Annealing Behavior of a Mg-Y-Zn-Al Alloy Processed by Rapidly Solidified Ribbon Consolidation.

Mg-Y-Zn-Al alloys processed by the rapidly solidified ribbon consolidation (RSRC) technique are candidate materials for structural applications due to their improved mechanical performance. Their outstanding mechanical strength is attributed to solute-enriched stacking faults (SESFs), which can form cluster-arranged layers (CALs) and cluster-arranged nanoplates (CANaPs) or complete the long-period stacking ordered (LPSO) phase. The thermal stability of these solute arrangements strongly influences mechanical performance at elevated temperatures. In this study, an RSRC-processed Mg-0.9%, Zn-2.05%, Y-0.15% Al (at%) alloy was heated at a rate of 0.666 K/s up to 833 K, a temperature very close to melting point. During annealing, in situ X-ray diffraction (XRD) measurements were performed using synchrotron radiation in order to monitor changes in the structure. These in situ XRD experiments were completed with ex situ electron microscopy investigations before and after annealing. At 753 K and above, the ratio of the matrix lattice constants, c/a, decreased considerably, which was restored during cooling. This decrease in c/a could be attributed to partial melting in the volumes with high solute contents, causing a change in the chemical composition of the remaining solid material. In addition, the XRD intensity of the secondary phase increased at the beginning of cooling and then remained unchanged, which was attributed to a long-range ordering of the solute-enriched phase. Both the matrix grains and the solute-enriched particles were coarsened during the heat treatment, as revealed by electron microscopy.

Heme: A link between hemorrhage and retinopathy of prematurity progression.

Neovascularization is implicated in the pathology of retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD), which are the leading causes of blindness worldwide. In our work, we analyzed how heme released during hemorrhage affects hypoxic response and neovascularization. Our retrospective clinical analysis demonstrated, that hemorrhage was associated with more severe retinal neovascularization in ROP patients. Our heme-stimulated human retinal pigment epithelial (ARPE-19) cell studies demonstrated increased expression of positive regulators of angiogenesis, including vascular endothelial growth factor-A (VEGFA), a key player of ROP, DR and AMD, and highlighted the activation of the PI3K/AKT/mTOR/VEGFA pathway involved in angiogenesis in response to heme. Furthermore, heme decreased oxidative phosphorylation in the mitochondria, augmented glycolysis, facilitated HIF-1α nuclear translocation, and increased VEGFA/GLUT1/PDK1 expression suggesting HIF-1α-driven hypoxic response in ARPE-19 cells without effecting the metabolism of reactive oxygen species. Inhibitors of HIF-1α, PI3K and suppression of mTOR pathway by clinically promising drug, rapamycin, mitigated heme-provoked cellular response. Our data proved that oxidatively modified forms of hemoglobin can be sources of heme to induce VEGFA during retinal hemorrhage. We propose that hemorrhage is involved in the pathology of ROP, DR, and AMD.

Variability of theory of mind versus pragmatic ability in typical and atypical development.

INTRODUCTION: Numerous studies have linked deficits in Theory of Mind (ToM) with language problems. We aimed to explore the similarities and differences between children's patterns of performance on a ToM task that requires minimal linguistic skill and a pragmatic inference task that relies on both ToM and language. We assessed variability in pragmatic inference skills and ToM across populations of children (8-14 years) displaying varying cognitive profiles. We further compared the sensitivity of ToM versus pragmatic ability to core language skills, memory and executive functioning (EF). METHOD: ToM was tested using the Social Attribution Task (SAT-MC-II). Pragmatic ability was assessed in an implicature comprehension task. Receptive vocabulary, grammar comprehension, short-term and working memory (STM and WM) capacity and EF were measured using Hungarian adaptations of standard tasks and tests developed by the authors' lab. In addition to typically developing (TD) children (n = 33), we included children with neurodevelopmental disorders where ToM and/or language abilities are vulnerable: autism spectrum disorder (ASD, n = 26), attention deficit hyperactivity disorder (ADHD, n = 25) and developmental language disorder (DLD, n = 18). RESULTS: Results revealed a significant but only moderate positive correlation between pragmatic inference and ToM indicating that the two abilities are related but distinct. The ASD group showed impairments in both ToM and pragmatic inference ability but no significant deficit was observed in ADHD or DLD relative to TD children in either skill. However, while SAT-MC-II results were only affected by verbal WM and vocabulary measures, pragmatic performance was associated with STM, verbal WM, EF, grammatical skills and vocabulary. CONCLUSION: Our findings indicate that disentangling the contributions of different cognitive skills to ToM tasks may help clarify the role of ToM in language skills and identify distinct patterns of ToM and pragmatic skills in developmental disorders.

