HIV treatment strategies against viral enzymes are continuously hampered by viral drug resistance. Recent findings show that viral substrate Gag contributes to HIV-1 Protease Inhibitor (PI) resistance, leading to demands for new strategies in HIV treatment where Gag is recognized as a drug target. To successfully target Gag, there is a need of in-depth understanding of the Gag polyprotein and the effects of Gag mutations. Here, we propose new strategies in designing novel Gag inhibitors against existing and novel emerging Gag mutations via a structural understanding of the Gag-Protease relationship in PI resistance. In this review, we discuss the role of both novel and previously reported mutations, revealing insights to how they aid in PI resistance, and how new Gag inhibitors can be designed.

The high mutation rate of human immunodeficiency virus type 1 (HIV-1) plays a major role in treatment resistance from the development of vaccines to long-lasting drugs. In addressing the crux of the issue, various attempts to estimate the mutation rate of HIV-1 resulted in a large range of 10-5 - 10-3 errors/bp/cycle due to the use of different types of investigation methods. In this review, we discuss the different assay methods, their findings on the mutation rates of HIV-1 and how the location of these mutations can be further analyzed for their potential allosteric effects to reveal potentially new inhibitors with different pharmacodynamics that can be used to circumvent fast occurring HIV drug resistance. Given that HIV is one of the fastest mutating viruses, it is a good model for comprehensive study of its mutations that can give rise to much horizontal understanding towards overall viral drug resistance as well as emerging viral diseases.

Different water treatment regiments are revealed to have potential in enriching antibiotic resistant bacteria (ARB). Advanced oxidation processes (AOPs) based disinfection techniques have been studied widely in the recent times due to their advantages over conventional treatment methods. However, bacterial response and adaptations against the hostile environments of AOPs is not clearly understood yet. Based on the existing knowledge on the ways in which bacteria surpass the antibiotic treatment, here we propose few important aspects of bacterial adaptation which could be true for AOPs as well since both antibiotics and AOPs generate reactive oxygen species (ROS) during their modes of action. We discuss the plausible role of ROS in the selection of ARB and bacterial heterogeneity as a strategy to bypass the lethal action of AOPs. Understanding bacterial adaptation during disinfection plays a vital role in devising strategies to outclass the bacterial survival. Hence, more importance should be given to such studies in the near future for the successful implementation of AOPs.

Antimicrobial resistance (AMR) is a public health problem exacerbated by the overuse and misuse of antibiotics and an inadequate capacity of laboratories to conduct AMR surveillance. This study assessed the capacity of laboratories in seven faith-based hospitals to conduct bacteriology, AMR testing and surveillance in Zambia. This multi-facility, cross-sectional exploratory study was conducted from February 2024 to April 2024. We collected and analysed data using the self-scoring Laboratory Assessment of Antibiotic Resistance Testing Capacity (LAARC) tool. This study found an overall score of 39%, indicating a low capacity of laboratories to conduct AMR surveillance. The highest capacity score was 47%, while the lowest was 25%. Only one hospital had full capacity (100%) to utilise a Laboratory Information System (LIS). Three hospitals had good capacity to perform data management with scores of 83%, 85%, and 95%. Only one hospital had full capacity (100%) to process specimens, and only one hospital had good safety requirements for a microbiology laboratory, with a score of 89%. This study demonstrates that all the assessed hospitals have a low capacity to conduct AMR surveillance. Therefore, there is an urgent need to strengthen the microbiology capacity of laboratories to enhance surveillance in faith-based hospitals in Zambia.

The SiBOC precursor ceramics were fabricated by polymer-derived method SiBOC precursors with different B/Si molar ratios were synthesized by controlling monomer content. The effects of different process conditions on SiBOC ceramics and the oxidation resistance of SiBOC ceramics at a high temperature (1400 ℃) were studied. The SiBOC precursor’s bonds of Si-O-C, Si-O-Si, and Si-O-B were detected by FTIR. The precursor is converted to a rigid ceramic material that has an 85.3 wt % ceramic yield of SiBOC ceramics with B/Si=0.4 by TG-DSC. The results of SEM analysis show that the SiBOC ceramics surface bulges and folds increase with the increase of boric acid content. With the increase of pyrolysis temperature and pyrolysis time, the size and number of pores on the surface of SiBOC ceramics also increase. Static oxidation tests show that SiBOC ceramics with B/Si=0.4 have better oxidation resistance under other conditions being the same.

The synergistic effect of silicon and cerium addition on the oxidation resistance of pack cementation aluminide coating applied on Ni-based superalloy substrate was investigated. The effect of cerium and silicon on the scale morphology, oxidation behavior, and scale spallation tendency are discussed based on the experimental results, using X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive X-ray analyses (EDX). In addition, the oxidation resistance was evaluated by measuring the weight of samples after each 16-hour cycle at 1100˚C for 50 cycles. The experiments indicated that silicon addition to aluminide coating improves the oxidation resistance through the formation of β-NiAl1-nSin and δ-Ni2Al3-nSin and δ-Ni2Si phases. Furthermore, the addition of 1% cerium to modified aluminide enhances the formation of the fine-grained microstructure of the β-NiAl and δ-Ni2Al3 and reduces the outward/inward diffusion of elements (so-called blocking effect) which significantly modifies the hot oxidation resistance. The addition of 2% cerium, owing to the distortion of the β-NiAl and δ-Ni2Al3 phases, strictly decreases the hot oxidation resistance and the coating is exfoliated after 450 h at 1100 °C. The cyclic oxidation tests showed that the samples containing 1% cerium and 6% silicon possess the highest hot oxidation resistance in which 2 mg/cm2 weight loss of Ce-Si-aluminide was reported after 800 h. This is attributed to the simultaneous effect of cerium and silicon during the deposition process which reduces the oxygen diffusion and reduces the growth rate of α-Al2O3 during oxidation tests. The α-Al2O3 oxidation layer morphology showed that finer grains are formed in samples containing optimum ratios of cerium and silicon which indicates that these elements improve the coating adhesion and oxidation resistance simultaneously.

High temperature titanium alloys are widely used in aerospace hot parts, however, the thermal barrier temperature of 600 oC limits its service temperature. In this paper, a two-step hot-dip plating method is proposed to prepare the composite coating containing Ce on the surface of titanium alloy, which can make the oxidation resistance temperature of titanium alloy reach 800 oC The microstructure, phase composition and element distribution of Ce-containing Ti-Al-Si hot-dip coating, Ce-containing Ti-Al-Si pre-oxidation coating and Ce-containing Ti-Al-Si high-temperature oxidation coating were studied by X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS), respectively. The results show that the Ti-Al-Si hot-dip coating containing Ce is mainly composed of (Ti,Ce)(Al,Si)3 alloy phase layer, and the Ti-Al-Si pre-oxidation coating containing Ce is mainly composed of Ti-Al binary system phase layer and dense Al2O3 layer rich in CeO2. Ce in the high temperature oxidation coating of Ti-Al-Si containing Ce is mainly distributed in Ti3Al, TiAl, TiAl3+Ti5Si3 mixed phase layer and Al2O3. The addition of Ce can promote the formation of continuous Al2O3 layer, improve the uniformity of composite coating, prevent the spread of cracks, and improve the high temperature oxidation resistance of Ti-Al-Si coating.

The global burden of antimicrobial resistance is on the rise, resulting in higher morbidity and mortality in our communities. The spread of antimicrobial resistance in the environment and development of resistant microbes is a challenge to the control of antimicrobial resistance. Approaches, such as antimicrobial stewardship programmes, and enhanced surveillance, have been devised to curb its spread. However, particularly in lower- and middle-income countries, the overall extent of antimicrobial resistance, and knowledge on on-going surveillance, stewardship or investigation efforts, re often poorly understood. This study aimed to look at the efforts that have been undertaken to combat antimicrobial resistance in Uganda as a means of establishing an overview of the situation, to help inform future decisions. We conducted a systematic literature review of the PubMed database to assess the efforts that have been done in Uganda to investigate and combat antimicrobial resistance. A search combining keywords associated with antimicrobial resistance were used to look up relevant studies between 1995 and 2020 on surveillance of antimicrobial resistance in Uganda, and susceptibility of microbes to different drugs. The search yielded 430 records, 163 of which met the inclusion criteria for analysis. The studies were categorized according to country and region, the type of antimicrobial resistance, context of the study, study design and outcome of the study. Antibacterial resistance and antimalarial resistance had the most published studies while antiviral and antifungal resistance each were represented by very few studies. Most studies were conducted in humans and hospital settings, with very few in veterinary and One Health contexts. The results from our work can inform public health policy on antimicrobial stewardship as it contributes to understanding the status of antimicrobial resistance surveillance in Uganda, and can also help to guide future research efforts. Notably, a One Health approach needs to be followed with re-spect to surveillance of antimicrobial resistance to better understand the mechanisms of resistance transfer across the human-animal–environment interface, including additional investigation in antiviral and antifungal resistance.

Enterococci are gastrointestinal commensals whose hardiness allowed them to colonize very diverse environments, including soils, water, food and feed. This ability to overcome adverse conditions makes enterococci problematic once they colonize hospital niches. Together with the malleability of their genomes, the capacity to acquire and disseminate determinants of antibiotic resistance have contributed to convert what was once just another opportunistic pathogen into a first-class clinical problem. This review discusses the dimension of the emergence of enterococcal resistance to key antimicrobial agents, the dissemination of this resistance and its significance in terms of public health, with the aim of raising the awareness to the need to devise and implement monitoring programmes and effective antibiotic usage guidelines.

Antibiotic resistance among bacterial pathogens is recognized as a major threat to human health worldwide. The emergence of multidrug-resistant bacteria can also be found in the community settings, apart from hospital environment, which indicates that reservoirs of antibiotic resistance genes do exist outside the hospital. The growth of antibiotic resistance is a consequence of bacterial adaptations in response to selective pressures. To survive in this hostile environment, bacteria develop defence mechanisms such as chemical modification of antibiotics, enzyme-catalysed antibiotic degradation, altered permeability, antibiotic efflux, mutation of target sites and biofilm formation, resulting in resistance to nearly all currently available antibiotics used in the clinical practice. The present review summarizes insights into the molecular mechanisms underlying the antibiotic resistance which is useful for planning strategies to combat antibiotic resistance and devise innovative therapeutic tools to fight against multidrug-resistant bacterial species.

Antibiotics were once called miracle drugs which hit the market with astounding impact as it was considered the ultimate cure for infectious diseases in the mid-20th century. However, today nearly all bacteria that afflict humankind have become resistant to these wonder drugs once developed to stop them, imperilling the foundation of modern medicine. During the COVID pandemic, there was a surge in macrolide use to treat secondary infections and this persistent use of macrolide antibiotics has provoked the emergence of macrolide resistance. In view of the current dearth of new antibiotics in the pipeline, it is essential to find an alternative way to combat drug resistance. Antibiotic potentiators or adjuvants are non-antibacterial active molecules that, when combined with antibiotics, increase their activity. Thus, potentiating the existing antibiotics is one of the promising approaches to tackle and minimize the impact of antimicrobial resistance. Several natural and synthetic compounds have demonstrated effectiveness in potentiating macrolide antibiotics against MDR pathogens. The present review summarizes the different resistance mechanisms adapted by bacteria to resist macrolides and further emphasizes the major macrolide potentiators identified which could serve to revive the antibiotic and can be used for the reversal of macrolide resistance.

The exponential rise of bacterial resistance poses a threat to antibiotic efficacy, with a great impact on public health. This study aims to analyze the correlation between antibiotic consumption and the emergence of bacterial resistance. Conducted retrospectively at Charles Nicolle Hospital in Tunis, Tunisia from 2010 to 2022, this study was based on STKMED® software for antibiotic consumption data, hospital administrative records for the number of hospitalization days, and SIRSCAN® software for bacteriological data. Data processing was performed using Excel® software, and analysis was conducted using SPSS23®. In 2022, Consumption was almost evenly split between the two major “AWaRe” groups, with 49.33% for "Access" and 46.89% for "Watch", and the consumption of the "Reserve" group also increased, accounting for 3.77% of the total. Bacterial resistances, notably carbapenem-resistant Klebsiella pneumoniae, increased. Seventy-four significant correlations were identified, including those be-tween carbapenem consumption and resistance in Escherichia coli and Klebsiella pneumoniae strains. However, no significant corre-lation was observed with imipenem-resistant Pseudomonas aeruginosa strains. The significant correlations between the emergence of bacterial resistance and antibiotic use, particularly with antibiotics in the "Watch" and "Reserve" groups, underscore the urgent need to continue efforts to combat this threat through rational antibiotic use.

The i-4-1-Health project is a One Health project on the prevalence and spread of antimicrobial resistance in the human and veterinary domain in the Dutch-Belgian cross-border region. This paper describes the main components of the laboratory protocol that was developed to standardise the microbiological methods used for the detection of intestinal carriage of highly-resistant microorganisms.

: As antibiotic resistance undermines efforts to treat bacterial infections, phage therapy is being increasingly considered as an alternative in clinical settings and agriculture. However, a major concern in using phages is that pathogens will develop resistance to the phage. Due to the constant evolutionary pressure by phages, bacteria have evolved numerous mechanisms to block infection. If we determine the most common among them, we could use this knowledge to guide phage therapeutics. Here we compile data from 88 peer-reviewed studies where phage resistance was experimentally observed and linked to a bacterial gene, then assessed these data for patterns. In total, 141 host genes were identified to block infection against one or more of 80 phages (representing five families of the Caudovirales) across 16 microbial host genera. These data suggest that bacterial phage resistance is diverse, but even well-studied systems are understudied, and there are gaping holes in our knowledge of phage resistance across lesser-studied regions of microbial and viral sequence space. Fortunately, scalable approaches are newly available that, if broadly adopted, can provide data to power ecosystem-aware models that will guide harvesting natural variation towards designing effective, broadly applicable phage therapy cocktails as an alternative to antibiotics.

