldwide. Chemotherapy including gemcitabine, 5-fluorouracil, adriamycin and cisplatin, immunotherapy with immune checkpoint inhibitors and targeted therapy have been demonstrated to significantly improve prognosis of pancreatic cancer patients with advanced diseases. However, most patients developed drug resistance to these therapeutic agents, which leading to shortened patient survival. The detailed molecular mechanisms contributing to pancreatic cancer drug resistance remain largely unclear. The growing evidences have shown that noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), are involved in pancreatic cancer pathogenesis and development of drug resistance. In the present review, we systematically summarized the new insight on of various miRNAs, lncRNAs and circRNAs on drug resistance of pancreatic cancer. These results demonstrated that targeting the tumor-specific ncRNA may provide novel options for pancreatic cancer treatments.

Autophagy and cancer drug resistance in dialogue: Pre-clinical and clinical evidence

The emergence of drug resistance is a major challenge for oncologists. Resistance can be categorized as acquired or intrinsic; the alteration of several biological mechanisms contributes to both intrinsic and acquired resistance. Macroautophagy/autophagy is the primary process in eukaryotes for the degradation of macromolecules and organelles. This process is critical in maintaining cellular homeostasis. Given its function as either a pro-survival or a pro-death phenomenon, autophagy has a complex physio-pathological role. In some circumstances, autophagy can confer chemoresistance and promote cell survival, whereas in others it can promote chemosensitivity and contribute to cell death. The role of autophagy in the modulation of cancer drug resistance reflects its impact on apoptosis and metastasis. The regulation of autophagy in cancer is mediated by various factors including AMP-activated protein kinase (AMPK), MAPK, phosphoinositide 3-kinase (PI3K)-AKT, BECN1 and ATG proteins. Non-coding RNAs are among the main regulators of autophagy, e.g., via the modulation of chemoresistance pathways. Due to the significant contribution of autophagy in cancer drug resistance, small molecule modulators and natural compounds targeting autophagy have been introduced to alter the response of cancer cells to chemotherapy. Furthermore, nanotherapeutic approaches based on autophagy regulation have been introduced in pre-clinical cancer therapy. In this review we consider the potential for using autophagy regulators for the clinical treatment of malignancies.

Resveratrol as an Inhibitor of the NorA Efflux Pump and Resistance Modulator in Staphylococcus aureus.

Staphylococcus aureus can exhibit resistance to various antibiotics. Among its resistance mechanisms, the active efflux of antibiotics can be seen as relevant. This study aimed to evaluate the ability of resveratrol to modulate norfloxacin resistance in S. aureus. The antimicrobial activity of resveratrol was assessed using the broth microdilution method to determine the minimum inhibitory concentration (MIC). Then, the modulatory effect of resveratrol was evaluated using the MIC determination for the antibiotic or ethidium bromide in the presence and absence of resveratrol at a sub-MIC level. The MIC of norfloxacin against S. aureus SA1199B (NorA-overexpressing strain) decreased 16-fold when in the presence of resveratrol, with a similar behavior being observed for ethidium bromide. An evaluation of the ethidium bromide accumulation was also performed, showing that in the presence of resveratrol, the SA1199B strain had augmented fluorescence due to the accumulation of ethidium bromide. Altogether, the results suggested that resveratrol may act by inhibiting NorA. These in vitro data were supported by docking results, with interactions between resveratrol and the NorA efflux pump predicted to be favorable. Our findings demonstrated that resveratrol may modulate norfloxacin resistance through the inhibition of NorA, increasing the effectiveness of this antibiotic against S. aureus.

