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Abstract Background Colorectal cancer is still the second leading cause of cancer-related deaths and thus biomarkers allowing prediction of the resistance of patients to therapy and estimating their prognosis are needed. We designed a panel of 558 genes with pharmacogenomics records related to 5-fluorouracil resistance, genes important for sensitivity to other frequently used drugs, major oncodrivers, and actionable genes. We performed a target enrichment sequencing of DNA from tumors and matched blood samples of patients, and compared the results with patient prognosis stratified by systemic adjuvant chemotherapy. Results The median number of detected variants per tumor sample was 18.5 with 4 classified as having a high predicted functional effect and 14.5 moderate effect. APC, TP53, and KRAS were the most frequent mutated genes (64%, 59%, and 42% of mutated samples, respectively) followed by FAT4 (23%), FBXW7, and PIK3CA (16% for both). Patients with advanced stage III had more frequently APC, TP53, or KRAS mutations than those in stages I or II. KRAS mutation counts followed an increasing trend with grade (G1 5% frequency and positive Manhattan plot based on 3-year RFS, rs72753407 in NFACS, rs34621071 in ERBB4, and rs2444274 in RIF1 were significantly associated with RFS, OS or both. Conclusions The present study identified several putative somatic and germline genetic events with prognostic potential for colorectal cancer that should undergo functional characterization.

Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder that profoundly impacts cognitive function and the nervous system. Emerging evidence highlights the pivotal roles of iron homeostasis dysregulation and microbial inflammatory factors in the oral and gut microbiome as potential contributors to the pathogenesis of AD. Iron homeostasis disruption can result in excessive intracellular iron accumulation, promoting the generation of reactive oxygen species (ROS) and oxidative damage. Additionally, inflammatory agents produced by pathogenic bacteria may enter the body via two primary pathways: directly through the gut or indirectly via the oral cavity, entering the bloodstream and reaching the brain. This infiltration disrupts cellular homeostasis, induces neuroinflammation, and exacerbates AD-related pathology. Addressing these mechanisms through personalized treatment strategies that target the underlying causes of AD could play a critical role in preventing its onset and progression.

Background: Invasive candidiasis is a predominant mycosis in hospitalized patients, and Candida albicans is the species most often responsible for this infection. Most candidiasis cases originate from endogenous mycobiota; therefore, Candida strains can easily be transferred among hospital patients and personnel. The aim of this study was to assess the possible horizontal transmission of C. albicans in patients with severe COVID-19 infection requiring hospitalization in the intensive care unit. Methods: In total, 59 C. albicans strains from 36 patients were collected from blood and lower-respiratory samples. The strains were genotyped using the RAPD method with the OPA-18 primer (5′-AGCTGACCGT-3′). Antifungal susceptibility testing was performed for amphotericin B (AMB), fluconazole (FCZ), voriconazole (VCZ), and anidulafungin (ANF) using the EUCAST method. Results: C. albicans strains were separated into 13 different groups according to their RAPD pattern. Two predominant clonal clusters of 17 strains isolated from 12 patients and 12 strains from 7 patients were identified, followed by clusters with 6, 4, and 8 strains isolated from 5, 4, and 3 patients, respectively. C. albicans strains were sensitive to AMB, FCZ, VCZ, and ANF, and antifungal susceptibility profiles were similar in all genetic clusters. Conclusions: Our study indicates that C. albicans strains can spread horizontally. The routes of transmission for strains in the ward have not been explained due to there being insufficient data. The transmission could have been caused by the unintentional spread of pathogens by medical personnel.