Rosette caused by rose rosette virus (RRV) is the most devastating malady of rose in the United States. Because of the recent discovery of the virus and the completion of Koch’s postulates all assumptions about the disease are based on visual observations of material that may or may have not been infected by the virus. This study addresses several aspects of virus and disease epidemiology. Twenty rose genotypes were screened for mite and/or virus resistance. Phyllocoptes fructiphilus the only known vector of RRV, was able to establish, lay eggs and develop to nymphs and adults in all genotypes. ‘Stormy Weather’ shows resistance to the virus as assessed by both mite and cleft-grafting transmission experiments. The acquisition/latent and inoculation access periods were studied revealing long acquisition/latent periods but rapid inoculation time frames. The outputs of this study will assist in the better management of the vector and the disease. The resistant genotype identified could be used in areas with high disease pressure to minimize spread and for identification of the mechanisms behind resistance or as breeding material to incorporate virus resistance to new cultivars. The short inoculation access period indicates that chemical control for the vector may be a challenging undertaking.

Accurately monitoring insecticide resistance in target mosquito populations is important to combating malaria and other vector-borne diseases, and robust methods are key. The “WHO susceptibility bioassay” has been used for +60 years: mosquitoes of known physiological status are exposed to a discriminating concentration of insecticide. Several changes to the test procedures have been made historically which may seem minor but could impact bioassay results. The published test procedures and literature for this method were reviewed for methodological details. Areas where there was room for interpretation in the test procedures or where the test procedures were not being followed were assessed experimentally for impact on bioassay results: covering or uncovering of the tube end during exposure, number of mosquitoes per test unit, and mosquito age. Many publications do not cite the most recent test procedures, methodological details are reported which contradict the test procedures referenced or methodological details are not fully reported. As a result, the precise methodology is unclear. Experimental testing showed that using fewer than the recommended 15-30 mosquitoes per test unit significantly reduced mortality, covering the exposure tube had no effect, and using mosquitoes older than 2-5 days old increased mortality, particularly in the resistant strain. Recommendations are made for better reporting of experimental parameters.

Immunotherapy with programmed Cell Death Protein/Programmed Cell Death Ligand 1 (PD-1/PD-L1) targeting antibodies has transformed clinical outcomes for patients with non-small cell lung cancer (NSCLC) and has become an integral part of standard treatment regimens. However, the response to PD-1/PD-L1 inhibitors varies, and many tumors present with either primary or acquired resistance to immunotherapy. There are emerging data on potential mechanisms underlying resistance to immunotherapy which is derived mainly from either preclinical studies or secondary correlative analyses from clinical trials. Resistance to immunotherapy is complex and can present immediately after treatment initiation (primary resistance) or after initial clinical benefit (secondary or acquired resistance). The tumor microenvironment, particularly the presence, and activity of T cells, also significantly influences resistance with both tumor-extrinsic as well as tumor-intrinsic mechanisms such as lack of T-cell infiltration, insufficient neoantigens, or absence of an interferon signature identified as being associated with ICI resistance. Improved understanding of the molecular and immunologic mechanisms underlying immunotherapy resistance is essential for the future development of effective therapies targeting immunotherapy resistance. In this review, we discuss the emerging data identifying the molecular mechanisms of primary resistance to immunotherapy and explore potential therapeutic strategies to target these.

The emergence of antimicrobial resistance (AMR) in pathogens transmitted through food poses a significant threat to global public health, complicating infection treatment and increasing mortality rates. This review explores the role of resistome mapping as a crucial tool for understanding the transmission dynamics of antimicrobial resistance genes (ARGs) in foodborne pathogens, such as Salmonella, Escherichia coli, Listeria monocytogenes, and Campylobacter spp., as well as various techniques for resistome mapping, such as metagenomic sequencing, PCR-based methods, and whole-genome sequencing (WGS), highlighting the significance of horizontal gene transfer (HGT) as a key mechanism for ARG dissemination in foodborne pathogens. Additionally, we investigated the influence of agricultural practices and environmental factors on AMR development, highlighting the critical need for improved surveillance, antibiotic stewardship, and global collaboration to mitigate the spread of resistant ARGs through the food chain. The perceptions gained from resistome mapping play an essential role in developing effective approaches to address AMR and to ensure food safety.

Drought events are predicted to become more prevalent in the future. Evaluating the performance of herbicide-resistant and susceptible weed ecotypes to progressive drought can provide insights into whether resistance trait(s) increased or reduced the fitness of a resistant population. Two experiments were conducted in the greenhouse between January and May 2021 to evaluate drought tolerance differences between Palmer amaranth accessions resistant to S-metolachlor or glyphosate and their susceptible counterparts. The accessions used were: S-metolachlor-resistant (17TUN-A), a susceptible standard (09CRW-A), and glyphosate-resistant (22 to 165 EPSPS copies) and glyphosate-susceptible (3 to 10 EPSPS copies) plants from accession 16CRW-D. Daily transpiration of each plant was measured. The daily transpiration rate was converted to normalized transpiration ratio (NTR) using a double-normalization procedure. The daily soil water content was expressed as a fraction of transpirable soil water (FTSW). The threshold FTSW (FTSWcr), after which NTR decreases linearly, was estimated using a two-segment linear regression analysis. The data showed differences between S-metolachlor- resistant and -susceptible accessions (P ≤ 0.05). The FTSW remaining in the soil at the breakpoint for the S-metolachlor-susceptible accession (09CRW-A) was 0.17±0.007. The FTSW remaining in the soil at the breakpoint for the S-metolachlor-resistant accession (17TUN-A) was 0.23±0.004. Although the mechanism endowing resistance to S-metolachlor might have contributed to increased drought tolerance, follow-up experiments are needed to verify this finding. Increased EPSPS copy number did not improve drought tolerance of Palmer amaranth.

Urinary tract infections are a major cause of morbidity and mortality in Mozambique. They are sometimes treated empirically with nitrofurantoin. However, little is known about this antibiotic’s performance and bacterial resistance in the country. This study analyzed the results of nitrofurantoin sensitivity tests requested in the Central Hospital of Maputo during 2012 and 2013. As result, 181 samples were tested and most cases (66.9%) showed absolute sensitivity but there were considerable cases of resistance (29.8%). Morganella morganii was the only bacteria presenting no absolute or intermediate resistance. The sensitivity was also high in the case of Escherichia coli (90%) and Gram-negative bacteria (66.7%). Serratia marcescens was mostly resistant (64.3%). The remaining bacteria showed inconclusive results. Thus they shall be subjected to a sensitivity test before prescription. Factors such as seasonality, patients’ sex and urine transparency did not seem to be reliable indicators of microbial resistance in the urine. Yet, a longer time span (over 5 years) might be sufficient for the sensitivity profile to change.

Chili peppers (Capsicum annuum L.) are economically important crop worldwide. Pepper yellow leaf cure Thailand virus (PepYLCTHV), a Begomovirus causing yellow leaf mosaic disease of chili pepper has been reported to damage 95% economic loss under favorable epidemic conditions. Thirty-one chili genotypes were screened for resistance to PepYLCTHV disease through challenge inoculation using 10-15 viruliferous whiteflies per plant. We purified two resistant lines (PEP6 and PEP12) through four generations of selfing and selection through challenged inoculations. At the 28 days after inoculations two chili genotypes showed symptoms less based on disease severity and percentage of disease incidence of 30 plants PEP6 showed a disease severity 3.64 with 69.33 % DI and PEP12 showed a disease severity 3.83 with 77.67 % DI. PEP6 and PEP12 were selected for pure-line development for four cycles.Both varieties showed an increase in percentage of the resistant plant 12.78 % and 16.77 %, respectively. These lines have potential for release as resistant lines for improvement chili pepper resistance to PepYLCTHV and for developing maker associated with the resistant trait.

In the absence of information on Borrelia species causing Lyme borreliosis (LB) in Serbia, we were interested in the pathogenic potential of local strains of Borrelia burgdorferi sensu lato isolated from ticks. The susceptibility of B. burgdorferi sensu lato isolates to human complement was tested in vitro. A total of 31 strains were analysed by serum susceptibility testing - 12 Borrelia afzelii, 12 Borrelia lusitaniae, three Borrelia bavariensis, two Borrelia garinii, and two Borrelia valaisiana. The serum-resistant strains (B. afzelii, B. bavariensis and B. valaisiana) expressing OspA and OspB or OspA and OspC proteins might be related to the different pathogenic potential of the specific Borrelia strains and their ability to cause different clinical manifestations of LB in humans. Among the B. lusitaniae strains from Serbia, two were significantly more motile than others (all p < 0.05) and equally motile as human isolate (both p > 0.05), and since they express OspC, their pathogenic potential remains unclear. For further studies, it is of particular interest to explore the mechanism of resistance of B. valaisiana and to explain the fair motility of B. lusitaniae, a predominant Borrelia species in Serbia, in the presence of human complement.

BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.

Since the domestication of plants, pathogenic fungi have consistently threatened crop production, evolving genetically to develop increased virulence under various selection pressures. Understanding their evolutionary trends is crucial for predicting and designing control measures against future disease outbreaks. This paper reviews the evolution of fungal pathogens from natural habitats to agricultural settings, focusing on eight significant phytopathogens: Pyricularia oryzae, Botrytis cinerea, Puccinia spp., Fusarium graminearum, F. oxysporum, Blumeria graminis, Zymoseptoria tritici, and Colletotrichum spp. Also, we explore the mechanism used to understand evolutionary trends in these fungi. The studied pathogens have evolved in agroecosystems through either (1) introduction from elsewhere or (2) local origins involving co-evolution with host plants, host shifts, or genetic variations within existing strains. Genetic variation, generated via sexual recombination and various asexual mechanisms, often drives pathogen evolution. While sexual recombination is rare and mainly occurs at the center of origin of the pathogen, asexual mechanisms such as mutations, parasexual recombination, horizontal gene or chromosome transfer, and chromosomal structural variations are predominant. Farming practices like mono-cropping resistant cultivars and prolonged use of fungicides with the same mode of action can drive the emergence of new pathotypes. Furthermore, host range does not necessarily impact pathogen adaptation and evolution. Although halting pathogen evolution is impractical, its pace can be slowed by managing selective pressures, optimizing farming practices, and enforcing quarantine regulations. The study of pathogen evolution has been transformed by advancements in molecular biology, genomics, and bioinformatics, utilizing methods like next-generation sequencing, comparative genomics, transcriptomics and population genomics. However, continuous research remains essential to monitor how pathogens evolve over time and to develop proactive strategies that mitigate their impact on agriculture.

Periodic assessment of bacterial contamination is necessary as it allows proper guidance in cases of eye infections through the use of appropriate antibiotics. Due to the extensive use of antibiotic treatment, most of the contamination flora is resistant to the usual ophthalmic antibiotics. The present study shows an updated picture of the susceptibility of Gram-positive and Gram-negative bacteria found on the ocular surface to the most commonly used antibiotic agents in patients undergoing cataract surgery. A total of 993 patients were included in the study with ages between 44 and 98 years old. Conjunctival culture was collected 7 days before cataract surgery. The response of Gram-positive and Gram-negative bacteria to various antibiotic classes like glycopeptides, cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, phenicols, tetracyclines, rifamycins, macrolides and penicillins was assessed. From the tested antibiotics, vancomycin had 97.8% efficacy on Gram-positive bacteria. In the cephalosporin category, we observed an increased resistance of the cefuroxime for both Gram-positive and negative bacteria. Antibiotics that have more than 90% efficacy on Gram-positive bacteria are: meropenem, imipenem, netilmicin, amikacin and rifampicin. On Gram-negative bacteria, we found 100% efficacy of all tested fluoroquinolones, aminoglycosides (except for tobramycin), doxycycline, azithromycin, clarithromycin and chloramphenicol. The current study illustrates patterns of increased resistance of certain bacteria present on ocular surface to some of the commonly used antibiotics in ophthalmological clinical practice. One such revealing example is cefuroxime, which has been highly used as an intracameral antibiotic for the prevention of bacterial endophthalmitis after cataract surgery.

The spread of antimicrobial resistance (AMR) is a global challenge. Close and continuous surveillance for quick detection of AMR can be difficult, especially in remote places. This narrative review focuses on the contributions of pharmacovigilance (PV) as an auxiliary tool for identifying and monitoring the ineffectiveness of, resistance to, and inappropriate use of antibiotics (ABs). The terms “drug ineffective,” “therapeutic failure,” “drug resistance,” “pathogen resistance,” and “multidrug resistance” were found in PV databases and dictionnaires, and denote ineffectiveness. These terms cover a range of problems that should be better investigated because they are useful in warning about possible causes of AMR. “Medication errors,” especially those related to dose and indication, are highlighted in the literature, suggesting inappropriate use of ABs. Hence, the included studies show that the terms of interest related to AMR are not only present but frequent in PV surveillance programs. This review illustrates the feasibility of using PV as a complementary tool for antimicrobial stewardship activities, especially in scenarios where other resources are scarce.

Divulsuperbac (DSB) is a Service Learning project targeted at the educational community. It started in 2019 and has engaged Biology degree students in a Microbiology-focused initiative in the Valencian Community (Spain), for four academic years. The DSB project comprises various outreach activities intending to raise awareness of the superbugs' threat to pre-university students. We created an exhibition that contained 14 infographics on the topic of antimicrobial resistance which was presented every week in high schools. The infographics were presented by university students, who explained the problem to the pre-university students and subsequently assessed their comprehension of the topic. The surveys conducted yielded satisfactory results, which motivated us to extend this project to other regions of the world.