State-of-the-art local correlation methods enable affordable gold standard quantum chemistry for up to hundreds of atoms.

In this feature, we review the current capabilities of local electron correlation methods up to the coupled cluster model with single, double, and perturbative triple excitations [CCSD(T)], which is a gold standard in quantum chemistry. The main computational aspects of the local method types are assessed from the perspective of applications, but the focus is kept on how to achieve chemical accuracy (i.e., <1 kcal mol-1 uncertainty), as well as on the broad scope of chemical problems made accessible. The performance of state-of-the-art methods is also compared, including the most employed DLPNO and, in particular, our local natural orbital (LNO) CCSD(T) approach. The high accuracy and efficiency of the LNO method makes chemically accurate CCSD(T) computations accessible for molecules of hundreds of atoms with resources affordable to a broad computational community (days on a single CPU and 10-100 GB of memory). Recent developments in LNO-CCSD(T) enable systematic convergence and robust error estimates even for systems of complicated electronic structure or larger size (up to 1000 atoms). The predictive power of current local CCSD(T) methods, usually at about 1-2 order of magnitude higher cost than hybrid density functional theory (DFT), has become outstanding on the palette of computational chemistry applicable for molecules of practical interest. We also review more than 50 LNO-based and other advanced local-CCSD(T) applications for realistic, large systems across molecular interactions as well as main group, transition metal, bio-, and surface chemistry. The examples show that properly executed local-CCSD(T) can contribute to binding, reaction equilibrium, rate constants, etc. which are able to match measurements within the error estimates. These applications demonstrate that modern, open-access, and broadly affordable local methods, such as LNO-CCSD(T), already enable predictive computations and atomistic insight for complicated, real-life molecular processes in realistic environments.

Evaluation of floatability characteristics of gastroretentive tablets using VIS imaging with artificial neural networks.

Gastroretentive dosage forms are recommended for several active substances because it is often necessary for the drug to be released from the carrier system into the stomach over an extended period. Among gastroretentive dosage forms, floating tablets are a very popular pharmaceutical technology. In this study, it was investigated whether a rapid, nondestructive method can be used to characterize the floating properties of a tablet. To accomplish our objective, the same composition was compressed, and varied compression forces were applied to achieve the desired tablet. In addition to physical examinations, digital microscopic images of the tablets were captured and analyzed using image analysis techniques, allowing the investigation of the floatability of the dosage form. Image processing algorithms and artificial neural networks (ANNs) were utilized to classify the samples based on their strength and floatability. The input dataset consisted solely of the acquired images. It has been shown by our research that visible imaging coupled with pattern recognition neural networks is an efficient way to categorize these samples based on their floatability. Rapid and non-destructive digital imaging of tablet surfaces is facilitated by this method, offering insights into both crushing strength and floating properties.

Proviral and antiviral roles of phosphofructokinase family of glycolytic enzymes in TBSV replication.

