Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbab le, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

Structure-Based Discovery of High-Affinity Small Molecule Ligands and Development of Tool Probes to Study the Role of Chitinase-3-Like Protein 1.

Chitinase-3-like-1 (CHI3L1), also known as YKL-40, is a glycoprotein linked to inflammation, fibrosis, and cancer. This study explored CHI3L1's interactions with various oligosaccharides using microscale thermophoresis (MST) and AlphaScreen (AS). These investigations guided the development of high-throughput screening assays to assess interference of small molecules in binding between CHI3L1 and biotinylated small molecules or heparan sulfate-based probes. Small molecule binders of YKL-40 were identified in our chitotriosidase inhibitors library with MST and confirmed through X-ray crystallography. Based on cocrystal structures of potent hit compounds with CHI3L1, small molecule probes 19 and 20 were designed for an AS assay. Structure-based optimization led to compounds 30 and 31 with nanomolar activities and drug-like properties. Additionally, an orthogonal AS assay using biotinylated heparan sulfate as a probe was developed. The compounds' affinity showed a significant correlation in both assays. These screening tools and compounds offer novel avenues for investigating the role of CHI3L1.

The Influence of Genetic Polymorphic Variability of the Catechol-O-methyltransferase Gene in a Group of Patients with a Diagnosis of Behavioural Addiction, including Personality Traits.

Gambling Disorder (GD) is characterised by a harmful, enduring, and recurrent involvement in betting-related behaviours. Therefore, GD shares similar biological mechanisms and symptoms to substance use disorders (SUD). Therefore, in this study, we chose the behavioural addictions group. During the examination and recruitment to the study, it turned out that all the people undergoing treatment for gambling addiction were also addicted to amphetamines, which is consistent with the biological mechanism related to cerebral neurotransmission. The aim of the study was to investigate the association of the COMT gene polymorphism with behavioral addiction. The study group consisted of 307 participants: 107 men with gambling disorder and amphetamine dependency (mean age = 27.51, SD = 5.25) and 200 non-addicted, nor dependent, free from neuro-psychiatric disorders control group men (mean age = 20.20, SD = 4.51). Both groups were subjected to psychometric evaluation using the State-Trait Anxiety Inventory and the NEO Five-Factor Personality Inventory. Genomic DNA was extracted from venous blood following standard protocols. Determination of the rs4680 polymorphism in the COMT gene was performed using the real-time PCR technique. Statistically significant differences in the frequency of rs4680 genotypes were found in the tested sample of subjects compared with the control group (p = 0.03543). Subjects with gambling disorder and amphetamine use disorder compared to the control group obtained higher scores in the assessment of the STAI trait scale (p = 0.0019), state scale (p < 0.0000), and NEO-FFI Neuroticism scale (p < 0.0000). Significantly lower results were obtained for the NEO-FFI Agreeability scale (p < 0.0000). Additionally, a significant statistical impact of gambling disorder and amphetamine use disorder, and the COMT rs4680 genotype was demonstrated for the score of the STAI trait (p = 0.0351) and state (p = 0.0343) and the NEO-FFI Conscientiousness scale (p = 0.0018). We conclude that COMT and its polymorphic variant influence the development of addiction. Still, considering its multifactorial and polygenic nature, it should be combined with other factors such as personality.

The Pathophysiology and Treatment of Pyoderma Gangrenosum-Current Options and New Perspectives.

Pyoderma gangrenosum (PG) is an uncommon inflammatory dermatological disorder characterized by painful ulcers that quickly spread peripherally. The pathophysiology of PG is not fully understood; however, it is most commonly considered a disease in the spectrum of neutrophilic dermatoses. The treatment of PG remains challenging due to the lack of generally accepted therapeutic guidelines. Existing therapeutic methods focus on limiting inflammation through the use of immunosuppressive and immunomodulatory therapies. Recently, several reports have indicated the successful use of biologic drugs and small molecules administered for coexisting diseases, resulting in ulcer healing. In this review, we summarize the discoveries regarding the pathophysiology of PG and present treatment options to raise awareness and improve the management of this rare entity.

Superior sagittal sinus thrombosis in the course of mixed phenotype acute leukaemia treated with acute lymphoblastic leukaemia-like therapy-a case report.