Tomato is the highest-value fruit/vegetable crop worldwide. However, the quality and yield of tomatoes are severely affected by late blight. MicroRNA482s (miR482s) are involved in plant immune system. In this study, miR482c was transiently and stably overexpressed in tomatoes in transgenic plants to explore its mechanism in tomato resistance against late blight. Tomato in transgenic plants transiently overexpressed miR482c displayed larger lesion area than the control plants upon infection. Furthermore, compared with the WT tomato plants, the transgenic tomato plants stably overexpressing miR482c displayed decreased expression of target genes accompanied by lower POD, SOD, and PAL activity activities and higher MDA content, thereby leading to a decline in the ROS scavenging ability and aggravating the damage of lipid peroxidation product accumulation on the cell membrane, eventually enhancing plant susceptibility. This finding indicates that miR482c may act as a negative regulator in tomato resistance by regulating NBS-LRR expression levels and ROS levels.

Phytopathogenic oomycetes are known to infect a host plant successfully due to their ability to secrete a set of protein effectors. Of interest to many researchers are effectors with the N-terminal RxLR motif (Arginine-any amino acid-Leucine-Arginine). Owing to the genome sequencing, we can now comprehend the high level of diversity among oomycete effectors, and similarly, their conservation within and among species core RxLR effectors (CREs). Currently, there are a couple of putative CREs that have been identified in oomycetes. The functional characterization of these CREs proposes their virulence role with the potential of targeting central cellular processes that are conserved across diverse plant species. This could be harnessed in engineering plants for broad-spectrum and durable resistance.

Triple negative breast cancer (TNBC) is associated with a generally poor prognosis due to its highly aggressive and metastatic nature, lack of targetable receptors, as well as the frequent development of resistance to chemotherapy. We previously reported that AU1, a small molecule developed as an inhibitor of BPTF (bromodomain PHD finger containing transcription factor), was capable of sensitizing preclinical models of triple negative breast cancer to chemotherapy, in part via the promotion of autophagy. In studies reported here, we identify an additional property of this compound, specifically that sensitization is associated with inhibition of the P-glycoprotein efflux pump. In silico molecular docking studies indicate that AU1 binds to active regions of the efflux pump, in a manner consistent with inhibition of pump function. This work identifies a novel chemical structure that can influence multidrug efflux, an established mechanism of drug resistance in triple negative breast cancer, that has not yet been successfully addressed by clinical efforts.

Sodium hypochlorite (NaOCl) is widely used in public healthcare facilities; this exposure can result in the development of bacterial tolerance to disinfectant, which has known links to antibiotic cross-resistance. However, the mechanism through which cross-resistance to antibiotics and disinfectants develops remains ambiguous. Therefore, this study aimed to examine the phenotypic, and transcriptomic changes caused by disinfectant exposure in gram-negative bacteria and determine the cause of cross-resistance to antibiotics. The results demonstrated that the misuse of disinfectants plays an important role in the emergence of disinfectant resistance and in the increase in antibiotic resistance. Antibiotic resistance may occur from exposure of gram-negative bacteria to subminimal inhibitory concentrations (MICs) of NaOCl. Ten passages of gram-negative bacteria in increasingly higher subMICs of NaOCl disinfectant was sufficient to increase the MIC to &gt;2,500 µg/ml NaOCl, particularly in K. pneumoniae and P. aeruginosa. To determine the development of cross-resistance to antibiotics due to NaOCl exposure, the MICs for each antibiotic before and after exposure of each strain to sublethal concentrations of NaOCl were compared. After overnight incubation with a sublethal concentration of NaOCl, a statistically significant increase in MIC was only observed for imipenem (P&lt;0.01). Investigation of the mechanism of cross-resistance by means of transcriptome analysis revealed that 1,250 µg/ml NaOCl-adapted K. pneumoniae and P. aeruginosa strains increased resistance to imipenem due to increased expression of the resistance-nodulation-cell division (RND) efflux pumps, such as AcrAB-TolC and MexAB/XY-OprM. Therefore, we suggest that exposure to NaOCl can influence the expression of RND efflux pump genes, contributing to imipenem cross-resistance.

Non-judicious antimicrobial use (AMU) is a major driver of antimicrobial resistance (AMR). In human hospitals, cumulative antibiograms are often used by clinicians to evaluate local susceptibility rates and to select the most appropriate empiric therapy with the aim of minimizing inappropriate AMU. However, use of cumulative antibiograms to guide empiric antimicrobial therapy in veterinary hospitals in the United States is limited, and there are no specific guidelines or standardized methods available for the construction of antibiograms in veterinary clinical settings. The objective of this methods article is to describe the approaches that were used to construct antibiograms from clinical samples collected from dogs seen at a veterinary teaching hospital. Laboratory data for 563 dogs for the period January 1, 2015 to December 31, 2015 was utilized. We used the Clinical and Laboratory Standards Institute (CLSI) guidelines for use in the construction of the antibiograms in human healthcare settings as the basis for the veterinary antibiograms. One general antibiogram, and antibiograms, stratified by hospital section, anatomic region of sample collection/ by sample type, were created and the challenges encountered in preparing these antibiograms are highlighted. The approaches described could be useful in guiding veterinary antibiogram development for empiric therapy.

Antibiotic resistance is a major public health issue that requires a multifaceted approach. One potential source of antibiotic-resistant bacteria is wastewater in developing countries, which often lacks proper treatment infrastructure and can release high levels of antibiotics and antibiotic-resistant bacteria into the environment. This review article summarizes current knowledge on strategies to combat antibiotic resistance in wastewater in developing countries. Our review highlights the importance of improving wastewater treatment infrastructure to effectively remove antibiotics and antibiotic-resistant bacteria, implementing measures to reduce the release of antibiotics into the environment, and monitoring and surveillance to track the presence and spread of antibiotic-resistant bacteria in wastewater. We also discuss the potential challenges and barriers to implementing these strategies and the need for further research to determine their effectiveness in real-world settings. Overall, this review highlights the need for a comprehensive approach to address antibiotic resistance in wastewater in developing countries and underscores the importance of addressing this issue to protect public health.

Soluble inorganic pyrophosphatase (sPPase), a pyrophosphate hydrolase, has been shown to play an important role in several physiological processes such as plant growth and development, metabolic activities, and response to abiotic stresses, but sPPase has been less studied in woody plants. In order to preliminarily verify whether the soluble inorganic pyrophosphatase in Eucommia ulmoides Oliver (E. ulmoides) has a role in resistance to drought stress, we amplified the EuSIP5 (E. ulmoides soluble inorganic pyrophosphatase 5) cDNA sequence from E. ulmoides by RT-PCR. In order to study the drought resistance of the Eucommia ulmoides soluble inorganic pyrophosphatase 5 (EuSIP5) gene, the cDNA sequence of the EuSIP5 gene was amplified from Eucommia ulmoides Oliver by RT-PCR. Bioinformatic analysis indicated that EuSIP5 might be an unstable amphipathic protein, mainly located in the cytoplasm. E. ulmoides, the highest expression of the EuSIP5 gene was found in male leaves and pericarp from April to October, and in leaves of E. ulmoides in July and September. During drought, the expression of EuSIP5 in seedling E. ulmoides leaves was significantly higher than that of the control. An overexpression vector harboring the EuSIP5 was constructed and introduced into the tobacco (Nicotiana tabacum cv. Xanthi). We found that during drought stress, the appearance of wilting was delayed by 4 days in transgenic tobacco plants (OE) compared with wild type plants (WT), and the expression of drought-related genes DET2, CYP85A1, P5CS, ERF1 and F-box was found to be increased in transgenic tobacco leaves, as well as the enzyme activities of the protective enzymes: peroxidase (POD), superoxide dismutase (SOD) and catalase (CAT) were significantly higher than those of the WT, and the malondialdehyde (MDA) content was lower than the WT. These results indicated that the introduction of EuSIP5 gene into tobacco increased the expression of drought-related genes, enhanced the anti-membrane oxidation ability of tobacco, and reduced the oxidative stress damage, thus improving the drought resistance of tobacco.

Pancreatic cancer has a poor prognosis with its five-year survival rate lower than that of any other cancer type because it is difficult to detect in the early stages. Gemcitabine, a standard treatment for pancreatic cancer, often has poor outcomes for patients as a result of chemoresistance. Therefore, novel therapeutic targets must be identified to overcome gemcitabine-resistance. Here, we found that SLC38A5, a glutamine transporter, is more highly overexpressed in gemcitabine-resistant patients than in gemcitabine-sensitive patients. Furthermore, the deletion of SLC38A5 decreased the proliferation and migration of gemcitabine-resistant PDAC cells. We also found that the inhibition of SLC38A5 triggered the ferroptosis signaling pathway via RNA sequencing. Also, silencing SLC38A5 induced mitochondrial dysfunction and reduced glutamine uptake and glutathione (GSH) levels, and downregulated the expressions of GSH-related genes NRF2 and GPX4. The blockade of glutamine uptake negatively modulated the mTOR-SREBP1-SCD1 signaling pathway. Therefore, suppression of SLC38A5 triggers ferroptosis via two pathways that regulate lipid ROS levels. Similarly, we observed knockdown of SLC38A5 restored gemcitabine sensitivity by hindering tumor growth and metastasis in the orthotopic mouse model. Altogether, our results demonstrated that SLC38A5 could be a novel therapeutic target to overcome gemcitabine-resistance in PDAC therapy.

Salvia hispanica (chia) is a highly nutritious food source and has gained popularity due to its high omega-3 fatty acid content. Red spider mites are a serious problem in the production of S. hispanica. However, no study has been conducted to analyse the defensive response to the infestation of red spider mites in S. hispanica. To elucidate the molecular mechanisms of the defensive response of S. hispanica to red spider mites, we performed a transcriptomic analysis of S. hispanica when infested by red spider mites. In the comparative assessment of leaf transcriptomes, a total of 1743 differentially expressed genes (DEGs) were identified between control and mite-infested S. hispanica. From these, 1208 (69%) transcripts were up-regulated and 535 (31%) were down-regulated. The DEGs included transcription factors, defense hormones, and secondary metabolites that were either suppressed or activated in response to spider mite herbivory. Gene Ontology (GO) enrichment analysis revealed that plant secondary metabolites such as glucosinolates, and signalling pathways, including the jasmonic acid signalling pathway, may play an important role in the defence against red spider mites. This study provides novel insights into the defence response of S. hispanica in response to insect herbivory and could be a resource for the improvement of pest resistance in the chia.

Culex quinquefasciatus is an important target for vector control because of its ability to transmit pathogens that cause disease. Most populations are resistant to pyrethroids and often to organophosphates, the two most common classes of active ingredients used by public health agencies. A knockdown resistance (kdr) mutation, resulting in a change from a leucine to phenylalanine in the voltage gated sodium channel, is one mechanism contributing to the pyrethroid resistant phenotype. Enzymatic resistance has also been shown to play a very important role. Recent studies have shown strong resistance in populations even when kdr is relatively low which indicates factors other than kdr may be larger contributors to resistance. In this study, we examined on a statewide scale (over 70 populations), the strength of the correlation between resistance in the CDC bottle bioassay and the kdr genotypes and allele frequencies. Spearman correlation analysis showed only moderate (-0.51) and weak (-0.29) correlation between the kdr genotype and permethrin and deltamethrin respectively. The frequency of the kdr allele was an even weaker correlate. These results indicate, in contrast to Aedes aegypti, assessing kdr in populations of Culex quinquefasciatus is not a good surrogate for phenotypic resistance testing.

Activating mutations in the Epidermal Growth Factor Receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20-30% of patients do not respond or respond for a very short time (< 3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.

Rice is an important cereal crop worldwide, the growth of which is affected by rice blast disease, caused by the fungal pathogen Magnaporthe oryzae. As climate change increases the diversity of pathogens, the disease-resistance genes (R genes) in plants must be identified. The major blast-resistance genes have been identified in indica rice varieties; therefore, japonica rice varieties with R genes now need to be identified. Because leucine-rich repeat (LRR) domain proteins possess R-gene properties, we used bioinformatics analysis to identify the rice candidate LRR domain receptor-like proteins (OsLRR-RLPs). OsLRR-RLP2, which contains six LRR domains, showed differences in the DNA sequence, containing 43 single-nucleotide polymorphisms (SNPs) in indica and japonica subpopulations. The results of M. oryzae inoculation analysis indicated that indica varieties with partial deletion of OsLRR-RLP2 showed susceptibility, whereas japonica varieties with intact OsLRR-RLP2 showed resistance. oslrr-rlp2 mutant generated using clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) showed increased pathogen susceptibility, whereas plants overexpressing this gene showed pathogen resistance. These results indicate that OsLRR-RLP2 confers resistance to rice, and OsLRR-RLP2 may be useful for breeding resistant cultivars.

Bacterial antibiotic resistance has become a major global health concern. One of the main reasons for the development of multi-drug resistance properties in bacteria is due to the bacterial efflux pump systems. They are important transport proteins, mainly involved in the removal of toxic substrates like antibiotics from inner cell environment. These pumps are responsible for the intrinsic ability of bacteria to get resistant to the antibiotic. Various types of efflux pumps are present in the Gram-positive and Gram-negative bacteria. Plant-derived products like Capsaicin, Olympicin A, and Indirubicin were found to be inhibitors of an efflux pump in Staphylococcus aureus similarly Ursolic acid derivatives; Daidzein and Lanatoside C were plant-derived inhibitors of an efflux pump in Escherichia coli. In this review detail information have been provided about efflux pump inhibitors that have been found to be effective in the Gram-positive bacteria and Gram-negative bacteria. The aim of this review is to focus on the role of plant-derived compounds as effective efflux pumps inhibitors with reference to mainly Staphylococcus aureus and Escherichia coli.