Positive-strand RNA viruses build viral replication organelles (VROs) with the help of co-opted host factors. The biogenesis of the membranous VROs requires major metabolic changes in infected cells. Previous studies showed that tomato bushy stunt virus (TBSV) hijacks several glycolytic enzymes to produce ATP locally within VROs. In this work, we demonstrate that the yeast Pfk2p phosphofructokinase, which performs a rate-limiting and highly regulated step in glycolysis, interacts with the TBSV p33 replication protein. Deletion of PFK2 reduced TBSV replication in yeast, suggesting proviral role for Pfk2p. TBSV also co-opted two plant phosphofructokinases, which supported viral replication and ATP production within VROs, thus acting as proviral factors. Three other phosphofructokinases inhibited TBSV replication and they reduced ATP production within VROs, thus functioning as antiviral factors. Altogether, different phosphofructokinases have proviral or antiviral roles. This suggests on-going arms race between tombusviruses and their hosts to control glycolysis pathway in infected cells.

Proviral role of ATG2 autophagy related protein in tomato bushy stunt virus replication through bulk phospholipid transfer into the viral replication organelle.

Subversion of cellular membranes and membrane proliferation are used by positive-strand RNA viruses to build viral replication organelles (VROs) that support virus replication. The biogenesis of the membranous VROs requires major changes in lipid metabolism and lipid transfer in infected cells. In this work, we show that tomato bushy stunt virus (TBSV) hijacks Atg2 autophagy related protein with bulk lipid transfer activity into VROs via interaction with TBSV p33 replication protein. Deletion of Atg2 in yeast and knockdown of Atg2 in Nicotiana benthamiana resulted in decreased TBSV replication. We found that subversion of Atg2 by TBSV was important to enrich VRO membranes with phosphatidylethanolamine (PE), phosphatidylserine (PS) and PI(3)P phosphoinositide. Interestingly, inhibition of autophagy did not affect the efficient recruitment of Atg2 into VROs, and overexpression of Atg2 enhanced TBSV replication, indicating autophagy-independent subversion of Atg2 by TBSV. These findings suggest that the proviral function of Atg2 lipid transfer protein is in VRO membrane proliferation. In addition, we find that Atg2 interacting partner Atg9 with membrane lipid-scramblase activity is also coopted for tombusvirus replication. Altogether, the subversion of Atg2 bridge-type lipid transfer protein provides a new mechanism for tombusviruses to greatly expand VRO membranes to support robust viral replication.

The epidemiology of lung cancer in Hungary based on the characteristics of patients diagnosed in 2018.

Among malignant diseases, lung cancer has one of the highest mortality and incidence. Most epidemiological studies conclude that Hungary faces the most severe burden in association with this disease. However, for various reasons estimates and population-based studies show discrepancies. In this study, an intense data cleansing was performed on lung cancer cases that were reported to the Hungarian National Cancer Registry in 2018, and the major clinico-pathological parameters as well as survival characteristics were described. Our population-based figures were compared to the European estimates. As a result of our thorough revision, the corrected incidence of lung cancer has fallen below the number of cases that were reported to the Registry from 11,746 to 9,519. We also demonstrate that Hungary did not show the highest incidence and mortality in Europe, but it is still among the ones with the worst raking countries, with 92.9 and 50.6 age standardized rate per 100 thousand capita among males and females, respectively. Analysis of the annually reported case numbers revealed a gender-specific difference in incidence trends: while from 2001 to 2019 it slightly decreased among males, it increased among females. The most dominant subtype was adenocarcinoma, which was more frequent among female patients. Unfortunately, most of the newly diagnosed cases were in advanced stage; thus, 5 year overall survival was 14.8%. We anticipate that in the longer term, a decrease in incidence and improvement in survival rates may be expected as a result of the development of primary and secondary prevention programs in the country.

Basis-Set Limit CCSD(T) Energies for Large Molecules with Local Natural Orbitals and Reduced-Scaling Basis-Set Corrections.

