Search Results (167)

Cyclophosphamide (CPX) is an alkylating agent commonly used for various hematological and solid malignancies. In addition to its use as a cytotoxic agent to directly kill tumor cells, numerous immunomodulatory properties of CPX in the tumor microenvironment (TME) of several cancer types have also been documented. These properties include the selective depletion of immune-suppressive regulatory T cells (Tregs), triggering of immunogenic cell death (ICD) and enhanced antigen presentation, and release of type I interferons (IFNs). Moreover, preclinical models as well as human clinical trials have investigated the efficacy of the low-dose “metronomic” scheduling of CPX in combination with immunotherapies such as immune checkpoint inhibitors, dendritic cell tumor vaccines, and tumor antigen peptide vaccines. The metronomic dosing schedule involves administering a continuous (or frequent, such as daily) low dose of chemotherapy rather than using the canonical approach of administering the maximum tolerated dose. Despite the approval of immune checkpoint inhibitors for clinical usage against an increasing number of cancers, many malignancies simply do not respond to checkpoint inhibition, in part due to the heterogeneous intratumoral network of immune-suppressive cell populations. The immunomodulatory effects of cyclophosphamide have strong translational applicability and could serve to enhance and bolster anti-tumor immunity, potentially synergizing with immune checkpoint inhibitors and other existing immunotherapy agents. Full article

Introduction: Genetic plasticity and adaptive camouflage in critical pathogens have contributed to the global surge in multidrug-resistant (MDR) infections, posing a serious threat to public health and therapeutic efficacy. Antimicrobial resistance, now a leading cause of global mortality, demands urgent action through diagnostics, vaccines, and therapeutics. In India, the Indian Council of Medical Research’s surveillance network identifies Escherichia coli as a major cause of urinary tract infections, with increasing prevalence in human gut microbiomes, highlighting its significance across One Health domains. Methods: Whole-genome sequencing of E. coli strain ECG015, isolated from a human gut sample, was performed using the Illumina NextSeq platform. Results: Genomic analysis revealed multiple antibiotic resistance genes, virulence factors, and efflux pump components. Phylogenomic comparisons showed close relatedness to pathovars from both human and animal origins. Notably the genome encoded protein tyrosine kinases (Etk/Ptk and Wzc) and displayed variations in the envelope stress-responsive CpxAR two-component system. Promoter analysis identified putative CpxR-binding sites upstream of genes involved in resistance, efflux, protein kinases, and the MazEF toxin–antitoxin module, suggesting a potential regulatory role of CpxAR in stress response and persistence. Conclusions: This study presents a comprehensive genomic profile of E. coli ECG015, a gut-derived isolate exhibiting clinically significant resistance traits. For the first time, it implicates the CpxAR two-component system as a potential central regulator coordinating antimicrobial resistance, stress kinase signaling, and programmed cell death. These findings lay the groundwork for future functional studies aimed at targeting stress-response pathways as novel intervention strategies against antimicrobial resistance. Full article

An electrochemical aptasensor was developed for the rapid and sensitive detection of ciprofloxacin (CPX) in milk samples. The device was fabricated on a polyethylene terephthalate (PET) substrate using a screen-printing technique with carbon-based conductive ink. Gold nanoparticles (AuNPs) were incorporated to enhance aptamer immobilization and facilitate electron transfer at the electrode surface. The sensor’s analytical performance was optimized by adjusting key parameters, including AuNP volume, DNA aptamer concentration, and incubation times for both the aptamer and the blocking agent (6-mercapto-1-hexanol, MCH). Differential pulse voltammetry (DPV) measurements demonstrated a linear response ranging from 10 to 50 nmol L⁻¹ and a low detection limit of 3.0 nmol L⁻¹. When applied to real milk samples, the method achieved high recovery rates (101.4–106.7%) with a relative standard deviation below 3.1%, confirming its robustness. This disposable and cost-effective aptasensor represents a promising tool for food safety monitoring, with potential for adaptation to detect other pharmaceutical residues in dairy products. Full article