Anthelmintic drugs are the major line of defense against parasitic nematode infections, but the arsenal is limited and resistance threatens sustained efficacy of the available drugs. Discoveries of the modes of action of these drugs and mechanisms of resistance have predominantly come from studies of a related non-parasitic nematode species, Caenorhabditis elegans, and the parasitic nematode Haemonchus contortus. Here, we discuss how our understanding of anthelmintic resistance and modes of action came from the interplay of results from each of these species. We argue that this “cycle of discovery”, where results from one species inform the design of experiments in the other, can use the complementary strengths of both to understand anthelmintic modes of action and mechanisms of resistance.

Antimicrobial resistance is one of the most important global health issues identified in recent decades. Different approaches have been used to establish the presence and abundance of antimicrobial resistance genes (ARGs) in the environment. In this study, we analyzed soil samples from Fildes Peninsula (King George Island, maritime Antarctica), exposed to different types of impact. The objective of the work was to identify ARGs in the samples, and evaluate if these genes were located in plasmids, using two different strategies. A metagenomic analysis was used to identify ARGs and if they were associated to plasmid sequences. The analysis showed that the site highly exposed to anthropogenic activity had a higher number of ARGs compared to other sites. A high percentage of those ARGs (19.4%), were located in plasmidic contigs. We also assessed replicon mobilization, using microbial communities from these soil samples as donors through an exogenous plasmid isolation method. In this case, we could recover plasmids with ARGs in a Tcr transconjugant clone. Although they could not be fully assembled, we could detect broad host range IncP1 and IncQ plasmid sequences. Our results indicate that sewage impacted soils could be a hotspot for ARGs spread into the Antarctic environment

Enteric protozoan pathogenic infections significantly contribute to the global burden of gastrointestinal illnesses. Their occurrence is considerable within remote and indigenous communities and regions due to reduced access to clean water and adequate sanitation. The robustness of these pathogens means requirement of harsh treatment methods such as medicinal drugs or antibiotics. However, such treatments impact the gut microbiome, and create dysbiosis, often leading to opportunistic pathogens, anti-microbial resistance, or functional gastrointestinal disorders (FGIDs) such as irritable bowel syndrome (IBS). Recent studies have shown that these impacts do not remain confined to gut, and are reflected across the gut-brain, gut-liver, and gut-lung axes, among others. Therefore, apart from the medicinal treatment, nutritional supplementation is also a key aspect of providing the recovery from this dysbiosis. Future proteins, prebiotics, probiotics, synbiotics, and food formulations offer a good solution to remedy this dysbiosis. Furthermore, the nutritional supplementation also helps to build a resilience against the opportunistic pathogens and potential future infections and disorders that may arise due to the dysbiosis. Systems biology techniques have shown to be highly effective tools to understand the biochemistry of these processes. Systems biology techniques characterises the fundamental host-pathogen interaction biochemical pathways, at various infection and recovery stages. This same mechanism also allows to track the impact of abovementioned treatment methods of gut microbiome remediation. This manuscript is organised in sections delving into system biology approaches and upcoming developments to understand (1) Infection mechanism and current global status; (2) Cross-organ impacts of dysbiosis, particularly within gut-liver and gut-lung axes; (3) Nutritional interventions. It highlights the impact of antimicrobial resistance (AMR) and Multi-drug resistance (MDR) from a perspective of protozoal infections. It also highlights the role of nutritional interventions to add resilience against the chronic problems caused by these phenomena.

The rapid evolution of drug resistance is one of the greatest health issues of the 21st century. There is an alarming situation to find new therapeutic strategies or candidate drugs to tackle ongoing multi-drug resistance development. The marine environment is one of the prime natural ecosystems on Earth, the majority of which is still unexplored, especially when it comes to the microbes. A wide variety of bioactive compounds have been obtained from a varied range of marine organisms, however, marine bacteria-produced bacteriocins are still undermined. Owing to the distinct environmental stresses that marine bacterial communities encounter, their bioactive compounds frequently undergo distinct adaptations that confer on them a variety of shapes and functions, setting them apart from their terrestrial counterparts. The ribosomally-synthesized and posttranslationally modified peptides (RiPPs), bacteriocins are of special interest because of their variety in structure and diverse potential biological activities. Additionally, the gut microbiome of marine creatures are largely unexplored source of new bacteriocins with promising activities. There is a huge possibility of novel bacteriocins from marine bacterial communities that might come out as efficient candidates to fight against antibiotic resistance, especially in light of the growing pressure from antibiotic-resistant diseases and industrial desire for innovative treatments. The present review summarizes known bacteriocins from marine bacteria, evolutionary aspects, challenges, and huge possibilities of unexplored bacteriocins from marine bacterial communities.

Urinary tract infections (UTIs) are a prevalent bacterial infection in both community and healthcare settings. They account for approximately 40% of all bacterial infections and require around 15% of all antibiotic prescriptions. Although antibiotics have traditionally been used to treat UTIs for several decades, the significant increase in antibiotic resistance in recent years has made many previously effective treatments ineffective. Biofilm on medical equipment in healthcare settings creates a reservoir of pathogens that can be easily transmitted to patients. Urinary catheter infections are frequently observed in hospitals and are caused by microbes that form a biofilm after the catheter is inserted into the bladder. Managing infections caused by biofilms is challenging due to the emergence of antibiotic resistance. Biofilms enable pathogens to evade the host's innate immune defences, resulting in long-term persistence. The incidence of sepsis caused by urinary tract infections that have spread to the bloodstream is increasing, and drug-resistant infections may be even more prevalent. While the availability of upcoming tests to identify the bacterial cause of infection and its resistance spectrum is critical, it alone will not solve the problem; innovative treatment approaches are also needed. This review analyses the main characteristics of biofilm formation and drug resistance in recurrent uropathogen-induced UTI. The importance of innovative and alternative therapies to combat biofilm-caused UTI is emphasised.

Bananas, a staple food globally and a key agricultural commodity, face a severe threat from the fungus Fusarium oxysporum form specialis cubense (Foc), significantly impacting production. Genetic improvement to develop resistant cultivars stands out as a crucial strategy to mitigate this disease. This study focused on assessing and recommending enhanced diploid banana varieties for resistance against Foc subtropical race 4 (ST4) and Foc race 1 (R1). Twenty-five improved diploids developed by Embrapa, Brazil, underwent evaluation. Utilizing a scale for internal symptoms at 90 days post-inoculation, genotypes were categorized from highly resistant to highly susceptible based on the internal symptom index. The diploid M53 exhibited high resistance to R1 and resistance to Foc ST4, while only the diploid CNPMF 0534 demonstrated complete resistance to both R1 and ST4, with resistance to the latter likely associated with penetration. These findings provide valuable insights for banana and plantain breeding programs, offering selected diploids for crossbreeding with commercial cultivars to develop new, resistant genotypes against Foc.

Bacteria that have become resistant to antibiotics, also known as superbugs,pose a huge threat to the human population. This is because these developed resistance to antibiotics. Antibiotics are a type of medicine that fights bacteria by either killing it or preventing it from growing. Although antibiotics make the once deadly now easily treatable, they can become ineffective as bacteria develop resistance to the antibiotic, causing diseases to become potentially fatal once more. Thus, scientists are rushing to find solutions in this arms race against evolving bacteria by either evolving current antibiotics or discovering new stands to fight evolving bacteria. In order to discover whether bacteria can develop resistance to household antibiotics, a controlled experiment was conducted. This was done by growing bacteria on agar plates with antibiotic ointments applied (in dilution series) to see if antibiotic resistance could build. Theorizing that by lowering the concentration of over the counter antibiotics, resistant bacteria would be selected and my bacterial population would evolve antibiotic resistance.In conclusion of the experiment antibiotic resistance did appear as a trait, but the level of it was inconsistent across the different bacteria populations.

Background: In treatment-refractory cancers, tumor tissues damaged by therapy initiate the repair response; therefore, tumor tissues must be exposed to an additional burden before successful repair. We hypothesized that an agent recognizing a molecule that responds to anticancer treatment–induced tissue injury could deliver an additional antitumor agent including a radionuclide to damaged cancer tissues during repair. We selected the extracellular matrix glycoprotein tenascin-C (TNC) as such a molecule, and three antibodies recognizing human and murine TNC were employed to evaluate X-irradiation–induced changes in TNC uptake by subcutaneous tumors. Methods: TNC expression was assessed by immunohistochemical staining of BxPC-3 tumors treated with or without X-irradiation (30 Gy) for 7 days. Antibodies against TNC (3-6, 12-2-7, TDEAR) and a control antibody were radiolabeled with 111In and injected into nude mice having BxPC-3 tumors 7 days after X-irradiation, and temporal uptake was monitored for an additional 4 days by biodistribution and single-photon emission computed tomography with computed tomography (SPECT/CT) studies. Intratumoral distribution was analyzed by autoradiography. Results: The immunohistochemical signal for TNC expression was faint in nontreated tumors but increased and expanded with time until day 7 after X-irradiation. Biodistribution studies revealed increased tumor uptake of all three 111In-labeled antibodies and the control antibody. However, a statistically significant increase in uptake was evident only for 111In-labeled 3-6 (35%ID/g for 30 Gy vs. 15%ID/g for 0 Gy at day 1, P &lt; 0.01; ID, injected dose), whereas limited changes in 111In-labeled TDEAR2, 12-2-27, and control antibody were observed (several %ID/g for 0 and 30 Gy). Serial SPECT/CT imaging with 111In-labeled 3-6 or control antibody provided consistent results. Autoradiography revealed noticeably stronger signals in irradiated tumors injected with 111In-labeled 3-6 compared with each of nonirradiated tumors and the control antibody. The signals were observed in TNC-expressing stroma. Conclusion: Markedly increased uptake of 111In-labeled 3-6 in irradiated tumors supports our concept that an agent, such as an antibody, that recognizes a molecule, such as TNC, involved in tissue-injury repair could enhance drug delivery to therapy-experienced tumor tissues. The combination of antibody 3-6 coupled to a tumoricidal drug and conventional therapy has the potential to achieve better outcomes for patients with refractory cancer.

Contagious pathogens have very high costs for dairy herds, and they may have zoonotic and reverse-zoonotic potentials, and may contribute in spreading antimicrobial resistance. One of the most important risk factors for spreading these infections is milking, when liner contamination may transfer the pathogens from infected to healthy cows. There is no effective protocol for avoiding the transmission of infection out of the segregation of infected cows. Recently, the availability of elastomers including patented antimicrobial components in their formulations has opened the way to explore alternative methods to decrease infection risk. Two different types of elastomers (rubber and silicon) and 9 different receipts were challenged by three major mastitis pathogens (S. aureus, S. agalactiae, and E. coli). The results showed interesting and unexpected results. Indeed, for the first time to our knowledge, we have shown that basic rubber materials have intrinsic antimicrobial activity. Silicon elastomers did not exhibit the same levels of killing activity, although they did exhibit some antibacterial capacity. Generally, a significant decrease in bacterial survival curves was observed with the tested formulations. The results observed for the various products are likely due to the specific activity of the chemical components, as well as the diverse chemical reactions that occur during their production. The availability of new tools able to reduce the risks for the spread of infections and generally decrease the bacterial load at milking, would be an important step forward to achieve a higher global sustainability of dairy production from a One Health perspective.

Verticillium wilt (VW) is a soil borne fungal diseases caused by Verticillium dahliae Kleb, and lead to serious damage to cotton production annually in the world. In our previous study, a transmembrane protein 214 protein (TMEM214) gene associated with VW resistance was map-based cloned from Gossypium barbadense (G. barbadense). TMEM214 proteins are a kind of transmembrane protein, but their function in plants is rarely studied. To reveal the function of TMEM214s in VW resistance, all six TMEM214s were cloned from G. barbadense in this study. These genes were named as GbTMEM214-1, GbTMEM214-4 and GbTMEM214-7 according to their location on the chromosomes, and the encoded proteins are all located on cell membrane. TMEM214 genes were all induced by Verticillium dahliae inoculation and showed significant differences between resistant and susceptible varieties, but the expression patterns of GbTMEM214s under different hormone treatments were significantly different. Virus-induced gene silencing analysis showed the resistance to VW of GbTMEM214s-silenced lines decreased significantly, which further proves the important role of GbTMEM214s in the resistance to Verticillium dahliae. Our study provides an insight into the involvement of GbTMEM214s in VW resistance, which was helpful to better understand the disease resistance mechanism of plants.

Doravirine (DOR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with efficacy against some NNRTI resistant mutants. Although DOR resistance mutations are established for HIV-1 subtype B, it is less clear for non-B subtypes. This study investigated prevalent NNRTI resistance mutations on DOR susceptibility in HIV-1 subtype C. Prevalent drug resistance mutations were identified from a South African genotypic drug resistance testing database. Mutations, single or in combination, were introduced into replication defective pseudoviruses and assessed for DOR susceptibility in vitro. The single V106M and Y188L mutations caused high-level resistance while others didn’t significantly impact DOR susceptibility. We observed agreement between our in vitro and the Stanford HIVdb predicted susceptibilities. However, the F227L mutation was predicted to cause high-level DOR resistance but was susceptible in vitro. Combinations of mutations containing K103N, V106M or Y188L caused high-level resistance, in agreement with the predictions. These mutations are frequently observed in patients failing efavirenz or nevirapine-based first-line regimens. However, they are also observed in those failing a protease inhibitor-based second-line regimen, as we have observed in our database. Genotypic drug resistance testing is therefore vital prior to initiation on DOR-based treatment for those previously exposed to efavirenz or nevirapine.