The calculation of density-based basis-set correction (DBBSC), which remedies the basis-set incompleteness (BSI) error of the correlation energy, is combined with local approximations. Aiming at large-scale applications, the procedure is implemented in our efficient local natural orbital-based coupled-cluster singles and doubles with perturbative triples [LNO-CCSD(T)] scheme. To this end, the range-separation function, which characterizes the one-electron BSI in space, is decomposed into the sum of contributions from individual localized molecular orbitals (LMOs). A compact domain is constructed around each LMO, and the corresponding contributions are evaluated only within these restricted domains. Furthermore, for the calculation of the complementary auxiliary basis set (CABS) correction, which significantly improves the Hartree-Fock (HF) energy, the local density fitting approximation is utilized. The errors arising from the local approximations are examined in detail, efficient prescreening techniques are introduced to compress the numerical quadrature used for DBBSC, and conservative default thresholds are selected for the truncation parameters. The efficiency of the DBBSC-LNO-CCSD(T) method is demonstrated through representative examples of up to 1000 atoms. Based on the numerical results, we conclude that the corrections drastically reduce the BSI error using double-ζ basis sets, often to below 1 kcal/mol compared to the reliable LNO-CCSD(T) complete basis set references, while significant improvements are also achieved with triple-ζ basis sets. Considering that the calculation of the DBBSC and CABS corrections only moderately increases the wall-clock time required for the post-HF steps in practical applications, the proposed DBBSC-LNO-CCSD(T) method offers a highly efficient and robust tool for large-scale calculations.

Novel insights into the modulation of the voltage-gated potassium channel KV1.3 activation gating by membrane ceramides.

Membrane lipids extensively modulate the activation gating of voltage-gated potassium channels (KV), however, much less is known about the mechanisms of ceramide and glucosylceramide actions including which structural element is the main intramolecular target and whether there is any contribution of indirect, membrane biophysics-related mechanisms to their actions. We used two-electrode voltage-clamp fluorometry capable of recording currents and fluorescence signals to simultaneously monitor movements of the pore domain (PD) and the voltage sensor domain (VSD) of the KV1.3 ion channel after attaching an MTS-TAMRA fluorophore to a cysteine introduced into the extracellular S3-S4 loop of the VSD. We observed rightward shifts in the conductance-voltage (G-V) relationship, slower current activation kinetics, and reduced current amplitudes in response to loading the membrane with C16-ceramide (Cer) or C16-glucosylceramide (GlcCer). When analyzing VSD movements, only Cer induced a rightward shift in the fluorescence signal-voltage (F-V) relationship and slowed fluorescence activation kinetics, whereas GlcCer exerted no such effects. These results point at a distinctive mechanism of action with Cer primarily targeting the VSD, while GlcCer only the PD of KV1.3. Using environment-sensitive probes and fluorescence-based approaches, we show that Cer and GlcCer similarly increase molecular order in the inner, hydrophobic regions of bilayers, however, Cer induces a robust molecular reorganization at the membrane-water interface. We propose that this unique ordering effect in the outermost membrane layer in which the main VSD rearrangement involving an outward sliding of the top of S4 occurs can explain the VSD targeting mechanism of Cer, which is unavailable for GlcCer.

Lactoperoxidase catalytically oxidize hydrogen sulfide via intermediate formation of sulfheme derivatives.

The biological chemistry of hydrogen sulfide (H2S) with physiologically important heme proteins is in the focus of redox biology research. In this study, we investigated the interactions of lactoperoxidase (LPO) with H2S in the presence and absence of molecular dioxygen (O2) or hydrogen peroxide (H2O2). Under anaerobic conditions, native LPO forms no heme-H2S complex upon sulfide exposure. However, under aerobic conditions or in the presence of H2O2 the formation of both ferrous and ferric sulfheme (sulfLPO) derivatives was observed based on the appearances of their characteristic optical absorptions at 638 nm and 727 nm, respectively. Interestingly, we demonstrate that LPO can catalytically oxidize H2S by H2O2 via intermediate formation of relatively short-lived ferrous and ferric sulfLPO derivatives. Pilot product analyses suggested that the turnover process generates oxidized sulfide species, which include sulfate S O 4 2 - and inorganic polysulfides ( H S x - ; x = 2-5). These results indicated that H2S can serve as a non-classical LPO substrate by inducing a reversible sulfheme-like modification of the heme porphyrin ring during turnover. Furthermore, electron paramagnetic resonance data suggest that H2S can act as a scavenger of H2O2 in the presence of LPO without detectable formation of any carbon-centered protein radical species, suggesting that H2S might be capable of protecting the enzyme from radical-mediated damage. We propose possible mechanisms, which explain our results as well as contrasting observations with other heme proteins, where either no sulfheme formation was observed or the generation of sulfheme derivatives provided a dead end for enzyme functions.