Mixed phenotype acute leukaemia (MPAL) is associated with worse overall survival, compared with other acute leukaemias in adults. Lack of clear treatment guidelines makes the therapy challenging. ALL-like induction and consolidation treatment followed by allo-HSCT is the preferred first-line treatment. We present a case of a 36-year-old woman diagnosed with MPAL (EGIL Myelo/B) with KMT2A rearrangement, treated with the PALG-ALL-7 (including PEG-asparaginase) protocol. On day 25 after the induction therapy initiation, numbness of limbs and dizziness were observed. Therefore, the imaging studies (CT and MRI) were performed and a diagnosis of thrombosis of superior sagittal sinus of the brain was established. Routinely performed blood coagulation tests showed prolonged APTT and PT, decreased antithrombin III activity and decreased free protein S concentration. LMWH treatment and substitutional therapy with antithrombin III were started, which resulted in a significant reduction in the thrombosis associated symptoms and improvement of the neurological status after 3 days. After induction and consolidation therapy, the patient obtained complete haematological remission and negative measurable residual disease. Six months after the diagnosis, allo-HSCT was successfully performed. During the 4 months follow-up, the patient remained MRD negative and thrombotic symptoms free. To the best of our knowledge, our communication has been the first report of such complication in an MPAL patient treated with PEG-asparaginase containing protocol in adults. We recommend increased vigilance in patients manifesting any mild neurological symptoms and early decision about the MRI study performance.

Impact of COVID-19 Pandemic on Daily Mobility of the Elderly Living in Small Cities in Lodz Province.

The article presents a study into the impact that the COVID-19 pandemic had on the daily mobility of those over 60 residing in small towns in the Lodz Province. The study determines the impact on the trip destination, trip frequency, preferred means of transport, distance and duration of trips, and length of the target activity. To achieve these objectives, a survey was conducted using the CATI technique (Computer Assisted Telephone Interviewing), which comprised 500 residents of small towns in the Lodz Province aged 60+, who were divided into three classes of small towns (by population size). In order to determine the impact of the COVID-19 pandemic on the daily mobility of those over 60, the tools the authors decided to use descriptive statistics and hypothesis testing. Overall, the pandemic was found to have had only a minor impact on the changes in transport behavior of those over 60 in small towns. Only 9% of respondents declared any effect on their daily mobility. The impact mainly involved a reduction in travel time and frequency, primarily among the oldest residents. Since a low level of daily mobility leads to low social activity, especially for the elderly-with a consequent sense of loneliness or even depression-towns should take measures to improve the already poor situation, one that has been further exacerbated by the pandemic.

Iron inactivation by Sporobolomyces ruberrimus and its potential role in plant metal stress protection. An in vitro study.

The endophytic Basidiomycete Sporobolomyces ruberrimus protects its host Arabidopsis arenosa against metal toxicity. Plants inoculated with the fungus yielded more biomass and exhibited significantly fewer stress symptoms in medium mimicking mine dump conditions (medium supplemented with excess of Fe, Zn and Cd). Aside from fine-tuning plant metal homeostasis, the fungus was capable of precipitating Fe in the medium, most likely limiting host exposure to metal toxicity. The precipitated residue was identified by Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), X-Ray Diffraction (XRD) and electron microscopy (SEM/TEM) with energy dispersive X-Ray analysis (EDX/SAED) techniques. The performed analyses revealed that the fungus transforms iron into amorphous (oxy)hydroxides and phosphates and immobilizes them in the form of a precipitate changing Fe behaviour in the MSR medium. Moreover, the complexation of free Fe ions by fungi could be obtained by biomolecules such as lipids, proteins, or biosynthesized redox-active molecules.

Endophytic yeast protect plants against metal toxicity by inhibiting plant metal uptake through an ethylene-dependent mechanism.

Toxic metal pollution requires significant adjustments in plant metabolism. Here, we show that the plant microbiota plays an important role in this process. The endophytic Sporobolomyces ruberrimus isolated from a serpentine population of Arabidopsis arenosa protected plants against excess metals. Coculture with its native host and Arabidopsis thaliana inhibited Fe and Ni uptake. It had no effect on host Zn and Cd uptake. Fe uptake inhibition was confirmed in wheat and rape. Our investigations show that, for the metal inhibitory effect, the interference of microorganisms in plant ethylene homeostasis is necessary. Application of an ethylene synthesis inhibitor, as well as loss-of-function mutations in canonical ethylene signalling genes, prevented metal uptake inhibition by the fungus. Coculture with S. ruberrimus significantly changed the expression of Fe homeostasis genes: IRT1, OPT3, OPT6, bHLH38 and bHLH39 in wild-type (WT) A. thaliana. The expression pattern of these genes in WT plants and in the ethylene signalling defective mutants significantly differed and coincided with the plant accumulation phenotype. Most notably, down-regulation of the expression of IRT1 solely in WT was necessary for the inhibition of metal uptake in plants. This study shows that microorganisms optimize plant Fe and Ni uptake by fine-tuning plant metal homeostasis.