In the absence of fully effective therapies and preventive strategies against the development of urosepsis, a deeper understanding of the virulence mechanisms of Uropathogenic Escherichia coli (UPEC) strains is needed. UPEC strains employ a wide range of virulence factors (VFs) to persist in the urinary tract and bloodstream. UPEC strains were isolated from patients with sepsis and a control group without sepsis. PCR was used to detect 36 genes encoding various groups of virulence and fitness factors. Profiling of both intracellular and extracellular bacterial proteins was also included in our approach. Bacterial metabolites were identified and quantified using GC-MS and LC-MS techniques. The UpaG autotransporter, a trimeric E. coli AT adhesin, was significantly more prevalent in urosepsis strains (p = 0.00001). Iron uptake via aerobactin and the Iha protein also appeared to be predictive of urosepsis (p = 0.03 and p = 0.002, respectively). While some studies suggest an association between S fimbriae and the risk of urosepsis, we observed no such correlation (p = 0.0001). Proteomic and metabolomic analyses indicated that elevated levels of bacterial citrate, malate, coenzyme Q10, pectinesterase (YbhC), and glutamate transport proteins, as well as the regulators PhoP two-component system, CpxR two-component system, Nitrate/nitrite response regulator protein NarL, and the Ferrienterobactin receptor FepA, may play a role in sepsis. These genetic biomarkers, proteins, and metabolites derived from UPEC could potentially serve as indicators for assessing the risk of developing sepsis. Full article

The Paleoproterozoic Kovdozero complex, one of largest in the Fennoscandian Shield, was emplaced in a peripheral region of the SB–TB–LBB (Serpentinite Belt–Tulppio Belt–Lapland–Belomorian Belt) megastructure. Coronitic rocks of ultrabasic–basic compositions, investigated along a cross-section in the Gabrish area, are members of a cryptically layered series. They crystallized from the northern margin inward, as indicated by variations in mineral compositions and geochemical trends. Unsteady conditions of crystallization arose because of uneven cooling of the shallowly emplaced complex. Rapid drops in temperature likely caused the forced deposition of different generations of variously textured pyroxenes and chromian spinel or resulted in the unique development of narrow recurrent rims of orthopyroxene hosted by olivine. The unstable conditions of crystallization are expressed by (1) textural diversity, (2) broad variations in values of Mg#, and (3) virtual presence of double trends of Mg# as a function of distance. The coronitic textures are intimately associated with interstitial grains of plagioclase (An_≤65), also present as relics in a rim of calcic amphibole. The coronas are results of (1) rapid cooling leading to unsteady conditions of crystallization, which caused the sudden cessation of olivine crystallization and the development of an orthopyroxene rim on olivine and (2) an intrinsic enrichment in H₂O (and essential Cl in scapolite) coupled with a progressive accumulation of Al and alkalis, giving rise to fluid-rich environments in the intercumulus melt at advances stages of crystallization. These processes were followed by deuteric composite rims of calcic amphibole and reaction of fluid with early rims or grains of pyroxenes and late plagioclase. The coronitic sequences Ol → Opx → Cpx → calcic Amp → Pl (plus Qz + Mca) observed at a microscopic scale reproduce, in miniature, the normal order of crystallization in an ultrabasic–basic complex. A composite orthopyroxene + calcic amphibole corona resembles some rocks in complexes of the Serpentinite Belt. The prominence of such coronas may well be characteristic of the crystallization of komatiite-derived melts. Full article