IntroductionBiofilm-associated infections persist as a therapeutic challenge in contemporary medicine. The efficacy of antibiotic therapies is ineffective in numerous instances, necessitating a heightened focus on exploring novel anti-biofilm medical strategies. Among these, iminosugars emerge as a distinctive class of compounds displaying promising biofilm inhibition properties.MethodsThis study employs an in vivo wound infection mouse model to evaluate the effectiveness of PDIA in treating biofilm-associated skin wound infections caused by Staphylococcus aureus and Pseudomonas aeruginosa. Dermic wounds in mice were infected with biofilm-forming strains, specifically S. aureus 48 and P. aeruginosa 5, which were isolated from patients with diabetic foot, and are well-known for their strong biofilm formation. The subsequent analysis included clinical, microbiological, and histopathological parameters. Furthermore, an exploration into the susceptibility of the infectious strains to hydrogen peroxide was conducted, acknowledging its potential presence during induced inflammation in mouse dermal wounds within an in vivo model.ResultsThe findings revealed the efficacy of PDIA iminosugar against the S. aureus strain, evidenced by a reduction in bacterial numbers within the wound and the inflammatory focus.DiscussionThis study suggests that PDIA iminosugar emerges as an active and potentially effective antibiofilm agent, positioning it as a viable treatment option for staphylococcal infections.

As an extraordinarily diverse group of bacteria, lactobacilli are now classified into several genera, many of which still include “Lactobacillus” in their names. Despite their names, this group of lactic acid bacteria comprises microorganisms that are crucial for human health, especially during the early development of the human microbiota and immune system. The interactions between lactobacilli and components of the mucosal immunity lead to its shaping and development, which is possibly considered a prime mover in the advancement of the human immune system. Although much of the evidence backing the pivotal role of lactobacilli in maintaining human health comes from studies on probiotics aiming to elucidate the mechanisms of their functional activities and studies on mucosal immunity in germ-free mice, it is justifiable to extend observations on the properties of the individual probiotic Lactobacillus that are related to health benefits onto other strains sharing common characteristics of the species. In this review, we will discuss the acquisition, presence, and functions of lactobacilli in different human microbiota throughout their whole life, including those arising in the amnion and their interactions with mucosal and immune cells. Examples of immune system modulation by probiotic lactobacilli include their colonic competition for available nutrients, interference with colonization sites, competition for binding sites on gut epithelial cells, bacteriocin production, reduction of colonic pH, and nonspecific stimulation of the immune system.

The microstructure evolution due to the tensile deformation of the equiatomic quinary high-entropy alloy Ho-Dy-Y-Gd-Tb (HEA-Fb) is assessed. HEA-Fb has extraordinarily similar alloying elements. It is one of the few hexagonal-close-packed single-phase representatives of HEA. HEA-Fb is compared to the equiatomic quaternary medium-entropy alloy (MEA) Ho-Dy-Gd-Tb with no Y (4-Y). For a hexagonal HEA, in contrast to the cubic HEA, little information on plastic deformation and underlying mechanisms is available. A detailed study using electron microscopy-based multi-scale characterization (SEM, S/TEM, and STEM-EDS) explains significant differences between the ductile behavior of the quaternary MEA 4-Y and the brittle behavior of the quinary HEA-Fb at room temperature. Twinning during plastic deformation is decisive for ductility, which challenges the widely discussed high-entropy effect on the mechanical behavior of the HEA. For the quaternary MEA 4-Y, a twinning-induced plasticity effect is found. In the latter, oxidized twins are present in the undeformed state. In both alloys, the twin orientations are indexed as [ 2 ¯ 201 ] , while the matrices have the perpendicular [ 11 2 ¯ 0 ] orientation. Additionally, the analysis of twin structures confirms the importance of twin boundaries as obstacles for dislocations and stacking fault mobilities. The results are discussed in the context of the existing knowledge gaps in the field of hexagonal MEAs and HEAs. [ABSTRACT FROM AUTHOR]