Analysis of the Methylation Level of the DAT1 Dopamine Transporter Gene in Patients Addicted to Stimulants, Taking into Account an Analysis of Personality Traits.

Drug addiction is a chronic biochemical drug use disorder that affects the human brain and behavior and leads to the uncontrolled use of legal or illicit drugs. It has been shown that three factors are involved in the development of addiction: genetic factors, a diverse environment, and the effect of medication on gene expression. The comprehensive approach and holistic analysis of the problem are due to the multigenic and multifactorial nature of addiction. Dopamine, one of the major neurotransmitters in the brain, is believed to be the "culprit" that leads to a drug abuse-induced "high". That is why, in our research, we focused mainly on the genes related to dopaminergic reuptake. In the present study, we chose methylation of the DAT1 dopamine transporter gene based on molecular reasons related to the dopaminergic theory of addiction. This study included two groups: 226 stimulant-dependent and 290 non-stimulant-dependent subjects. The analysis consisted of a case-control comparison of people addicted to psychostimulants compared to a control group of healthy and non-addicted people. There were differences in the levels of statistical significance between the groups. Our research shows lower methylation of islands 1, 9, and 14 in addicted people and greater methylation of islands 32 and 33. The difference in individual CpG methylation islands of the gene under study provides valuable information about the DNA methylation process in patients addicted to psychostimulants. Pearson's linear correlation analysis in stimulant dependence showed a negative correlation between total methylation island levels and the NEO-FFI Neuroticism scale. In subjects with neuroticism, the methylation level was statistically significantly lower. Pearson's linear correlation analysis of stimulant-dependent subjects showed a positive correlation between total methylation island levels and the NEO-FFI Openness scale and the NEO-FFI Conscientiousness scale.

Comparison of INTEGRA and the Manual Method to Determine the Axis for Intraocular Lens Implantation-A Case Series of 60 Eyes.

(1) Background: To compare the results of a new intraoperative contactless device (INTEGRA Optomed, Poland) with the result of a manual method for determining the axis for toric intraocular lens implantation. (2) Material and Methods: This retrospective observational study included 60 eyes of 40 patients (17 men, 23 women) who had toric intraocular lenses implanted. A video recording of each surgery that used the INTEGRA system was made for the analysis. Two researchers then independently assessed the location of the implant axes determined with both digital and manual slit-lamp methods, and compared the results between methods. (3) Results: The implantation axes suggested through the manual and INTEGRA methods were similar. The median axis disparities were 0.0 degrees for both groups. The standard deviation was 0.63 and 0.75 for researcher 1 and 2, respectively. The dominant value was 0.0 in both groups. The INTEGRA axis designation was statistically significantly different from the manual method for researcher 1 (p < 0.05), but it was statistically insignificant for researcher 2 (p = 0.79). (4) Conclusions: The INTEGRA system is a digital ink-free device for image tracking scleral vessels. It was helpful for determining the implantation axis in a precise manner, and the measurements were comparable with those obtained through a manual technique.

Low emission zones reduced PM10 but not NO2 concentrations in Berlin and Munich, Germany.

Low emission zones (LEZs) aiming at improving the air quality in urban areas have been implemented in many European cities. However, studies are limited in evaluating the effects of LEZ, and most of which used simple methods. In this study, a general additive mixed model was utilized to account for confounders in the atmosphere and validate the effects of LEZ on PM10 and NO2 concentrations in two German cities. In addition, the effects of LEZ on elemental carbon (EC) and total carbon (TC) in Berlin were also evaluated. The LEZ effects were estimated after taking into account air pollutant concentrations at a reference site located in the regional background, and adjusting for hour of the week, public holidays, season, and wind direction. The LEZ in Berlin, and the LEZ in combination with the heavy-duty vehicle (HDV) transit ban in Munich significantly reduced the PM10 concentrations, at both traffic sites (TS) and urban background sites (UB). The effects were greater in LEZ stage 3 than in LEZ stages 2 and 1. Moreover, compared with PM10, LEZ was more efficient in reducing EC, a component that is considered more toxic than PM10 mass. In contrast, the LEZ had no consistent effect on NO2 levels: no effects were observed in Berlin; in Munich, the combination of the LEZ and the HDV transit ban reduced NO2 at UB site in LEZ stage 1, but without further reductions in subsequent stages of the LEZ. Overall, our study indicated that LEZs, which target the major primary air pollution source in the highly populated city center could be an effective way to improve urban air quality such as PM mass concentration and EC level.