Biofilm plays a crucial role in the pathogenesis and chronicity of urinary tract infections (UTIs). The present work aimed to evaluate the anti-biofilm effects of Formulation (DIF17BRO^® plus NAC) in combination with ciprofloxacin (CPX) on Escherichia coli strains. The antimicrobial activity of ciprofloxacin was evaluated by minimum inhibitory concentration (MIC) determination, and the antibiofilm effects of ciprofloxacin alone and combined with Formulation were evaluated on E. coli ATCC700926, E. coli ATCC10536, E. coli PNT, and E. coli PCA mature biofilms in terms of CFU/mL and biomass quantifications. Moreover, the potential protective effects of Formulation plus ciprofloxacin was tested in a Galleria mellonella in vivo infection assay. Our results underlined the increased microbial reduction in the mature biofilm in the presence of the combination Formulation and CPX, even at a lower concentration of CPX. Formulation increased the percentage of biofilm biomass reduction, inducing a disruption of the biofilm structure itself. Our present findings confirm that MIC CPX combined with Formulation also induced an antimicrobial effect in the G. mellonella assay. Formulation facilitated the perturbation of the biofilm polymeric matrix, enhancing the antibiotic penetration and its antimicrobial action on bacteria, underlining Formulation’s role as an enhancer of ciprofloxacin antibacterial action. Full article

Infectious bronchitis virus (IBV) of the GI-23 lineage, which first emerged in the Middle East in the late 1990s, has since spread worldwide. The factors driving its expansion, whether human involvement, wild bird migration, or the virus’s biological traits, are still unclear. This study aimed to trace the genome evolution of GI-23 IBV in chickens and its adaptability to quails, which are susceptible to both gamma- and deltacoronaviruses. Thirty specific-pathogen-free (SPF) birds, aged between two and three weeks, were used. Initially, three birds were inoculated with the G052/2016 IBV via the oculo-nasal route. On the third day post-infection (dpi), oropharyngeal swabs were collected from the whole group, pooled, and subsequently used to infect three next birds. This process was repeated nine more times during consecutive IBV passages (P-I–P-X), and eventually, virus sequencing was performed using Next-Generation Sequencing (NGS). The obtained results showed that quails were not susceptible to the IBV GI-23 lineage, as the virus RNA was detected in low amounts only during the first passage (QP-I) with no further detections in later rounds of IBV passaging. In chickens, only mild diarrhea symptoms appeared in a few individuals. The NGS analysis identified sixty-two single nucleotide variants (SNVs), thirty of which caused amino acid changes, twenty-eight were synonymous, and one SNV introduced a stop codon. Three SNVs were found in untranslated regions. However, none of these SNVs lasted beyond seven passages, with forty-four being unique SNVs. The Shannon entropy values measured during passages varied for pol1a, pol1b, S, 5a, 5b, and N genes, with overall genome complexity peaking at CP-VI and CP-X. The highest complexity was observed in the pol1a (CP-X) and S genes (CP-IV, CP-VI, CP-VIII, and CP-X). Along with the S gene that was under positive selection, eight codons in pol1a were also positively selected. These findings suggest that even in an adapted host, IBV variability does not stabilize without immune pressure, indicating continuous molecular changes within its genome. Full article

The water contents and geochemical evidence of nominally anhydrous minerals in peridotite xenoliths provide critical insights into lithospheric mantle features, offering a deep understanding of cratonic destruction and mantle evolution processes. Damaping, located in the central part of the intra-North China Craton, hosts abundant mantle peridotite xenoliths’ samples, providing new constraints on lithospheric mantle evolution. In this study, spinel lherzolite samples from Damaping Cenozoic basalts were analyzed for major and trace elements, water content, and oxygen isotope to investigate the factors controlling mantle water distribution and lithospheric mantle modification. The olivines of Damaping spinel lherzolite have a range of Mg# values from 89.73 to 91.01, indicating moderately refractory mantle characteristics. Clinopyroxenes display an LREE-depleted pattern, suggesting a consistency with 1–6% of batch partial melting and 1–5% fractional partial melting. The high (La/Yb)_N (0.20–0.73) and low Ti/Eu (3546.98–5919.48) ratios of Damaping clinopyroxenes reveal that the lithosphere mantle beneath the Damaping has undergone silicate metasomatism. The water contents of Damaping clinopyroxenes and orthopyroxenes range from 13.39 to 19.46 ppm and 4.60 to 7.82 ppm, respectively. The water contents of the olivines are below the detection limit (<2 ppm). The whole-rock water contents can be estimated based on the mineral modes and partition coefficients, with values ranging from 3.21 to 5.44 ppm. Partial melting indicators (Mg# in Ol and Yb_n in Cpx) correlate with the water content in clinopyroxenes and orthopyroxenes but show no correlation with the redox state (Fe³⁺/∑Fe ratios in spinel) or metasomatism ((La/Yb)_N in clinopyroxene). These results suggest that the degree of partial melting primarily controls the heterogeneous water distribution in Damaping spinel lherzolite, rather than the redox state or metasomatism. The δ¹⁸O values of clinopyroxenes from Damaping spinel lherzolites (5.27–5.59‰) fall within the range of mid-ocean ridge basalts (MORB), indicating a mantle source characterized by MORB-like isotopic signatures. The low whole-rock water contents are attributed to lithospheric reheating resulting from asthenospheric upwelling during the Late Mesozoic–Early Cenozoic. Therefore, the lithosphere is predominantly composed of ancient Proterozoic residues, with localized contributions of younger asthenospheric material near deep faults. Full article