Resistance transient dynamics in switchable perovskite memristors

Memristor devices have been investigated for their properties of resistive modulation that can be used in data storage and brain-like computation elements as artificial synapses and neurons. Memristors are characterized by an onset of high current values under applied voltage that produces a transition to a low resistance state or successively to different stable states of increasing conductivity that implement synaptic weights. Here, we develop a nonlinear model to explain the variation with time of the voltage and the resistance and compare it to experimental results on ionic–electronic halide perovskite memristors. We find separate experimental signatures of the capacitive discharge and inductive current increase. We show that the capacitor produces an increase step of the resistance due to the influence of the series resistance. In contrast, the inductor feature associated with inverted hysteresis causes a decrease of the resistance, as observed experimentally. The chemical inductor feature dominates the potentiation effect in which the conductivity increases with the voltage stimulus. Our results enable a quantitative characterization of highly nonlinear electronic devices using a combination of techniques such as time transient decays and impedance spectroscopy.

Mechanisms involved in the HMGB1 modulation of tumor multidrug resistance (Review).

Tumor multidrug resistance (MDR) remains one of the most challenging barriers to successful cancer treatment. Several previous studies have suggested that high mobility group box 1 (HMGB1) may be a promising therapeutic target for overcoming cancer drug resistance. Emerging evidence has indicated that HMGB1 functions as a 'double‑edged sword' that plays both pro‑ and anti‑tumor roles in the development and progression of multiple types of cancer. HMGB1 has also been found to be a key regulator of several cell death and signaling pathways, and is involved in MDR by mediating cell autophagy and apoptosis, ferroptosis, pyroptosis and multiple signaling pathways. Additionally, HMGB1 is regulated by a variety of non‑coding RNAs (ncRNAs), such as microRNAs, long ncRNAs and circular RNAs that are involved in MDR. Thus far, studies have been conducted to identify strategies with which to overcome HMGB1‑mediated MDR by the targeted silencing of HMGB1 and the targeted interference of HMGB1 expression using drugs and ncRNAs. Therefore, HMGB1 is closely associated with tumor MDR and is a promising therapeutic target.

Potential role of intratumor bacteria outside the gastrointestinal tract: More than passengers.

Tumor-associated bacteria and gut microbiota have gained significant attention in recent years due to their potential role in cancer development and therapeutic response. This review aims to discuss the contributions of intratumor bacteria outside the gastrointestinal tract, in addition to exploring the mechanisms, functions, and implications of these bacteria in cancer therapy. We reviewed current literature on intratumor bacteria and their impact on tumorigenesis, progression, metastasis, drug resistance, and anti-tumor immune modulation. Additionally, we examined techniques used to detect intratumor bacteria, precautions necessary when handling low microbial biomass tumor samples, and the recent progress in bacterial manipulation for tumor treatment. Research indicates that each type of cancer uniquely interacts with its microbiome, and bacteria can be detected even in non-gastrointestinal tumors with low bacterial abundance. Intracellular bacteria have the potential to regulate tumor cells' biological behavior and contribute to critical aspects of tumor development. Furthermore, bacterial-based anti-tumor therapies have shown promising results in cancer treatment. Understanding the complex interactions between intratumor bacteria and tumor cells could lead to the development of more precise cancer treatment strategies. Further research into non-gastrointestinal tumor-associated bacteria is needed to identify new therapeutic approaches and expand our knowledge of the microbiota's role in cancer biology.

Epitaxial growth of EuNiO3 on SrTiO3 and its application to stacked protonation resistance switching devices

The application of strongly correlated oxides as electronic devices is crucial issues to both modern physics and industry. In this work, the strongly correlated oxides EuNiO3 epitaxial thin film on SrTiO3 is synthesized, and the metal–insulator transition at 193 °C is identified. By injecting proton into EuNiO3 via a Pt catalyst, the huge resistance modulation up to six orders of magnitude is achieved. Moreover, the resistance switching is also observed in a prototype device built by protonated EuNiO3 and Nb-SrTiO3. Due to the intrinsic low activation energy of proton diffusion, comparing with oxygen-driven devices with the same structure, the switching speed of the proton-driven prototype device is 102–103 faster and might be further enhanced by optimizing the device design.