Expansion of a SARS-CoV-2 Delta variant with an 872 nt deletion encompassing ORF7a, ORF7b and ORF8, Poland, July to August 2021.

Routine genomic surveillance on samples from COVID-19 patients collected in Poland during summer 2021 revealed the emergence of a SARS-CoV-2 Delta variant with a large 872 nt deletion. This change, confirmed by Sanger and deep sequencing, causes complete loss of ORF7a, ORF7b, and ORF8 genes. The index case carrying the deletion is unknown. The standard pipeline for sequencing may mask this deletion with a long stretch of N's. Effects of this deletion on phenotype or immune evasion needs further study.

Spatiotemporal Characteristics and Driving Factors of Black Carbon in Augsburg, Germany: Combination of Mobile Monitoring and Street View Images.

The study investigates the spatial pattern of black carbon (BC) at a high spatial resolution in Augsburg, Germany. Sixty two walks were performed to assess the concentrations of equivalent black carbon (eBC), ultraviolet particulate matter (UVPM), and equivalent brown carbon (eBrC) in different seasons and at different times of the day with a mobile platform (i.e., trolley). Along with BC measurements, images of street microenvironments were recorded. Meteorological parameters, including temperature, relative humidity, and wind speed, were monitored. The BC concentrations showed significant spatial heterogeneity and diurnal variations peaking in the morning and at night. The highest BC concentrations were observed near dense traffic. The correlations between BC and street views (buildings, roads, cars, and vegetation) were weak but highly significant. Moreover, meteorological factors also influenced the BC concentration. A model based on street view images and meteorological data was developed to examine the driving factors of the spatial variability of BC concentrations at a higher spatial resolution as different microenvironments based on traffic density. The best results were obtained for UVPM and eBC (71 and 70% explained variability). eBrC (53%), to which other sources besides road traffic can also make significant contributions, is modeled less well.

The SARS-CoV-2 ORF10 is not essential in vitro or in vivo in humans.

SARS-CoV-2 genome annotation revealed the presence of 10 open reading frames (ORFs), of which the last one (ORF10) is positioned downstream of the N gene. It is a hypothetical gene, which was speculated to encode a 38 aa protein. This hypothetical protein does not share sequence similarity with any other known protein and cannot be associated with a function. While the role of this ORF10 was proposed, there is growing evidence showing that the ORF10 is not a coding region. Here, we identified SARS-CoV-2 variants in which the ORF10 gene was prematurely terminated. The disease was not attenuated, and the transmissibility between humans was maintained. Also, in vitro, the strains replicated similarly to the related viruses with the intact ORF10. Altogether, based on clinical observation and laboratory analyses, it appears that the ORF10 protein is not essential in humans. This observation further proves that the ORF10 should not be treated as the protein-coding gene, and the genome annotations should be amended.

Discovery of OATD-01, a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.

Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase.

Human acidic mammalian chitinase (hAMCase) is one of two true chitinases in humans, the function of which remains elusive. In addition to the defense against highly antigenic chitin and chitin-containing pathogens in the gastric and intestinal contents, AMCase has been implicated in asthma, allergic inflammation, and ocular pathologies. Potent and selective small-molecule inhibitors of this enzyme have not been identified to date. Here we describe structural modifications of compound OAT-177, a previously developed inhibitor of mouse AMCase, leading to OAT-1441, which displays high activity and selectivity toward hAMCase. Significantly reduced off-target activity toward the human ether-à-go-go-related gene (hERG) and a good pharmacokinetic profile make OAT-1441 a potential candidate for further preclinical development as well as a useful tool compound to study the physiological role of hAMCase.

Assessment of Risk Hospitalization due to Acute Respiratory Incidents Related to Ozone Exposure in Silesian Voivodeship (Poland).