HIV-1 genotyping and drug resistance tests are routinely performed in virology laboratories in some countries, aiding clinical management. In Istanbul, between January 2021 and March 2024, plasma samples from 1029 HIV-1-infected patients were analyzed using the NGS method, and mutation and drug resistance results were retrospectively evaluated alongside demographic data. Subtype B (54.4%) was most frequent in Turkish patients, while Subtype A1 (43.5%) was predominant among foreign nationals. The most common CRFs were CRF02_AG (3.8%) and CRF56_cpx (1.6%). According to the change in detection rates during the study period, Subtype B decreased, and Subtype A increased. The most frequent mutations detected were A62V (38.7%) and M184V (22.4%) for NRTIs; E138A (55.5%) and E138G (11.5%) for NNRTIs; M46I (33.3%) and M46L (25%) for PIs; and E92Q and G for INIs (total rate: 35.2%). Darunavir/ritonavir had the highest sensitivity rate, while resistance rates for NNRTIs and INIs increased over time. We anticipate that this study, in which we evaluate the routine use of an FDA-approved NGS kit alongside integrated bioinformatics data analysis and automated reporting software for the first time in Türkiye, will contribute to both national and international molecular epidemiological data and public health strategies by providing reliable results that align with international standarts. Full article

Background: Staphylococcus aureus is a highly lethal Gram-positive bacterium that is responsible for over one million deaths annually. As a member of the ESKAPE pathogens, its methicillin-resistant strains (MRSA) are prevalent worldwide and exhibit significant antimicrobial resistance (AMR). Bacterial efflux pumps play a pivotal role in the development of AMR by facilitating the expulsion of a range of antimicrobial agents. Methods: The S. aureus strain SA-1199B, which overexpresses NorA and carries a GrlA mutation, was utilized to comprehensively profile the mechanism of the compounds PQQ16P and PQK4F. To assess the toxicity and genotoxicity of these compounds, RAW macrophages, HEK 293T, and HepG2 cell lines were utilized. Female BALB/c mice were utilized to assess the in vivo synergism of EPIs with CPX, Results: NorA efflux pump inhibitors (EPIs), PQQ16P and PQK4F, enhanced the efficacy of the antibacterial ciprofloxacin (CPX) against resistant S. aureus strains. The mechanism of EPIs involved the inhibition of NorA efflux pump, without compromising bacterial membrane permeability, ATP levels, or mammalian calcium channels. Moreover, the EPIs significantly augmented the bactericidal and post-antibiotic effects of CPX, elevating its mutation prevention concentration without manifesting substantial toxicity to human cells. Furthermore, the EPIs reduced S. aureus invasiveness in macrophages, indicating a role for NorA in bacterial virulence. Notably, the in vivo synergism of these EPIs with CPX was observed in a mouse infection model. Conclusions: This study provides substantial evidence for the potential of employing EPIs in a combination with CPX to counteract AMR, both in vitro and in vivo. Full article