The plant immunity system is more and more revisited and new elements and roles are attributed to participate in the response to biotic stress. New terminology is also applied trying to identify different players in the whole scenario of immunity: Phytocytokines are one of those elements that are gaining more attention due the characteristics of processing and perception, and showing they are part of a big family of compounds that can amplify the immune response. This review aims to highlight the last findings about the role of phytocytokines in the whole immune response on biotic stress, including basal and adaptive immunity, and to expose the complexity in their action in plant perception and signaling events.

Available options to combat bacterial infections are getting scarce. We require innovative and imaginative approaches to enhance the identification and discovery of effective antimicrobials capable of combating bacteria resistant to multiple or all available drugs. These methods should either directly eliminate the resistant bacteria or influence their viability indirectly by inhibiting their virulence or reducing their resistance to antibacterial agents. One interesting approach is to analyze ancient remedies presumably used to treat bacterial infections, try formulating them, and test them against modern microbes. The field was recently named ancientbiotics. This approach allows us to take advantage of centuries of accumulated empirical knowledge, from several traditional medicines of various ancient cultures across the world. The strategy has already resulted in promising formulations to combat the ESKAPE group of nosocomial pathogens. Moreover, molecular de-extinction consists of genome analysis of extinct species in the search for useful antimicrobials, such as peptides. The de-extinction of simple organisms such as bacteriophages may eventually become a resource for novel tools to combat multidrug-resistant bacteria. In this review, we summarize and discuss the reported antimicrobial effects of ancient remedies and de-extinct molecules known to modern science, and discuss possible new strategies to further harness the potential of past remedies and molecules to help us fight the rise of superbugs.

Rice blast, caused by Magnaporthe oryzae, poses significant threat to rice production. Rice blast susceptibility has been observed in Japanese rice varieties with excellent eating quality. Enhancing blast resistance is essential to ensure minimal use of agricultural chemicals. Two types of blast resistance are observed: true resistance, which is a type of qualitative resistance expressed by a major gene, and field resistance, which is a type of quantitative resistance expressed by multiple micro-acting genes. ‘Resistance collapse’, in which a variety with a true resistance gene becomes diseased by blast fungus races compatible with the resistance gene, has been observed. Varieties carrying blast-resistance genes, such as Pb1 (panicle blast resistance 1), have been developed through DNA marker-assisted selection. In this review, we focus on the Pb1, which expresses strong quantitative resistance to panicle blast and has been widely used in Japan without showing ‘resistance collapse’ for 40 years. Pb1 is an ‘adult plant resistance gene’ that does not exert strong selection pressure on the blast population during the leaf blast stage, thus preventing the selective multiplication of Pb1-compatible blast strains. This epidemiological mechanism prevents ‘resistance collapse’. Interdisciplinary research and breeding are required to sustainably use genes that induce high field resistance.

Background: Resistance to antimalarial drugs often used in emerging countries, including combination therapies, has forced scientists to search for and develop drugs with novel mechanisms of action, especially resistance to Plasmodium falciparum and Plasmodium vivax, which are highly prevalent in Southeast Asia, Africa, and South America. Objective: evaluate whether there is a relationship between urinalysis and resistance to in-hospital treatment of malaria in Angola. Methodology: This was a cross-sectional, prospective study with a quantitative approach. Results: of the 214 patients, the resistance rate was 24.1%, men (53.6%), between 21 and 40 years old (72.7%), employees (46.4%), from peri-urban regions (77.7%), treated with artemether (90.9), with high parasitemia (57.7%) and after 5 days of treatment, remained hospitalized (61.4%). Was a significant relationship between resistance in unemployed individuals [OR: 0.03 (95% CI: 0.01-0.29), p =0.003] and high levels of parasitemia [OR: 1.09 (95% CI: 1.09-3.95), p=0.040], remained hospitalized for more than 5 days [OR: 5.28 (95% CI: 0.65-43.1), p=0.121] and death [OR: 2.59 (95% CI: 0.32-20.9), p=0.371] when compared with other subgroups. Was a significant relationship between resistance to clear urine [OR: 5.55 (95% CI: 0.72-42.7), p =0.016], few urinary crystals [OR: 11.3 (95% CI: 5.07-25.3), p <0.001] and who presented some microorganisms that were not bacteria or fungi [OR: 3.02 (95% CI: 1 .32-6.90), p=0.009]. Conclusion: urine results, especially the appearance of cloudy urine, the presence of few crystals, and the presence of other microorganisms that are not bacteria or fungi, may be clear signs of resistance to hospital treatment with injectable antimalarials.

Arterial hypertension is a common condition worldwide and an important risk factor for cardio- and cerebrovascular events, renal diseases as well as microvascular eye diseases. Established hypertension leads to chronic vasoconstriction of small arteries as well as to decreased lumen diameter and thickening of the arterial media or wall with a consequent increased media-to-lumen ratio (MLR) or wall-to-lumen ratio (WLR). This process, defined as vascular remodeling, was first demonstrated in small resistance arteries isolated from subcutaneous biopsies and measured by micromyography, and this is still considered the gold-standard method for the assessment of structural alteration in small resistance arteries; however microvascular remodeling seems to represent a generalized phenomenon. An increased MLR may impair organ flow reserve, being relevant in the maintenance and, probably, also in the progressive worsening of hypertensive disease, as well as in the development of hypertension-mediated organ damage/cardiovascular events, possessing, therefore, a prognostic relevance. New, non-invasive techniques, such as Scanning Laser Doppler Flowmetry or Adaptive Optics, are presently under development, focusing mainly on the evaluation of WLR in retinal arterioles; recently, also retinal microvascular WLR was demonstrated to have a prognostic impact in term of cardio- and cerebrovascular events. A rarefaction of capillary network has also been reported in hypertension which may contribute to flow reduction and impairment in oxygen delivery to different tissues. These microvascular alterations seem to represent an early step in hypertension-mediated organ damage since they might concur to microvascular angina, stroke, and renal dysfunction. In addition, they could be a marker useful in monitoring the beneficial effect of antihypertensive treatment. Also conductance arteries may be affected by a remodeling process in hypertension, and a cross-talk may exist between structural changes in the small and large arteries. The review will address the possible relations between structural microvascular alterations and hypertension-mediated organ damage and their potential improvement with antihypertensive treatment.

In many parts of the Asia, particularly in the arid regions of the middle east the date palm i.e. Phoneix dactylifera L. is considered a significant plant both culturally and economically. Over the past decade numerous biotechnological tools have been applied to revolutionize the date palm research and its cultivation process. In this comprehensive review ,we provided the in depth overview of the cutting edge developments in the date palm biotechnology, mentioning the important areas such as genomics, genetic engineering, in vitro propagation, omics technologies, and the integration of the artificial intelligence and machine learning (AI-ML).Due to these advancements ,in the date palm production how the date palm production lead the production of superior date palm cultivars with the improved yield ,fruit quality and resilience to biotic and abiotic stresses. Also it explores the application of the biotech tools in the enhancing pest and disease management strategies, increasing date palm productivity and developing the date palm based bio-factories for the production of high value compounds. This review highlights the current challenges faced by the date palm industries ,including the limited water resources ,genetic erosion , pests and disease and the need for improved postharvest handling and processing. It examines how these tools coupled with AI-based approaches can be leveraged to address these challenges and ensure the long term sustainability of date palm cultivation.

Clopidogrel is one of the thienopyridine antiplatelet drugs commonly used as a prophylactic medication to prevent coagulation in vessels and cardiovascular events. The molecule of clopidogrel is metabolized in the liver via phase-I and phase-II metabolism pathways. The sulfenic acid clopidogrel metabolite undergoes phase-II metabolism through conjugation with glutathione by the glutathione-s-transferase (GST) to form a glutathione conjugate of clopidogrel (inactive metabolite). A glutaredoxin enzyme removes the glutathione conjugated with clopidogrel to form cis-thiol-clopidogrel. This review focused on the polymorphisms of genes related to phase-II metabolism during the clopidogrel bioactivation process. Overall, no well-controlled studies were done about the relationship between the clopidogrel bioactivation process and genes related to phase-II metabolism’s enzymes. Nevertheless, some polymorphisms of G6PD, GCLC, GCLM, GSS, GST, GSR, HK, and GLRX genes could be responsible for clopidogrel resistance due to low glutathione conjugate or glutaredoxin plasma levels. Studies needed to be concerned with the relationship between clopidogrel resistance and phase-II metabolism issues in the near future.

Mealybugs cause economic loss to vineyards through physical damage, fouling fruit and leaves with honeydew, and the transmission of viruses. Planococcus ficus is one of several mealybug species in vineyards, and one that causes economic damage over a relatively large global range. To develop novel management tools, host resistance to P. ficus, which has not previously been identified for any grape cultivars, was studied. Ten grape lines (species, cultivars, and rootstocks) were evaluated for P. ficus resistance across two separate potted plant assays. Significant differences were detected among cultivars and rootstocks in the recorded number of P. ficus juveniles, adults and egg sacs. Cabernet Sauvignon and Chardonnay were two of the most susceptible grape cultivars for mealybug population growth, whereas rootstocks IAC 572, 10-17A and RS-3 all demonstrated some level of resistance. Southern fire ant (Solenopsis xyloni) was positively associated with mealybug populations, but did not have a negative effect on the observed presence of other arthropod species including potential predators.

Background: Bacterial resistance to several antibiotic classes is seen as a grave threat worldwide. Bacterial resistance to antibiotics was mostly caused by the abuse and overuse of antibiotics, particularly penicillins and first-generation cephalosporins, in Egypt's primary healthcare facilities. Aim of the study: To investigate the main resistant bacteria to a few chosen penicillins and first-generation cephalosporins, as well as the characterization of these antibiotics' resistant genes and their detrimental effects in Egypt's main medical facilities. Methodology: Two hundred respiratory and urinary tract infection (RTI and UTI) specimens were gathered from Egyptian primary medical center patients. The turbidimetric assay at 630 nm wavelength, the broth dilution technique, and the nanopore sequencing homology approach were used to characterize the major resistant pathogenic bacteria and their resistant genes to cefadroxil (first generation cephalosporins) and nafcillin (antipseudomonal penicillin). Moreover, adverse outcomes resulting from antibiotic resistance were noted. Results: Out of 200 specimens with RTI and UTI, 186 samples showed the proliferation of resistant bacteria isolates. Enterococcus faecium strain NFC and Staphylococcus aureus strain CDX were among them. Nanopore sequencing confirmed that the antibiotic-resistant gene in Enterococcus faecium was the NFC gene, whereas the antibiotic-resistant gene in Staphylococcus aureus was the CDX gene. Penicillin-binding proteins with modest affinity were encoded by both genes. These bacterial resistance patterns were linked to a low death rate of 5% and a high morbidity rate of 47%. Conclusion: By expressing low-affinity penicillin-binding proteins through resistant NFC and CDX genes, Enterococcus faecium strain NFC and Staphylococcus aureus strain CDX were found to be the predominant bacterial isolates that cause antibiotic resistance to first-generation cephalosporins and penicillins.

To explore the effects of pymetrozine on the reproductive behavior of N. lugens, we established a bioassay method to accurately evaluate the toxicity of pymetrozine in N. lugens and establish the level of pymetrozine resistance of N. lugens in the field. In this study, pymetrozine’s effects on the fecundity of N. lugens were evaluated using the topical application method and rice-seedling dipping method. Moreover, the resistance of N. lugens to pymetrozine in a pymetrozine-resistant strain (Pym-R) and two field populations (YZ21 and QS21) was determined using the rice-seedling dipping method and fecundity assay methods. The results showed that treatment of N. lugens third-instar nymphs with LC15, LC50, and LC85 doses of pymetrozine resulted in significantly reduced male fertility and female fecundity. In addition, N. lugens adults treated with pymetrozine using the rice-seedling dipping and topical application method also exhibited significantly in-hibited male courtship, fertility, and female receptivity. Using the rice-stem dipping method, pymetrozine resistance was shown to be at high levels in Pym-R (194.6-fold), YZ21 (205.9-fold), and QS21 (212.8-fold), with LC50 values of 522.520 mg/L (Pym-R), 552.962 mg/L (YZ21), and 571.315 (QS21) mg/L. However, when using the rice-seedling dipping or topical application fe-cundity assay method, Pym-R (EC50: 14.370 mg/L, RR=12.4-fold; ED50: 0.560 ng/adult, RR=10.8-fold), YZ21 (EC50: 12.890 mg/L, RR=11.2-fold; ED50: 0.280 ng/adult; RR=5.4-fold), and QS21 (EC50: 13.70 mg/L, RR=11.9-fold) exhibited moderate or low levels of resistance to pymet-rozine. Our studies show that pymetrozine can significantly inhibit the fecundity of N. lugens. The fecundity assay results showed that N. lugens only developed low to moderate levels of resistance to pymetrozine, indicating that pymetrozine can still achieve effective control on the next gen-eration of N. lugens populations.

Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable ‘genetic escape’. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata will be highlighted.

Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

Conyza canadensis is a species invading large agricultural areas throughout the world, mainly to its ability to evolve herbicide resistance. Specifically, in Hungary, extensive areas have been infested by this species due to the difficulty in controlling it with glyphosate. To corroborate this fact as resistance and not as an incorrect herbicide application, eight suspicious glyphosate-resistant C. canadensis populations from different Hungarian regions were studied. In dose-response assays with glyphosate, the LD50 and GR50 values indicated that populations 1 to 5 were resistant to this herbicide (H-5 population the most resistant). Besides, the shikimic acid accumulation tests corroborated the results observed in the dose-response assays. 11 alternative herbicides from 6 different mode of action (MOA) were applied at field doses as control alternatives on populations H-5 and H-6 (both in the same regions). The H-5 population showed an unexpected resistance to flazasulfuron (ALS-inhibitor). The ALS enzyme activity studies indicated that the I50 for H-5 was 63.3 fold higher compared to its correspondent susceptible population (H-6). Therefore, the H-5 population exhibited multiple-resistance to flazasulfuron and glyphosate, being the first case reported in Europe for this two MOA. For that reason, the other herbicides with different MOA have to be tested here.

Antibiotics are the most magnificent discovery of 20th century that have saved millions of lives from infectious diseases. Microbes have developed acquired antimicrobial resistance (AMR) to many drugs due to high selection pressure from increasing use and misuse of antibiotics over the years. The transmission and acquisition of AMR occur primarily via human–human interface both within and outside of the healthcare facilities. A huge number of interdependent factors related to healthcare and agriculture govern the development of AMR through various drug resistance mechanisms. The emergence and spread of AMR from the unrestricted use of antimicrobials in livestock feed has been a major contributing factor. The prevalence of AMR bacteria has attained its incongruous level worldwide and threatening global public health as silent pandemic, necessitating urgent intervention. Therapeutic options of AMR bacterial infections are limited resulting in significant morbidity and mortality with high financial impact. The paucity in discovery and supply of new novel antimicrobials to treat life-threatening AMR infections stands in sharp contrast to demand. Immediate interventions to contain AMR include surveillance and monitoring, minimizing over the counter antibiotics and antibiotics in food animals, access to quality and affordable medicines, vaccines and diagnostics, and enforcement of legislation. An orchestral collaborative action within and between multiple national and international organizations are required urgently, otherwise, a post-antibiotic era can be a real possibility than an apocalyptic fantasy for the 21st century. This narrative review highlights on the basis, mechanisms and factors in microbial resistance and key strategies to combat antimicrobial resistance.

In obesity, white adipose tissue expresses inflammatory cytokines leading to insulin resistance. Non-physiological meta-tyrosine and ortho-tyrosine (meta-Tyr and ortho-Tyr), produced from phenylalanine by free radicals, may contribute to the development of insulin resistance. The resulting insulin resistance may have a significant impact on macrophage function. In this study we aim to investigate microscopically the effect of meta- and ortho-Tyr on insulin sensitivity and M1/M2 polarization of macrophages using Akt phosphorylation and the arginase 1/iNOS ratio. Macrophage cell lines were cultured in media containing para-, meta- or ortho-Tyr, 5 mmol/L or 25 mmol/L glucose (para25-Tyr group) and treated with insulin. Para25, meta- and ortho-Tyr increased pAkt levels and decreased the arginase 1/iNOS ratio in macrophages in the absence of insulin. In the case of physiological para-tyrosine treatment, insulin increased the amount of pAkt and decreased the arginase 1/iNOS ratio. Both meta- and ortho-Tyr treatment were able to abolish or reverse the insulin’s increasing effect on pAkt and the decreasing effect on arginase 1/iNOS ratio. Our results suggest that non-physiological tyrosine isomers may affect the insulin signaling of macrophages and influence their M1/M2 polarization.

Due to the global warming and dynamic changes in pathogenic virulence, leaf rust caused by Puccinia triticina has greatly expanded its epidermic region and become a severe threat to global wheat production. Genetic bases of wheat resistance to leaf rust mainly relies on the leaf rust resistance (Lr) gene or quantitative trait locus (QLr). Although these genetic loci have been insensitively studied during the last two decades, an updated overview of Lr/QLr in a genome-wide level is urgently needed. This review summarized recent progresses in genetic studies of wheat resistance to leaf rust. Wheat germplasms with great potentials in genetic improvement of resistance to leaf rust were highlighted. Key information about the genetic loci carrying Lr/QLr were summarized. A genome-wide chromosome distribution map for all the Lr/QLr was generated based on the released wheat reference genome. In conclusion, this review has provided valuable sources for both wheat breeders and researchers to understand the genetics of resistance to leaf rust in wheat.

The optimized design of catalyst layer (CL) plays a vital role to improve the performance of polymer electrolyte membrane fuel cells (PEMFCs). The need to improve transport and catalyst activity is especially important at low Pt loading, where local oxygen and ionic transport resistances decrease the performance due to an inevitable reduction of active catalyst sites. In this work, local oxygen and ionic transport are analyzed using direct numerical simulation on virtually reconstructed microstructures. Four morphologies are examined: (i) heterogeneous, (ii) uniform, (iii) uniform vertically-aligned, and (iv) meso-porous ionomer distributions. The results show that the local oxygen transport resistance can be significantly reduced, while maintaining good ionic conductivity, through the design of high porosity CLs (ε≃0.6−0.7) with low agglomerated ionomer morphologies. Ionomer coalescence into thick films can be effectively mitigated by increasing the uniformity of thin films and reducing the tortuosity of ionomer distribution (e.g., good ionomer interconnection in supports with a vertical arrangement). The local oxygen resistance can be further decreased by the use of blended ionomers with enhanced oxygen permeability and meso-porous ionomers with oxygen transport routes in both water and ionomer. In summary, achieving high performance at low Pt loading in next-generation CLs must be accomplished through a combination of high porosity, uniform and low tortuosity ionomer distribution, and oxygen transport through activated water.

Ultrafast chip nanocalorimetry opens up remarkable possibilities in materials science by allowing samples to be cooled and heated at extremely high rates. Due to heat transfer limitations, controlled ultrafast cooling and heating can only be achieved for tiny samples in calorimeters with a micron-thick membrane. Even if ultrafast heating can be controlled under quasi-adiabatic conditions, ultrafast controlled cooling can be performed if the calorimetric cell is located in a heat-conducting gas. It was found that the maximum possible cooling rate increases as 1/r0 with decreasing radius r0 of the hot zone of the membrane. The possibility of increasing the maximum cooling rate with decreasing r0 was successfully implemented in many experiments. In this regard, it is interesting to answer the question: what is the maximum possible cooling rate in such experiments if r0 tends to zero? Indeed, on submicron scales, the mean free path of gas molecules lmfp becomes comparable to r0, and the temperature jump that exists at the membrane/gas interface becomes significant. Considering the limitation associated with thermal resistance at the membrane/gas interface and considering the transfer of heat through the membrane, we show that the controlled cooling rate can reach billions of K/s, up to 1010 K/s.

Fungal infections impact the lives of at least 12 million people every year, killing over 1.5 million. Wide-spread use of fungicides and prophylactic antifungal therapy have driven resistance in many serious fungal pathogens, and there is an urgent need to expand the current antifungal ar-senal. Recent research has focused on improving azoles, our most successful class of antifungals, by looking for synergistic interactions with secondary compounds. Synergists can co-operate with azoles by targeting steps in related pathways, or they may act on mechanisms related to re-sistance like active efflux or on totally disparate pathways or processes. A variety of sources of potential synergists have been explored, including pre-existing antimicrobials, pharmaceuticals approved for other uses, bioactive natural compounds and phytochemicals, and novel synthetic compounds. Synergy can successfully widen the antifungal spectrum, decrease inhibitory dosag-es, reduce toxicity, and prevent the development of resistance. This review highlights the diversity of mechanisms that have been exploited for the purposes of azole synergy and demonstrates that synergy remains a promising approach for meeting the urgent need for novel antifungal strate-gies.

Fusarium wilt diseases severely influence the growth and productivity of numerous crop plants. The consortium of antagonistic rhizospheric Bacillus strains and quercetin were evaluated imperatively as a possible remedy to effectively manage the Fusarium wilt disease of tomato plants. The selection of Bacillus strains was made based on in-vitro antagonistic bioassays against Fusarium oxysporum f.sp. lycoprsici (FOL). Whereas, quercetin was selected after screening a library of phytochemicals during in-silico molecular docking analysis using tomato LysM receptor Kinases “SILKY12” based on its dual role in symbiosis and plant defense responses. After the selection of test materials, pot trials were conducted where tomato plants were provided consortium of Bacillus strains as soil drenching and quercetin as a foliar spray in different concentrations. The combined application of consortium () and quercetin (1.0 mM) reduced the Fusarium wilt disease index up to 69% also resulting in increased plant growth attributes. Likewise, the imperative application of the Bacillus consortium and quercetin (1.0 mM) significantly increased total phenolic contents and activities of the enzymes of the phenylpropanoid pathway. Non-targeted metabolomics analysis was performed to investigate the perturbation in metabolites. FOL pathogen negatively affected a range of metabolites including carbohydrates, amino acids, phenylpropanoids, and organic acids. Thereinto, combined treatment of Bacillus consortium and quercetin (1.0 mM) ameliorated the production of different metabolites in tomato plants. These findings prove the imperative use of Bacillus consortium and quercetin as an effective and sustainable remedy to manage Fusarium wilt disease of tomato plants and to promote the growth of tomato plants under pathogen stress conditions.

The potential of A. baumannii for acquired resistance to last resort antibiotics (colistin and tigecycline) during treatment has important clinical implications, especially when dealing with patients failing to improve despite treatment with an active antimicrobial. However, the relevant literature remains scattered. Therefore, a systematic search was conducted in PubMed and Scopus. Several studies reported emergence of resistance to colistin or tigecycline during treatment, in most cases (86%) resulting in persistent or recurrent infections, especially in cases of emergent resistance without fitness cost. Lipopolysaccharide modification in the case of colistin and overexpression of efflux pumps in the case of tigecycline were the main mechanisms of resistance. Emergent colistin resistance is often associated with fitness cost resulting in re-emergence of the fitter and more virulent colistin susceptible strain after cessation of antibiotic pressure. Prospective studies are needed to determine the frequency of emergent resistance during treatment and its impact on patient outcomes.

Background and Aims Insulin resistance is pivotal in the pathogenesis of Metabolic Syndrome (MetS), which predisposes to both type 2 diabetes mellitus (T2DM) and premature atherosclerotic cardiovascular disease (ASCVD). The triglyceride-glucose index (Ty-G index), a validated measure of insulin resistance also predicts MetS, T2DM, severity of albuminuria and ASCVD. There is scantly data providing mechanistic insights into these sequalae. Accordingly, we investigated the relationship between the TyG index and biomarkers of inflammation, oxidative stress, free fatty acids (FFA) levels and adipokine dysregulation in a cohort comprising both controls and patients with nascent MetS. Patients and Methods Participants included 47 patients with MetS and 41 controls. Persons with diabetes, ASCVD, smoking and macro-inflammation were excluded. Fasting blood was obtained for both plasma and monocyte isolation. Results: Receiver operating Characteristic (ROC) curve analysis revealed that TyG index was an excellent predictor of MetS with an area under the curve of 0.87 and it correlated with both hepatic and adipose tissue insulin ressitance .Both serum FFA levels and non-HDL-cholesterol increased significantly over tertiles of TyG index. Based on TyG index tertiles and or correlations, C reactive protein, endotoxin, chemerin , interleukin-6 levels and monocyte toll-like receptor (TLR)- 4 and TLR-2 and their cellular signaling were significantly associated with TyG index . Conclusion: Increased non-HDL-C and most importantly a pro-inflammatory state evidenced by both circulating and cellular biomarkers could be advanced as potential mechanisms explaining the increased risk for T2DM and ASCVD.

Chronic wasting disease is a fatal transmissible spongiform encephalopathy (TSE) of cervids caused by a misfolded variant of the normal cellular prion protein, and is closely related to sheep scrapie. Variations in a host’s prion gene, PRNP, and its primary protein structure, dramatically affect susceptibility to specific prion disorders, and breeding for PRNP variants that prevent scrapie infection has led to steep declines in the disease in North American and European sheep. While resistant alleles have been identified in cervids, a PRNP variant that completely prevents CWD has not yet been identified. Thus, control of the disease in farmed herds traditionally relies on quarantine and depopulation. In CWD-endemic areas, depopulation of private herds becomes challenging to justify, leading to opportunities to manage the disease in situ. In the present study, we developed a selective breeding program for farmed white-tailed deer in a CWD-endemic area, focused on reducing frequencies of highly susceptible PRNP variants and introducing animals with less-susceptible variants into historically high prevalence areas. We found that breeding followed predictable Mendelian inheritance, and early data support our project’s utility in reducing CWD prevalence. This project represents a novel approach to CWD management, with future efforts building on these findings.

Autoimmune blistering diseases represent a group of chronic severe, disabling, potentially fatal disorders of the skin and/or mucous membranes primarily mediated by pathogenic auto-antibodies. Despite their rarity, these diseases are associated with significant morbidity and mortality, a profound negative impact on the patient’s quality of life and impose a considerable economic burden. Rituximab, an anti CD-20 monoclonal antibody represents the first line of therapy for pemphigus, regardless of its severity as it ensures high rates of rapid, long-lasting complete remission. Nevertheless, disease recurrence is the rule, all patients requiring maintenance therapy with rituximab sooner or later. While innate resistance to rituximab in pemphigus patients is exceptional, acquired resistance is frequent and may develop even in patients with initial complete response to rituximab, representing a real challenge for physicians. We discuss the various resistance mechanisms and their complex interplay, as well as the numerous therapeutic alternatives that may be used to circumvent rituximab resistance. As no therapeutic measure is universally efficient, individualization of rituximab treatment regimen and tailored adjuvant therapies in refractory pemphigus cases are mandatory.