Abstract Background Sepsis in low-birth-weight neonates remains one of the most significant causes of neonatal morbidity and mortality. Approximately 3 million newborns suffer from sepsis globally every year. The aim of this study was to compare demographic and clinical features, as well as etiology and antibiotic susceptibility, of the main pathogens related to neonatal sepsis in two neonatal intensive units during a two-year period. Methods We observed early-onset (EO-BSI) and late-onset bloodstream infections (LO-BSI) cases in two high-reference neonatal intensive care units (NICU) over a 24-month period (2016–2017). Samples of patients’ blood were tested for the presence of the microorganisms. All bacterial isolates were tested for susceptibility to antibiotics. Results The majority of sepsis cases weighed above 1000 g and were born by cesarean section. About 10% of the EO-BSI group died. There were differences in the EO-BSI /LO-BSI ratio in the compared wards due to differences among the admitted children. The most common pathogens isolated from blood were coagulase-negative staphylococci (CoNS) were represented by two dominating species: S. epidermidis and S. haemolyticus, followed by Klebsiella spp. strains and E.coli, which were mostly found in EO-BSI cases. No single S. agalactiae (GBS) strain was isolated. The majority of CoNS strains were resistant to methicillin, half were resistant to aminoglycosides, and one-third were resistant to macrolides and lincosamides. Half of the Gram-negative rods were resistant to beta-lactams. Conclusions The epidemiology of sepsis in two observed NICUs is comparable to data obtained from other studies with a predominance of methicillin-resistant CoNS in LO-BSI and beta-lactam resistant E. coli in EO-BSI. It is of importance that the campaign for controlling GBS carriage in pregnant women in Poland resulted in the disappearance of GBS as a cause of sepsis. Unfortunately, there are no such measures to control E.coli related sepsis.

Abstract Background Colorectal cancer is a highly prevalent and deadly. The most common metastatic site is the liver. We performed a whole exome sequencing analysis of a series of metachronous colorectal cancer liver metastases (mCLM) and matched non-malignant liver tissues to investigate the genomic profile of mCLM and explore associations with the patients’ prognosis and therapeutic modalities. Methods DNA samples from mCLM and non-malignant liver tissue pairs (n = 41) were sequenced using whole exome target enrichment and their germline and somatic genetic variability, copy number variations, and mutational signatures were assessed for associations with relapse-free (RFS) and overall survival (OS). Results Our genetic analysis could stratify all patients into existing targeted therapeutic regimens. The most commonly mutated genes in mCLM were TP53, APC, and KRAS together with PIK3CA and several passenger genes like ABCA13, FAT4, PCLO, and UNC80. Patients with somatic alterations in genes from homologous recombination repair, Notch, and Hedgehog pathways had significantly prolonged RFS, while those with altered MYC pathway genes had poor RFS. Additionally, alterations in the JAK-STAT pathway were prognostic of longer OS. Patients bearing somatic variants in VIPR2 had significantly shorter OS and those with alterations in MUC16 prolonged OS. Carriage of the KRAS-12D variant was associated with shortened survival in our and external datasets. On the other hand, tumor mutation burden, mismatch repair deficiency, microsatellite instability, mutational signatures, or copy number variation in mCLM had no prognostic value. Conclusions The results encourage further molecular profiling for personalized treatment of colorectal cancer liver metastases discerning metachronous from synchronous scenarios.

Abstract In this paper, the molecular dynamics at different thermodynamic conditions of hydrogen-bonded (H-bonded) active pharmaceutical ingredient—ticagrelor (TICA) have been investigated. Extensive high-pressure (HP) dielectric studies revealed surprising high sensitivity of the structural (α)-relaxation to compression. They also showed that unexpectedly the shape of the α-peak remains invariable at various temperature (T) and pressure (p) conditions at constant α-relaxation time. Further infrared measurements on the ordinary and pressure densified glasses of the examined compound indicated that the hydrogen-bonding pattern in TICA is unchanged by the applied experimental conditions. Such behavior was in contrast to that observed recently for ritonavir (where the organization of hydrogen bonds varied at high p) and explained the lack of changes in the width of α-dispersion with compression. Moreover, HP dielectric measurements performed in the glassy state of TICA revealed the high sensitivity of the slow secondary (β)-relaxation (Johari–Goldstein type) to pressure and fulfillment of the isochronal superpositioning of α- and JG-β-relaxation times. Additionally, it was found that the activation entropy for the β-process, estimated from the Eyring equation (a high positive value at 0.1 MPa) slightly increases with compression. We suggested that the reason for that are probably small conformational variations of TICA molecules at elevated p.