[County differences in incidence and mortality of malignant neoplasms in Hungary between 2005 and 2019]. / A rosszindulatú daganatos betegségek incidenciájának és mortalitásának vármegyénkénti különbségei Magyarországon 2005 és 2019 között.

The objective of our study was to map county differences in incidence and mortality by cancers and examine their changes over time. Based on the database of National Cancer Registry and Central Statistical Office, age-standardized incidence and mortality rates per 100,000 person-years were calculated for each county for 15 cancer types and 3 time periods. East-West divide was apparent in incidence and mortality of lung cancer, with larger weight in East (Borsod-Abaúj-Zemplén, Heves, Jász-Nagykun-Szolnok, Békés counties). Concentration of lip and oral cavity malignancies was identified in the northeastern periphery (Borsod-Abaúj-Zemplén, Szabolcs-Szatmár-Bereg counties). Breast cancer incidence was the highest in Budapest. As a conclusion, changes in cancer incidence and mortality over time were similar to developed countries; however, values were higher. Differences in spatial distribution follow territorial pattern of social deprivation, which correspond to higher prevalence of health risk factors. Our study contributes to planning of public health programs by pinpointing regional inequalities in different cancer types.

[The pitfalls of lung cancer coding practices based on the evaluation of the National Cancer Registry]. / A tüdorákhoz kötodo kódolási gyakorlat buktatói a Nemzeti Rákregiszter felmérése alapján.

The quality of input data determines the reliability of epidemiological assessments. Thus, the verification of cases reported to the National Cancer Registry is required. The objective of our study was evaluating the reliability of cases diagnosed by lung cancer, exploring the patterns of erroneous reports. The validation of the 11,750 lung cancer cases reported to the Cancer Registry in 2018 was performed with the involvement of the recording hospitals, analyzing the characteristics of reports by gender, age and attributes of the reporting institutions. 81.3 percent of the reported cases was confirmed, in 40.4 percent of the false reports, malignancy was not present at all. Among the erroneous cases women and the elderly age group were overrepresented. The highest deleted rate occurred in Borsod- Abaúj-Zemplén county. As a conclusion, there is a strong need for the improvement of the efficiency in encoding lung cancer. The most common errors: confusion of malignant-benign, cancerous-non-cancerous and primary-metastatic lesions. The reliability is not affected by the role of individual institutions in the hierarchy of health care. The availability of reliable epidemiological data is crucial in the fight against cancer, which requires broad professional cooperation.

Optical genome mapping with genome sequencing identifies subtelomeric Xq28 deletion and inserted 7p22.3 duplication in a male with multisystem developmental disorder.

We report a 17-year-old male with supravalvular stenosis, initial failure to thrive and delayed early development, short stature, acromelia, dysmorphic facial features, hypertelorism, macrocephaly, syringomyelia, hypertension, and anxiety disorder. Fluorescent in situ hybridization (FISH), chromosomal microarray analysis (CMA), and exome sequencing (ES) were nondiagnostic. Combined optical genome mapping (OGM) and genome sequencing (GS) showed a complex rearrangement including an X chromosome with a 22.5 kb deletion in band Xq28 replaced by a 61.4 kb insertion of duplicated chromosome 7p22.3 material. The deletion removes the distal 3' untranslated region (UTR) of FUNDC2, the entire CMC4 and MTCP1, and the first five exons of BRCC3. Transcriptome analysis revealed absent expression of CMC4 and MTCP1 and BRCC3 with normal transcript level of FUNDC2. The inserted duplication includes only one known gene: UNCX. Similar overlapping Xq28 deletions have been reported to be associated with Moyamoya disease (MMD), short stature, hypergonadotropic hypogonadism (HH), and facial dysmorphism. Although he has short stature, our patient does not have signs of Moyamoya arteriopathy or hypogonadism. The structurally abnormal X chromosome was present in his mother, but not in his unaffected brother, maternal uncle, or maternal grandparents. We propose that the combination of his absent Xq28 and duplicated 7p22.3 genomic material is responsible for his phenotype. This case highlights the potential of combined OGM and GS for detecting complex structural variants compared with standard of care genetic testing such as CMA and ES.