The main aim of this work is the estimation of health risks arising from exposure to ozone or other air pollutants by different statistical models taking into account delayed health effects. This paper presents the risk of hospitalization due to bronchitis and asthma exacerbation in adult inhabitants of Silesian Voivodeship from 1 January 2016 to 31 August 2017. Data were obtained from the daily register of hospitalizations for acute bronchitis (code J20-J21, International Classification of Diseases, Tenth Revision - ICD-10) and asthma (J45-J46) which is governed by the National Health Fund. Meteorological data and data on tropospheric ozone concentrations were obtained from the regional environmental monitoring database of the Provincial Inspector of Environmental Protection in Katowice. The paper includes descriptive and analytical statistical methods used in the estimation of health risk with a delayed effect: Almon Distributed Lag Model, the Poisson Distributed Lag Model, and Distributed Lag Non-Linear Model (DLNM). A significant relationship has only been confirmed by DLNM for bronchitis and a relatively short period (1-3 days) from exposure above the limit value (120 µg/m3). The relative risk value was RR = 1.15 (95% CI 1.03-1.28) for a 2-day lag. However, conclusive findings require the continuation of the study over longer observation periods.

Long-term trends in PM2.5 mass and particle number concentrations in urban air: The impacts of mitigation measures and extreme events due to changing climates.

Urbanisation and industrialisation led to the increase of ambient particulate matter (PM) concentration. While subsequent regulations may have resulted in the decrease of some PM matrices, the simultaneous changes in climate affecting local meteorological conditions could also have played a role. To gain an insight into this complex matter, this study investigated the long-term trends of two important matrices, the particle mass (PM2.5) and particle number concentrations (PNC), and the factors that influenced the trends. Mann-Kendall test, Sen's slope estimator, the generalised additive model, seasonal decomposition of time series by LOESS (locally estimated scatterplot smoothing) and the Buishand range test were applied. Both PM2.5 and PNC showed significant negative monotonic trends (0.03-0.6 µg m-3. yr-1 and 0.40-3.8 × 103 particles. cm-3. yr-1, respectively) except Brisbane (+0.1 µg m-3. yr-1 and +53 particles. cm-3. yr-1, respectively). For the period covered in this study, temperature increased (0.03-0.07 °C.yr-1) in all cities except London; precipitation decreased (0.02-1.4 mm. yr-1) except in Helsinki; and wind speed was reduced in Brisbane and Rochester but increased in Helsinki, London and Augsburg. At the change-points, temperature increase in cold cities influenced PNC while shifts in precipitation and wind speed affected PM2.5. Based on the LOESS trend, extreme events such as dust storms and wildfires resulting from changing climates caused a positive step-change in concentrations, particularly for PM2.5. In contrast, among the mitigation measures, controlling sulphur in fuels caused a negative step-change, especially for PNC. Policies regarding traffic and fleet management (e.g. low emission zones) that were implemented only in certain areas or in a progressive uptake (e.g. Euro emission standards), resulted to gradual reductions in concentrations. Therefore, as this study has clearly shown that PM2.5 and PNC were influenced differently by the impacts of the changing climate and by the mitigation measures, both metrics must be considered in urban air quality management.

Effect of NOx and NO2 Concentration Increase in Ambient Air to Daily Bronchitis and Asthma Exacerbation, Silesian Voivodeship in Poland.

There is a discussion in Europe about the dominant role of air pollution for health effects, most researchers claim that the particulate matter is responsible for inflammatory processes in the respiratory system, while others underline the role of nitrogen dioxide. The aim of the study was to assess the risk related to NOx, NO2 and PM2.5 concentration increase and daily outpatient visits or hospitalization due to bronchitis and asthma exacerbation in the entire population of Silesian Voivodeship, Poland. To assess the relationship between daily pollutants concentrations and the number of outpatient visits or hospitalizations due to bronchitis and asthma (available in the regional registry), the multivariable log-linear Poisson regression model was used. Results were presented by relative risk (RR) of health outcomes related to the increase in pollutant concentration by unit (interquartile range). Obtained results confirmed a statistically significant association between outpatient visits and hospitalizations due to bronchitis and asthma exacerbation and daily nitrogen oxides concentrations in Silesian voivodeship, Poland. The strongest relationship was observed in the case of NO2 and outpatient visits due to bronchitis, e.g., RR = 1.434 (1.308-1.571) for exposure expressed by the 50-day moving average concentration. In the case of hospitalizations, the health effect was lagged a few days in relation to the increase in exposure.