Abstract We present calculations based on density-functional theory with improved exchange-correlation approaches to investigate the electronic structure of $$\hbox {Ni}_2$$ Ni 2 MnGa magnetic shape memory alloy prototype. We study the effects of hybrid functionals as well as a Hubbard-like correction parameter U on the structural, electronic and magnetic properties of the alloy. We show that the previously successful application of U on Mn should be extended by including U on Ni to describe the d localized electrons more accurately and in better agreement with experiments. The bonding interactions within this intermetallic alloy are analysed including the role of non-transition metal. We found that the strongest and most stabilizing bond is formed between the Ga–Ni pairs due to the delocalized s–s and p–s orbital hybridization. Our findings suggest that minimization of the over-delocalization error introduced by standard semi-local exchange-correlation functionals leads to a better description of the $$\hbox {Ni}_2$$ Ni 2 MnGa alloy. Furthermore we propose that the experimental total magnetic moment of Ni–Mn–Ga alloys could be increased after carefully selected heat treatment procedures.

Abstract In this paper, thermal properties, atomic-scale structure, and molecular dynamics (at ambient and high pressure) of native melatonin (MLT) and its partially-deuterated derivative (MLT-d2) have been investigated. Based on infrared spectroscopy, it was shown that treating MLT with D2O causes the replacement of hydrogen atoms attached to the nitrogen by deuterium. The degree of such substitution was very high (> 99%) and the deuterated sample remained stable after exposure to the air as well as during the melting and vitrification processes. Further calorimetric studies revealed the appearance of a peculiar thermal event before the melting of crystalline MLT-d2, which was assigned by the X-ray diffraction to a local negative thermal expansion of the unit cell. Finally, the high-pressure dielectric experiments indicated a few interesting findings, including the variation in the shape of the structural relaxation peak during compression, the difference in the pressure evolution of the glass transition temperature, and the temperature dependence of activation volume for both MLT species. The variations in these parameters manifest a different impact of the compression/densification on the dynamics of hydrogen and deuterium bonds in the native and partially-deuterated MLT, respectively.

Materials combining photoluminescence (PL) with sorption properties, such as those based on supramolecular assemblies or coordination polymers, are considered good candidates for the construction of optical sensors of external stimuli. We report a new dynamic coordination polymer, {[K(H2O)3]8[Gd(H2O)6]14[Pt(CN)4]25·28H2O}n (1) based on tetracyanidoplatinate(II) ions as well as K(I) and Gd(III) aqua-complexes. These molecular building blocks are self-assembled by employing {Pt–CN–Gd} cyanido bridging and non-innocent {Pt–Pt} metallophilic interactions. 1 exhibits visible-light PL related to metal-to-metal-to-ligand charge transfer transitions occurring within the metallophilic {[PtII(CN)4]}n2n− stacks, water vapor sorption properties and reversible thermal dehydration. Thanks to these prerequisites, the PL features strongly depend on relative humidity (RH) and temperature, determining the number of interstitial water molecules. By changing RH, one can tune the emission from the strongest deep green emission at ca. 80% RH (1H1 phase), through weaker green emission at ca. 20% RH (1H2, denoted also as H), to yellow-orange PL at 0% RH (e.g., Ar atmosphere, 1A1). The return from low to high RH differs due to the hysteresis in the sorption isotherm. Thus, at ca. 20% RH (1A2, denoted also as A), the emission color is yellow; however, at ca. 80% RH, the recovery of 1H1 with its deep green emission appears. This switching effect is enriched by thermal dehydration. Starting from green-emissive H, on heating to 150 °C, the new blue-emissive phase 1T1 is produced. After cooling to room temperature and reaching ca. 20% RH, the new greenish blue PL is realized (1T2, denoted also T). The recovery of initial phases is done at a RH of ca. 80% providing the route to the original 1H1. As a result, at ca. 20% RH, three phases (A, T, and H) with different PL appear depending on the history of the material. This optical memory effect enables the usage of the reported material as an optical sensor of RH and temperature. In particular, this material can act as an alarm indicating the appearance of high temperatures or low RH. [ABSTRACT FROM AUTHOR]