The continuous monitoring of oxygen saturation (SpO₂) and respiratory rates (RRs) are major clinical issues in many cardio-respiratory diseases and have been of tremendous importance during the COVID-19 pandemic. The early detection of hypoxemia was crucial since it precedes significant complications, and SpO₂ follow-up allowed early hospital discharge in patients needing oxygen therapy. Nevertheless, fingertip devices showed some practical limitations. In this study, we investigated the reliability of the new Multisense^® pulse oximetry system compared to a reference pulse oximeter (Vyntus CPX Pulse Oximeter) during hypoxia. In a population of sixteen healthy male subjects (mean age: 31.5 ± 7.0 years, BMI: 24.9 ± 3.6 kg/m², and 35% with darker skin tones), simultaneous SpO₂ and RR measurements were collected over 12.4 h, during which FiO₂ was progressively reduced from 21% to 10.5%. The average root mean square error (ARMS) of SpO₂ for Multisense^® placed on the back and chest was 2.94% and 2.98%, respectively, with permutation testing confirming a significant ARMS below 3.5% for both positions and no statistically significant difference in the ARMS between patch placements. Positive correlations and acceptable accuracy between devices were observed at both locations (r = 0.92, p < 0.001 and r = 0.90, p < 0.001 for back and chest placements, respectively). Bland–Altman analysis further indicated limits of agreement that support consistency across placements, with similar agreement levels noted across skin tones. Similar findings were obtained with the RR measurements. In conclusion, Multisense^® demonstrated robust accuracy in measuring SpO₂ and RRs during hypoxia in humans comparable to standard hospital-grade equipment. The effectiveness of the findings suggests that this wearable device is a valuable tool for the continuous monitoring of SpO₂ and RRs, potentially enhancing patient safety and optimizing hospital resource allocation. Nevertheless, to overcome study limitations and allow generalized use, further work on a larger population sample, including more subjects with a high phototype and desaturation below 80%, would be useful. Full article

Ciclopirox (CPX) and its ethanolamine salt, ciclopirox olamine (CPO), are synthetic hydroxypyridone derivatives with a wide range of antimicrobial activity, making them valuable in dermatology for treating fungal infections. Their mechanism of action is multifaceted, impacting iron-dependent enzymes and disrupting mitochondrial function, cellular energy production, and membrane integrity. The compounds’ favorable physicochemical properties allow effective skin absorption, while the olamine salt enhances solubility and bioavailability. Research is ongoing to explore therapeutic uses beyond dermatology, including applications in autoimmune diseases, cancer, and neurodegenerative disorders. In cosmetics, ciclopirox is used primarily in anti-dandruff and skincare products, combining therapeutic effects with minimal side effects. Full article

Chloroplasts are not only places for photosynthesis, but also participate in plant immunity and are important targets of pathogens. Pathogens secrete chloroplast-targeted proteins (CTPs) that disrupt host immunity and promote infection. Sclerotinia sclerotiorum (Lib.) de Bary is a phytopathogenic fungus with a broad host range. However, little is known about the pathogenic mechanisms underlying this wide host range. In this study, we investigated the role of Chloroplast-Targeted Protein 1 (SsCTP1) secreted by S. sclerotiorum in pathogenesis, which inhibits plant immunity and promotes pathogen infections. SsCTP1 was highly up-regulated during the early stages of S. sclerotiorum infection in various hosts, and its transient expression in Nicotiana benthamiana revealed that it was predominantly localized within chloroplasts. Mutants with SsCTP1 deletion exhibited a similar growth rate and colony morphology to the wild type, but significantly reduced pathogenicity in various hosts. Moreover, SsCTP1 inhibited chitin-induced callose deposition and defense gene expression, and enhanced sensitivity to S. sclerotiorum in N. benthamiana. Similarly, transgenic Arabidopsis thaliana overexpressing SsCTP1 displayed an increased susceptibility to S. sclerotiorum. Furthermore, two host proteins that interact with SsCTP1, Coproporphyrinogen-III oxidase (GmCPX), and shikimate kinase 2 (GmSKL2) were identified by screening the soybean cDNA library, and these interactions were confirmed in vivo. Importantly, the silencing of NbCPX by virus-induced gene silencing enhanced N. benthamiana resistance to S. sclerotiorum. Our results indicate that SsCTP1 is an important pathogenic factor that contributes to the wide host range of S. sclerotiorum and may inhibit plant immunity by targeting the chloroplast proteins GmCPX and GmSKL2, which are ubiquitous in host plants. Full article

Two-component systems (TCS) of Salmonella enterica serovar Enteritidis are composed of a histidine kinase and a response regulator (RR) and represent a critical mechanism by which bacteria develop resistance to environmental stress. Here, we characterized the functions of RRs in TCS in the formation of stress tolerance, motility and biofilm using twenty-six S. Enteritidis RR-encoding gene deletion mutants. The viability results unraveled their essential roles in resistance to elevated temperature (GlrR), pH alterations (GlrR, TctD, YedW, ArcA and YehT), high salt (PhoB, BaeR, CpxR, PhoP, UvrY and TctD), oxidative stress (PhoB, YedW, BaeR, ArcA, PhoP, UvrY, PgtA and QseB) and motility (ArcA, GlnG, PgtA, PhoB, UhpA, OmpR, UvrY and QseB) of S. Enteritidis. The results of the crystal violet staining, microscopy observation and Congo red binding assays demonstrated that the absence of ArcA, GlnG, PhoP, OmpR, ZraR or SsrB in S. Enteritidis led to a reduction in biofilms and an impairment in red/dry/rough macrocolony formation, whereas the absence of UvrY exhibited an increase in biofilms and formed a brown/smooth/sticky macrocolony. The results indicated the regulatory effects of these RRs on the production of biofilm matrix, curli fimbriae and cellulose. Our findings yielded insights into the role of TCSs, making them a promising target for combating S. Enteritidis. Full article

Background/Objectives: The impact of exercise on affective disorders has been demonstrated in various studies. However, almost no data are available on performance effects. Therefore, this study investigated exercise performance related to the severity of depression symptoms in a pre–post within-subjects design in a 6-week standard inpatient psychiatric rehabilitation program. Methods: A total of 53 individuals (20 female; mean age, 40.98 ± 11.33) with a primary diagnosis of depression performed a cardiopulmonary exercise test (CPX) to obtain maximal oxygen uptake (VO_2max), maximal power output (P_max), and the first and second ventilatory threshold (VT₁, VT₂) at the start and the end of the rehabilitation. Degree of depression was assessed by Becks Depression Inventory (BDI) and the Brief Symptom Inventory test (BSI). Overall activity was measured by accelerometer step-counts. Results: Mean total step-count per day during rehabilitation was high (12,586 ± 2819 steps/day). Patients’ BDI and BSI at entry were 21.6 ± 8.83 and 65.1 ± 6.8, respectively, and decreased significantly (p < 0.001) following rehabilitation, to 10.1 ± 9.5 and 54.5 ± 11.3, respectively. P_max and VO_2max increased significantly (p < 0.001) from entry values (182.6 ± 58.7 W, 29.74 ± 5.92 mL·kg⁻¹·min⁻¹) following rehabilitation: by 11.91 ± 12.09 W and 1.35 ± 2.78 mL·kg⁻¹·min⁻¹, respectively. VT₁ and VT₂ showed a similar behavior. An increase in physical performance could predict improvement in BDI (R² = 0.104, F(1,48) = 5.582, p = 0.022) but not in BSI. Conclusions: The program was associated with improved mental health status in all patients and increased performance in the majority of patients, although increases were small. Since improvements in exercise performance may be positively related to depression symptoms and comorbidities, it is recommended to individualize and tailor exercise programs, which could yield larger effects. Full article