The discovery of first ATP-binding cassette (ABC) transporter, whose overexpression in cancer cells is responsible for exporting anticancer drugs out of tumor cells, initiated enormous efforts to overcome tumor cell multidrug resistance (MDR) by inhibition of ABC-transporter. Because of its many physiological functions, diverse studies have been conducted on the mechanism, function and regulation of this important group of transmembrane transport proteins. In this review, we will focus on the structural aspects of this transporter superfamily. Since the resolution revolution of electron microscope, experimentally solved structures increased rapidly. A summary of the structures available and an overview of recent structure-based studies are provided. More specifically, the artificial intelligence (AI)-based predictions from AlphaFold 2 will be discussed.

Molluscan aquaculture is a major contributor to global seafood production, but is hampered by infectious disease outbreaks which can cause serious economic losses. Selective breeding has been widely used to improve disease resistance in major agricultural and aquaculture species, and has clear potential in molluscs, albeit its commercial application remains at a formative stage. Advances in genomic technologies, especially development of cost-efficient genomic selection, have potential to accelerate genetic improvement. However, tailored approaches are required due to the distinctive reproductive and lifecycle characteristics of molluscan species. Transgenesis and genome editing, in particular CRISPR/Cas systems, have been successfully trialled in molluscs, and may further understanding and improvement of genetic resistance to disease through targeted changes to the host genome. Whole organism genome editing is achievable on a much greater scale compared to other farmed species, making genome-wide CRISPR screening approaches plausible. This review discusses the current state and future potential of selective breeding, genomic tools, and genome editing approaches to understand and improve host resistance to infectious disease in molluscs.

In sub-Saharan Africa, sweetpotato weevils are the most devastating pests of cultivated sweetpotato, causing estimated losses of between 60% and 100%, primarily during dry spells. The predominantly cryptic feeding behavior of the Cylas spp within the roots makes their control difficult, thus host plant resistance is one of the most promising lines of protection against these pests. However, progress in breeding for weevil-resistant cultivars has been slow in part due to the complex hexaploid genome of sweetpotato, which complicates conventional breeding in addition to the scarcity of varieties with significant levels of resistance for use as sources of resistance. Pollen sterility, cross incompatibility and poor seed set and germination in sweetpotato are also common challenges to improving weevil resistance. Accurate phenotyping of sweetpotato weevil resistance to enhance efficiency of selection has been equally difficult. Genomics-assisted breeding though in its infancy stages in sweetpotato has the potential application in overcoming some of these barriers. However, it will require the development of more genomic infrastructure; particularly single nucleotide polymorphism markers (SNPs), robust next generation sequencing plat-forms together with relevant statistical procedures for analyses. With the recent advances in genomics, we anticipate that genomic breeding for sweetpotato weevil resistance will be expedited in the coming years. This review sheds light on Uganda's efforts to date to breed against the Cylas puncticollis (Boheman) and Cylas brunneus (Fabricius) species of African sweetpotato weevil.

Salmonella remains one of the notable food-borne bacterial pathogens. It is associated with poultry and poultry products including eggs. This study investigated Salmonella distribution in eggshell and content, their antimicrobial resistance pattern, and the possible risk factors driving contamination in Ogun State, Nigeria. A total of 500 eggs (5 eggs pooled into one sample) were collected and culturally examined for the presence of Salmonella serovars. Isolates were further characterized biochemically using Microbact 20E (Oxoid) and Antimicrobial susceptibility determined by the Kirby-Bauer disk diffusion method. A total of 14 Salmonella isolates spread across 10 serovars were recovered from the 100 pooled egg samples; 10 (10%) from the market and 4 (4%) farms, 13(13%) eggshell, and 1(1%) egg content. All tested serovars were susceptible to ampicillin, chloramphenicol, florfenicol, and kanamycin. Resistance was mostly observed in sulfamethoxazole 8 (80%), followed by ciprofloxacin 5 (50%) and tetracycline 3 (30%). Sales of eggs in the market appears to be a strong factor encouraging contamination in addition to poor biosecurity and unhygienic handling of eggs on the farm.

HER2/neu positive breast tumors predict a high mortality and comprise 25-30% of breast cancer. We have shown that Flavokawain A (FKA) preferentially reduces the viabilities of HER2 overexpressing breast cancer cell lines (i.e. SKBR3 and MCF7/HER2) versus those with less HER2 expression (i.e. MCF7 and MDA-MB-468). FKA at cytotoxic concentrations to breast cancer cell lines also has minimal effect on the growth of non-malignant breast epithelial MCF10 cells. FKA induces G2M arrest in cell cycle progression of HER2 overexpressing breast cancer cell lines through inhibition of Cdc2 and Cdc25C phosphorylation and down-regulation of Myt1 and Wee1expression leading to increased Cdc2 kinase activities. In addition, FKA induces apoptosis in SKBR3 cells by increasing the protein expression of Bim and BAX and decreasing expression of Bcl₂, Bcl_x/L , XIAP and survivin. FKA also down-regulates the protein expression of HER-2 and inhibits AKT phosphorylation. Herceptin plus FKA treatment leads to enhanced growth inhibitory effect on HER-2 overexpressing breast cancer cell lines through down-regulation of Myt1, Wee1, Skp2, Survivin and XIAP. Our results suggest the promise of FKA as a novel apoptosis inducer and G2 checkpoint abrogating agent in combination with Herceptin for treatment of HER2 overexpressing breast cancer.

Viroids are known the smallest plant pathogens, and although their genome sequences do not encode proteins, they can cause disease in economically important crops. In order to control viroid diseases and mitigate their damage, genetic resources used for breeding of the viroid-resistant crop have been searched, but the practical resistant trait has not been found in almost all viroid-crop combinations, as well as the tolerant trait. Due to the difficulty in exploiting naturally occurring resistance or tolerance, various effective strategies have been devised to control viroid diseases using non-transforming or transforming techniques. Meanwhile, extensive findings related to viroid resistance and tolerance may lead to confer resistance or tolerance to viroid infection by combining with the recently emerged new technologies (e.g., spray-induced gene silencing and genome-editing technologies), which are believed to be more environmentally viable and acceptable to the general public than previously reported approaches. In particular, some genome-modified crops produced by the latter technology are already on the market. In this review, we comprehensively summarize the current status about investigation of naturally occurring genetic traits for viroid resistance and tolerance, accumulating knowledge about host factors involved in viroid pathogenicity, and various basic technologies developed to try to possible viroid disease control strategies. Furthermore, we discuss prospects and challenges for the achievement of more effective, practical, and sustainable disease control of viroid.

Under the pressure of fluoroquinolones, Pasteurella multocida (PM) can easily develop resistance to fluoroquinolones mediated by QRDR target mutation. It is imperative to find new drug resistance inhibitor targets to combat the rapid development of drug resistance. In order to overcome these problems, we sequenced the transcriptome of PM with different levels of resistance to ENR(0.03 μg/mL; 8 μg/mL; 32μg/Ml, Enrofloxacin). The results showed that with the increase of resistance to fluoroquinolones, the expression of satP gene was significantly up-regulated. The satP gene deletion strain and replenishment strain were constructed, and their drug resistance and tolerance were determined. The results showed that the deletion of satP gene did not affect the resistance of PM to fluoroquinolones, rather affected the time when PM developed resistance to fluoroquinolones. After 10 generations of drug induction, the MIC (minimum inhibitory concentration) of fluoroquinolones for wild strain was 64 μg/mL, while the MIC for satP gene deletion strain was only 8 μg/mL. The MDK99 test (time to kill 99% bacteria),agar diffusion test and mutation frequency test showed that the tolerance of satP gene deletion strain was significantly lower than that of wild strain. At the same time, the virulence of gene deletion strain and wild strain was tested, and about 400 times decreased virulence was observed for satP gene deletion strain. The mouse infection model confirmed that mice infected with satP gene deletion strains were more likely to be treated with ENR than mice infected with wild-type bovine PM strains. The results show that satP has potential to be a target of fluoroquinolone resistance inhibitors.

Oral cancer is a major public health burden worldwide. The lack of biomarkers for early diagnosis has increased the difficulty in managing this disease. Recent studies have reported that neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, is upregulated in various tumors. In our study we found that NGAL was significantly downregulated in primary malignant and metastatic tissues of oral cancer compared to normal tissues. The downregulation of NGAL was strongly correlated with the degree of differentiation and stage (I-IV), and can serve as a prognostic biomarker for oral cancer. Tobacco carcinogens were also found to be involved in the downregulation of NGAL. Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration, and also induced resistance against cisplatin. Silencing of NGAL activated mTOR signaling and reduced autophagy by the LKB1-AMPK-p53-Redd1 signaling axis. Moreover, cyclin-D1, Bcl-2, and MMP-9 were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration. Thus, from our study it is evident that downregulation of NGAL activates the mTOR pathway and helps in the progression of oral cancer.

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in Oncology be-cause of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein ex-tremely difficult. KRAS regulates development, cell growth, Epigenetically-dysregulated differ-entiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) and leads to an immunosuppressive tumor microenvironment (TME). In this context, the oncogenic mutation of KRAS induces an epigenetic program that leads to the initiation of PDAC. Several studies have identified multiple direct and indirect inhibitors of KRAS signaling. Therefore, KRAS dependency is so essential in KRASmu PDAC that cancer cells have secured several compensatory escape mechanisms to counteract the efficacy of KRAS inhibitors, such as activation of MEK/ERK signaling or YAP1 upregulation. This review will provide insights into KRAS dependency in PDAC and analyze recent data on inhibitors of KRAS signaling, focusing on how cancer cells establish compensatory escape mechanisms.

Breast cancer is the most commonly diagnosed cancer in women worldwide. Approximately, 70 % of breast cancer patients express hormone receptors (HR) (Luminal subtype). Adjuvant endocrine treatments are the standard of care in HR+/HER2- breast cancer. Over time, about 50% of those patients develop endocrine resistance and metastatic breast cancer. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacy increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic breast cancer patients. CDKi blocks kinases 4/6 ATP-binding domain preventing G1/S cell cycle transition. Despite this, not all patients respond to CDKi and those who respond, finally develop resistance to combination therapy. Different studies, in tumour tissue or cell lines, have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. In the last few years, liquid biopsy has contributed relevant information to this knowledge. Liquid biopsy can be performed in real-time, non-invasively and be repeated whenever needed. Circulating tumour material are potential prognostic markers in metastatic luminal breast cancer to determine patient prognosis, monitor disease and treatment selection. The objective of this review is to outline the different studies carried out in HR+ metastatic breast cancer patients treated with CDKi plus endocrine therapy using liquid biopsy approaches looking for possible resistance mechanisms.

Sources of resistance to powdery mildew in wild barley (Hordeum vulgare subsp. spontaneum) collected in Jordan, Lebanon, and Libya Jerzy H. Czembor 1, *, Elżbieta Czembor 1 1 Plant Breeding and Acclimatization Institute – National Research Institute (IHAR-PIB), Radzikow, 05-870 Błonie, Poland; e.czembor@ihar.edu.pl (E.C.) *Correspondence: j.h.czembor@ihar.edu.pl) Abstract Barley powdery mildew (BPM) is caused by the pathogen Blumeria graminis f.sp. hordei (Bgh). It is an economically important disease and plant pathologists are looking for new sources of resistance to BPM. Barley genetic resources present in gene banks are often a rich source of disease resistance to be used by breeders. These new sources of resistance to BPM are often used in combination (pyramiding) with those that are already used in modern cultivars. Barley accessions, including the wild subspecies Hordeum vulgare subsp. spontaneum (Hvs), are stored in many gene banks and often are a valuable source of economically important characteristics. This source of biodiversity should be more efficiently used to improve barley in the process of plant breeding. However, their proper characterization and availability are urgently needed. The resistance to BPM in 81 accessions of wild barley (Hvs) collected in Jordan (47), Lebanon (23), and Libya (11) was investigated. The seed samples of these accessions were obtained from the ICARDA gene bank and collected in 10 expeditions from 1981 to 1995. Twenty European differential isolates of BPM were used to select accessions with efficient resistance. Thirty-one resistant single plant lines were selected from 15 accessions from Jordan and Libya based on tests performed with the most avirulent isolate of Bgh available. These resistant single plant lines were tested for the presence of specific resistance genes using a differential set of Bgh isolates. After analysis of obtained results, it was concluded that all tested 31 single plant lines of wild barley have genes for resistance that are not represented in the Pallas isolines differential s. Twenty-six lines of Hvs selected from accessions originated in Jordan and Libya showed resistance reaction to all isolates used. Identified new sources of effective resistance to BPM in single plant lines of Hvs will be further tested and used in barley pre-breeding programs. Keywords: Blumeria graminis; resistance genes; resistance; germplasm; gene bank;

The emerging whitefly-transmitted crinivirus Tomato chlorosis virus (ToCV) causes substantial economic losses by inducing yellow leaf disorder in tomato crops. This study explores potential resistance mechanisms by examining early-stage molecular responses to ToCV. A time-course transcriptome analysis compared naïve, mock and ToCV-infected plants at 2, 7, and 14 days post-infection (dpi). Gene expression changes were most notable at 2 and 14 dpi, likely corresponding to whitefly feeding and viral infection. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed key genes and pathways associated with ToCV infection, including those related to plant immunity, flavonoids and steroids biosynthesis, photosynthesis, and hormone signalling. Additionally, virus-derived small interfering RNAs (vsRNAs) originating from ToCV predominantly came from RNA2 and were 22 nucleotides in lengt. To confirm these findings, two genes involved in plant immunity, Hsp90 (heat shock protein 90) and its co-chaperone Sgt1 (suppressor of the G2 allele of Skp1) were targeted through viral-induced gene silencing (VIGS), showing potential contribution to basal resistance against viral infections since their reduction correlated with increased ToCV accumulation. This study provides insights into tomato plants responses to ToCV, with potential implications for developing effective disease control strategies.