The effects of spatial leakage correction on the reliability of EEG-based functional connectivity networks.

Electroencephalography (EEG) functional connectivity (FC) estimates are confounded by the volume conduction problem. This effect can be greatly reduced by applying FC measures insensitive to instantaneous, zero-lag dependencies (corrected measures). However, numerous studies showed that FC measures sensitive to volume conduction (uncorrected measures) exhibit higher reliability and higher subject-level identifiability. We tested how source reconstruction contributed to the reliability difference of EEG FC measures on a large (n = 201) resting-state data set testing eight FC measures (including corrected and uncorrected measures). We showed that the high reliability of uncorrected FC measures in resting state partly stems from source reconstruction: idiosyncratic noise patterns define a baseline resting-state functional network that explains a significant portion of the reliability of uncorrected FC measures. This effect remained valid for template head model-based, as well as individual head model-based source reconstruction. Based on our findings we made suggestions how to best use spatial leakage corrected and uncorrected FC measures depending on the main goals of the study.

International Consensus on Standard Outcome Measures for Neurodevelopmental Disorders: A Consensus Statement.

Importance: The use of evidence-based standardized outcome measures is increasingly recognized as key to guiding clinical decision-making in mental health. Implementation of these measures into clinical practice has been hampered by lack of clarity on what to measure and how to do this in a reliable and standardized way. Objective: To develop a core set of outcome measures for specific neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD), communication disorders, specific learning disorders, and motor disorders, that may be used across a range of geographic and cultural settings. Evidence Review: An international working group composed of clinical and research experts and service users (n = 27) was convened to develop a standard core set of accessible, valid, and reliable outcome measures for children and adolescents with NDDs. The working group participated in 9 video conference calls and 8 surveys between March 1, 2021, and June 30, 2022. A modified Delphi approach defined the scope, outcomes, included measures, case-mix variables, and measurement time points. After development, the NDD set was distributed to professionals and service users for open review, feedback, and external validation. Findings: The final set recommends measuring 12 outcomes across 3 key domains: (1) core symptoms related to the diagnosis; (2) impact, functioning, and quality of life; and (3) common coexisting problems. The following 14 measures should be administered at least every 6 months to monitor these outcomes: ADHD Rating Scale 5, Vanderbilt ADHD Diagnostic Rating Scale, or Swanson, Nolan, and Pelham Rating Scale IV; Affective Reactivity Index; Children's Communication Checklist 2; Colorado Learning Disabilities Questionnaire; Children's Sleep Habits Questionnaire; Developmental-Disability Children's Global Assessment Scale; Developmental Coordination Disorder Questionnaire; Family Strain Index; Intelligibility in Context Scale; Vineland Adaptive Behavior Scale or Repetitive Behavior Scale-Revised and Social Responsiveness Scale; Revised Child Anxiety and Depression Scales; and Yale Global Tic Severity Scale. The external review survey was completed by 32 professionals and 40 service users. The NDD set items were endorsed by more than 70% of professionals and service users in the open review survey. Conclusions and Relevance: The NDD set covers outcomes of most concern to patients and caregivers. Use of the NDD set has the potential to improve clinical practice and research.

Study on Anatomical Structures of the Dromedary Udder.

The objectives of the present study were to describe specific anatomical structures of the dromedary udder. Eighty-six dromedary udders were examined, taking morphological measurements and producing injection casts using resin, gelatin, and paraffin. The udder of the dromedaries consists of four quarters. The shape of the udders and teats varies considerably between animals and is influenced by age, breeding, and lactation status. The most frequently found udder form was the globular udder (48.8%) and the most common teat form in this study was the funnel teat (44.2%). The most common teat tip shape was a smooth or a slightly rough ring teat (61.6%). Injection casts showed a complete separation of the teat canals. There is also no communication between tributary mammary complexes. Resin injections of the glandular tissue adjacent to the teat cistern showed an extensive branching into large, medium, and small milk ducts. Frozen sections of the udder revealed complete separation of the right and left mammary complex through the Sulcus intermammarius. The teat sections showed longitudinal folds from the tip of the teat to the base of the teat. A ring fold at the transition from the Ductus papillaris to the teat cistern was present. The results of this study increase the knowledge of the anatomical structures of the dromedary udder, which may be useful for breeding a selection of dairy dromedaries.

Molecular Markers and Antimicrobial Resistance Patterns of Extraintestinal Pathogenic Escherichia coli from Camel Calves Including Colistin-Resistant and Hypermucoviscuous Strains.

Extraintestinal pathogenic Escherichia coli (ExPEC) strains are capable of causing various systemic infections in both humans and animals. In this study, we isolated and characterized 30 E. coli strains from the parenchymatic organs and brains of young (<3 months of age) camel calves which died in septicemia. Six of the strains showed hypermucoviscous phenotype. Based on minimum inhibitory concentration (MIC) values, seven of the strains were potentially multidrug resistant, with two additional showing colistin resistance. Four strains showed mixed pathotypes, as they carried characteristic virulence genes for intestinal pathotypes of E. coli: three strains carried cnf1, encoding cytotoxic necrotizing factor type 1, the key virulence gene of necrotoxigenic E. coli (NTEC), and one carried eae encoding intimin, the key virulence gene of enteropathogenic E. coli (EPEC). An investigation of the integration sites of pathogenicity islands (PAIs) and the presence of prophage-related sequences showed that the strains carry diverse arrays of mobile genetic elements, which may contribute to their antimicrobial resistance and virulence patterns. Our work is the first to describe ExPEC strains from camels, and points to their veterinary pathogenic as well as zoonotic potential in this important domestic animal.

Application of comprehensive molecular genetic profiling in precision cancer medicine, Hungarian experiences.

Recent developments in molecular genetic testing methods (e.g. next-generation sequencing [NGS]-panels) largely accelerated the process of finding the most appropriate targeted therapeutic intervention for cancer patients based on molecularly targetable genetic alterations. In Hungary, a centralized approval system following the recommendation of the National Molecular Tumor Board was launched for the coordination of all aspects of comprehensive genetic profiling (CGP) including patient selection and therapy reimbursement. AIM: The study aims to evaluate the clinical benefit of CGP in our Comprehensive Cancer Center Methods and patients: CGP was introduced into our routine clinical practice in 2021. An NGS-based large (> 500 genes) gene panel was used for cases where molecular genetic testing was approved by the National Molecular Tumor Board. From 2021 until August 2023 163 cases were tested. The majority of them were ECOG 0-1 patients with advanced-stage diseases, histologically rare cancer, or cancers with unknown primary tumours. RESULTS: Seventy-four cases (74 of 163, 45%) had clinically relevant genetic alterations. In 34 patients, the identified variants represented an indication for an approved therapy (approved by the Hungarian authorities, on-label indication), while in 40 cases the recommended therapy did not have an approved indication in Hungary for certain tumour types, but off-label indication could be recommended. Based on our CGP results, 24 patients (24/163; 14.7%) received targeted therapy. Treatment duration was between 1 and 60 months. In total 14 (14/163; 8.5% of the tested cases) patients had a positive clinical response (objective response or stable disease) and were treated for more than 16 weeks. INTERPRETATION: NGS-based CGP was successfully introduced in our institution and a significant number of patients benefited from comprehensive genetic tests. Our preliminary results can serve as the starting point of Drug Rediscovery Protocol (DRUP) studies.