Fusarium head blight (FHB) can cause contamination of cereal grain with mycotoxins. Winter wheat is also infected with FHB. It is more resistant than durum wheat to head infection and less than other small grain cereals. The aim of this study was to identify winter wheat lines that combine low head infection and kernel damage with low toxin contamination. Resistance to FHB of 27 winter wheat lines and cultivars was evaluated over a three-year experiment established in two locations. At the anthesis stage, heads were inoculated with Fusarium culmorum isolates. The FHB index was scored and the percentage of Fusarium-damaged kernels (FDKs) assessed. The grain was analysed for type B trichothecenes (deoxynivalenol and derivatives, nivalenol) and zearalenone content. The average FHB index was 12.9%. The proportion of FDK was 6.9% (weight) and 8.5% (number). An average content of deoxynivalenol amounted to 3.543 mg/kg and nivalenol to 2.115 mg/kg. In total, it was 5.804 m/kg of type B trichothecenes. The zearalenone content in the grain was 0.214 mg/kg. Relationships between FHB index, FDK and mycotoxin contents were highly significant for wheat lines; however, they were stronger for FDK versus mycotoxins. Breeding lines combing all types of FHB resistance were found, and five of them had resistance similar to that of wheat lines with the Fhb1 gene.

Objective: About a third of schizophrenia patients are treatment-resistant to antipsychotic therapy. No studies established the fingerprints or pathway-phenotypes of treatment-resistant schizophrenia. The present study aimed to delineate the pathway-phenotypes of non-responders (NRTT) and partial responders (PRTT) to treatment using machine learning. Methods: We recruited 115 schizophrenia patients and 43 healthy controls and measured schizophrenia symptom dimensions, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and µ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Results: Machine learning showed that the NRTT group is a qualitatively distinct class and is significantly discriminated from PRTT with an accuracy of 100% using a neuro-immune-opioid-cognitive (NIOC) pathway-phenotype with as main determinants list learning, controlled word association, and Tower of London test scores, CCL11, IL-6, and EM2. The top-5 symptom domains separating NRTT from PRTT were in descending order: psychomotor retardation, negative symptoms, psychosis, depression, and mannerism. Moreover, a NIOC pathway also discriminated PRTT from healthy controls with an accuracy of 100% while all PRTT and controls were authenticated as belonging to their respective classes. Conclusion: A non-response to treatment with antipsychotics is determined by increased severity of specific symptom profiles coupled with deficits in executive functions, and episodic and semantic memory, and aberrations in neuro-immune and opioid pathways. No patients showed complete remission after treatment indicating that non-remitting in PRTT is attributable to increased HMGB1 and residual deficits in attention, executive functions, and semantic memory.

Bacterial biofilms can cause widespread infection. In addition to causing urinary tract infections and pulmonary infections in patients with cystic fibrosis, biofilms can help microorganisms adhere to the surfaces of various medical devices, causing biofilm-associated infections on the surfaces of biomaterials such as venous ducts, joint prostheses, mechanical heart valves, and catheters. Biofilms provide a protective barrier for bacteria and provide resistance to antimicrobial agents, which increases the morbidity and mortality of patients. This review introduces the formation process and drug resistance mechanism of biofilms in detail, and further summarizes the main characteristics of clinical persistent infection caused by biofilms and the many methods of treating biomaterial-related biofilm. This provides ideas and directions for the development of new biofilm infection strategies related to therapeutic materials.

Trehalose is a non-reducing disaccharide and participates in physiological activities such as or-gan formation, energy metabolism, and stress resistance of insects. In the present study, phylo-genetic analysis divided 21 Bmtret1 orthologs into three clades. These genes are equally distrib-uted on the nine chromosomes. Cis-elements in the promoter regions of Bmtret1s indicated the possible function of Bmtret1s in response to hormones and environmental stimulus. The qPCR analysis showed the significantly different expression levels of Bmtret1s in different tissues and organs, indicating possible functional divergence. In addition, most Bmtret1s showed disturbed expression levels in response to BmNPV stresses. Our results provide a foundation for further functional dissection of Tret1s in Bombyx mori and implicate them as potential regulators for an-tiviral responses.

Abstract: Targeted ubiquitination and proteasomal degradation regulates various cellular pathways, and the discovery that CPT induced rapid proteasomal degradation of topoI is the primary mechanism of CPT resistance was novel and compelling. CPTs are used extensively to treat various solid tumors like colorectal, gastric, pancreatic, ovarian and small cell lung cancer. The response rate is low and the classical mechanisms of drug resistance are yet to be validated. Remarkably, CPT resistant cells degrade topoI rapidly by UPP and recently we’ve published the molecular determinants of this pathway. To further understand the UPP mediated CPT resistance mechanism we used targeted proteasome prohibition by ixazomib (MLN9708) to stabilize topoI and determine its impact on CPT resistance. CPT resistant and sensitive cancer lines were both treated with ixazomib in combination with CPT. The CPT induced rate of topoI degradation, and its stabilization by ixazomib, was visualized and estimated by immunohistochemistry, immunofluorescence and immunoblotting assays, MTT and subG1 assays provided the drug sensitivity. Our results demonstrate that cells that degrade topoI rapidly are very resistant to CPT, and ixazomib significantly inhibits CPT induced topoI degradation. Notably, inhibition of proteasomal degradation by ixazomib overcomes the drug resistance and sensitizes the cells for CPTs.

Resistance of tumor cells to anticancer drugs is a major obstacle in tumor therapy. In this study, we investigated the mechanism of cordycepin-mediated resensitization to cisplatin inT24R2, a derived T24 cell line. Treatment with cordycepin or cisplatin (2 g/ml) alone could not induce cell death of T24R2, but combination treatment of these drugs significantly induced apoptosis of the cells through mitochondrial pathway including depolarization of mitochondrial membrane, decrease of anti-apoptotic proteins, Bcl-2, Bcl-xL, and Mcl-1, and increase of pro-apoptotic proteins, Bak and Bax. . High expression of MDR1 was the cause of cisplatin resistance in T24R2, and cordycepin significantly reduced MDR1 expression through inhibition of MDR1 promoter activity. MDR1 promoter activity was dependent on a transcription factor, Ets-1, in T24R2 cells. Although there is a correlation between MDR1 and Ets-1 expression in bladder cancer patients, active Ets-1, Thr-38 phosphorylated form (pThr-38), was critical to induce MDR1 expression. Cordycepin decreased pThr-38 Ets-1 level through inhibition of AKT, which reduced MDR1 transcription and induced the resensitization of T24R2 to cisplatin. The results suggest that cordycepin effectively resensitizes cisplatin-resistant bladder cancer cells to cisplatin, thus serving as a potential strategy for treatment of anti-cancer drug resistant patients.

The paper presents section models for analysis of the resistance of RC members subjected to bending moment with or without axial force. To determine the section resistance the nonlinear stress-strain relationship for concrete in compression is assumed, taking into account the concrete softening. It adequately describes the behavior of RC members up to failure. For the reinforcing steel linear elastic-ideal plastic model is applied. For the ring cross-section subjected to bending with axial force the normalized resistances are derived in the analytical form by integrating the cross-sectional equilibrium equations. They are presented in the form of interaction diagrams and compared with the results obtained by testing conducted on RC columns under eccentric compression. Furthermore, the ultimate normalized bending moment has been derived for the rectangular cross-section subjected to bending without axial force. It was applied in the cross-sectional analysis of steel and concrete composite beams, named BH beams, consisting of the RC rectangular core placed inside a reversed TT welded profile. The comparisons made indicated good agreements between the proposed section models and experimental results.

Saturated fatty acids are implicated in the development of metabolic diseases, including obesity and type 2 diabetes. There is evidence, however, that polyunsaturated fatty acids can counteract the pathogenic effects of saturated fatty acids. To gain insight into the early molecular mechanisms by which fatty acids influence hypothalamic inflammation and insulin resistance, we performed time-course experiments in a hypothalamic cell line, using different durations of treatment with the saturated fatty acid palmitate, and the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). Western blot analysis revealed that palmitate elevated the protein levels of phospho(p)AKT in a time-dependent manner. This effect seems involved in the pathogenicity of palmitate, as temporary inhibition of the PI3K/AKT pathway by selective PI3K inhibitors prevented palmitate-induced insulin resistance. Similarly to palmitate, DHA also increased levels of pAKT, but to a weaker extent. Co-administration of DHA with palmitate decreased pAKT close to the basal level after 8 h, and prevented palmitate-induced insulin resistance after 12 h. Measurement of the inflammatory markers pJNK and pNFκB-p65 revealed tonic elevation of both markers in the presence of palmitate alone. DHA alone transiently induced elevation of pJNK, returning to basal levels by 12 h treatment. Co-administration of DHA with palmitate prevented palmitate-induced inflammation after 12 h, but not at earlier time points.

Our world is rife with challenges, many of which arise from both natural phenomena and human-made issues. While natural problems like diseases and environmental changes often elude our immediate control, a troubling number of today's issues are unintended consequences of human innovations. A striking example is the evolution of drug resistance. The discovery of antibiotics in the early days of modern medicine marked a monumental breakthrough, drastically reducing mortality rates and improving quality of life. Pioneers like Alexander Fleming, who discovered penicillin in 1928, ushered in a new era of medical treatment, transforming healthcare by effectively combating bacterial infections.However, the widespread and often indiscriminate use of these drugs has led to the emergence of drug-resistant pathogens. This natural phenomenon, accelerated by human practices such as overprescription and the misuse of antibiotics in agriculture, exemplifies a double-edged sword—initially celebrated solutions have now become significant challenges. The same drugs that once cured deadly infections are losing efficacy, making us vulnerable to diseases previously thought under control.The inventors of these drugs acted with the intent to save lives and alleviate suffering, unaware of the long-term consequences. Today, the responsibility to address drug resistance lies with us, armed with hindsight and a deeper understanding of microbial resistance complexities. This review explores the origins and evolution of drug resistance, the role of scientific knowledge, and the implications for future actions.

Improvement of hydrophysical properties and corrosion resistance of self-compacting concrete to the effects of alternate freezing-thawing and aggressive soils of southern and central Kazakhstan is of interest to a wide range of researchers from the side of practical application of the obtained results in construction practice. It is proposed to form a spatially reinforced fine crystalline structure of cement matrix with maximum dense packing by using a complex modifier (Hyperplasticiser + Polymer + Microsilica + Fibro fibers) in the composition of self-compacting concretes (SCC). The introduction of the calculated amount of the above additives increases the operational reliability of the current SCC compositions, increasing the water resistance to W16, frost resistance to F=500, increasing the compressive strength by 20%, reducing the mass loss of samples during corrosion leaching to 50%. It has been experimentally established that the proposed addition of complex modifier (Hyperplasticiser + Polymer + Microsilica + Fiber fibers) to the SCC composition allows obtaining self-compacting concrete of high quality with improved performance characteristics (compressive strength, water resistance, frost resistance and corrosion resistance). Studies have shown that the complex modifier-modified SCC compositions have a high degree of resistance in aggressive environments and leaching corrosion. Based on the results of the conducted tests, it is possible to recommend the obtained SCC compositions for production of building products working in the zone of alternating freezing-thawing and aggressive soils.

Wheat dwarf disease (WDD) is an important disease of monocotyledonous species, including economically important cereals. The causative pathogen, the wheat dwarf virus (WDV), is a monopartite Mastrevirus that has a circular single-stranded (ss)DNA genome and is transmitted persistently and propagatively mainly by the leafhopper Psammotettix alienus. The disease can induce high yield losses in many European countries in a range of 20-100%. Due to climate change the periods of vector activity increased and the vectors spread to new habitats, leading to an increased importance of WDV in large parts of Europe. In the light of integrated pest management approaches cultivation practices and the use of resistant/tolerant host plants are currently the only effective methods for controlling WDV. To date, there is limited knowledge of the pathosystem and epidemiology of the disease. The few sources of genetic tolerance, indicate the need for further research. Considering the economic importance of the disease, and its likely increasing relevance in the coming decades, this review was prepared to compile and update knowledge on aspects of WDV.

Management of urinary tract infection is challenged by increasing antimicrobial re-sistance (AMR) worldwide. In this study we describe the trends in antimicrobial re-sistance of uropathogens isolated from the largest private sector laboratory in Ghana over a five-year period. We reviewed positive urine cultures at the MDS Lancet Laboratories from 2017 to 2021. Proportions of uropathogens with antimicrobial resistance to oral and parenteral antimicrobials recommended by the Ghana standard treatment guidelines were determined. The proportion of multi-drug resistant isolates, ESBL and car-bapenemase-producing phenotypes were determined. Of 94,134 urine specimens submitted for culture, 20,010 (22.1%) were culture positive. Enterobacterales were the commonest group of organisms, E. coli (70.6) being the commonest isolate and Enterococcus spp. the commonest gram positive (1.3%) organisms. Among oral antimicrobials the highest resistance was observed to ciprofloxacin (62.3%) and cefuroxime (60.2) %) and the least resistance to Fosfomycin (1.9%). The least resistance among parenteral antimicrobials was to meropenem ( 0.3%). Highest multi-drug resistance levels were observed among Klebsiella spp. (68.6%) and E. coli (64.0%). ESBL positivity was highest in Klebsiella spp. (58.6%) and E. coli (50.0%). There may be a need to review the Ghana standard treatment guidelines to reflect increased resistance among uropathogens to recom-mended antimicrobials

In this review we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients.