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Space analog research has increased over the last few years with new analogs appearing every year. Research in this field is very important for future real mission planning, selection and training of astronauts. Analog environments offer specific characteristics that resemble to some extent the environment of a real space mission. These analog environments are especially interesting from the psychological point of view since they allow the investigation of mental and social variables in very similar conditions to those occurring during real space missions. Analog missions also represent an opportunity to test operational work and obtain information on which combination of processes and team dynamics are most optimal for completing specific aspects of the mission. A group of experts from a European Space Agency (ESA) funded topical team reviews the current situation of topic, potentialities, gaps, and recommendations for appropriate research. This review covers the different domains in space analog research including classification, main areas of behavioral health performance research in these environments and operational aspects. We also include at the end, a section with a list or tool of recommendations in the form of a checklist for the scientific community interested in doing research in this field. This checklist can be useful to maintain optimal standards of methodological and scientific quality, in addition to identifying topics and areas of special interest., (© 2024. The Author(s).)

This study aimed to assess changes in the functional status of 956 patients with disabilities covered by day care in Day Medical Care Homes in Poland between 2017 and 2023. Medical records (admission reports and discharge reports) of patients admitted to seven Day Medical Care Homes managed by the Medical and Diagnostic Centre (Poland) were analyzed. The functional status of the patients was assessed using the Barthel Index and the Instrumental Activities of Daily Living (IADL) tool. Out of 956 patients, 77.4% were females, and the mean age was 74.4 (SD=8.6) years. The average Barthel Index score was 59.4 (SD=5.8; 40-65) on admission and 72.6 (SD=10.2; 25-100) on discharge (p<0.001). The average IADL score was 19.2 (SD=3.2; 8-24) on admission and 20.6 (SD=3.0; 8-24) on discharge (p<0.001). Significant improvement (p<0.001) in functional status defined with both the Barthel Index and IADL scale was observed in all demographic groups and facilities., Competing Interests: Declaration of competing interest The authors declare no conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA - DRB1 (OR=1.55, P=1.1×10 -25 ) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10 -20 ) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10 -09 ) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR . Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR , INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS , and ANKRD55 .

Human APOBEC single-strand (ss) specific DNA and RNA cytidine deaminases change cytosines to uracils (U's) and function in antiviral innate immunity and RNA editing and can cause hypermutation in chromosomes. The resulting U's can be directly replicated, resulting in C to T mutations, or U-DNA glycosylase can convert the U's to abasic (AP) sites which are then fixed as C to T or C to G mutations by translesion DNA polymerases. We noticed that in yeast and in human cancers, contributions of C to T and C to G mutations depend on the origin of ssDNA mutagenized by APOBECs. Since ssDNA in eukaryotic genomes readily binds to replication protein A (RPA) we asked if RPA could affect APOBEC-induced mutation spectrum in yeast. For that purpose, we expressed human APOBECs in the wild-type (WT) yeast and in strains carrying a hypomorph mutation rfa1-t33 in the large RPA subunit. We confirmed that the rfa1-t33 allele can facilitate mutagenesis by APOBECs. We also found that the rfa1-t33 mutation changed the ratio of APOBEC3A-induced T to C and T to G mutations in replicating yeast to resemble a ratio observed in long persistent ssDNA in yeast and in cancers. We present the data suggesting that RPA may shield APOBEC formed U's in ssDNA from Ung1, thereby facilitating C to T mutagenesis through the accurate copying of U's by replicative DNA polymerases. Unexpectedly, we also found that for U's shielded from Ung1 by WT RPA, the mutagenic outcome is reduced in the presence of translesion DNA polymerase zeta., (Published by Oxford University Press on behalf of The Genetics Society of America 2024.)

The domain-swapping mechanism involves the exchange of structural elements within a secondary or supersecondary structure between two (or more) proteins. The present paper proposes to interpret the domain-swapping mechanism using a model that assesses the structure of proteins (and complexes) based on building the structure of a common hydrophobic core in a micelle-like arrangement (a central hydrophobic core with a polar shell in contact with polar water), which has a considerable impact on the stabilisation of the domain structure built by domain swapping. Domains with a hydrophobicity system that is incompatible with the micelle-like structure have also been identified. This incompatibility is the form of structural codes related to biological function., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Environmental impacts and resource availability are significant concerns for the future of lithium-ion batteries. This study focuses on developing novel fluorine-free electrolytes compatible with aqueous-processed cobalt-free cathode materials. The new electrolyte contains lithium 1,1,2,3,3-pentacyanopropenide (LiPCP) salt. After screening various organic carbonates, a mixture of 30:70 wt.% ethylene carbonate and dimethyl carbonate was chosen as the solvent. The optimal salt concentration, yielding the highest conductivity of 9.6 mS·cm -1 at 20 °C, was 0.8 mol·kg -1 . Vinylene carbonate was selected as a SEI-stabilizing additive, and the electrolyte demonstrated stability up to 4.4 V vs. Li+/Li. LiFePO 4 and LiMn 0.6 Fe 0.4 PO 4 were identified as suitable cobalt-free cathode materials. They were processed using sodium carboxymethyl cellulose as a binder and water as the solvent. Performance testing of various cathode compositions was conducted using cyclic voltammetry and galvanostatic cycling with the LiPCP-based electrolyte and a standard LiPF6-based one. The optimized cathode compositions, with an 87:10:3 ratio of active material to conductive additive to binder, showed good compatibility and performance with the new electrolyte. Aqueous-processed LiFePO 4 and LiMn 0.6 Fe 0.4 PO 4 achieved capacities of 160 mAh·g -1 and 70 mAh·g -1 at C/10 after 40 cycles, respectively. These findings represent the first stage of investigating LiPCP for the development of greener and more sustainable lithium-ion batteries.

Introduction: Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are tauopathic atypical parkinsonisms. Given their overlap in terms of clinical manifestation, there is growing interest in the mechanisms leading to these entities., Materials and Methods: In total, 71 patients were included in the study, 19 of whom were clinically diagnosed with CBS, 37 with PSP, and 15 with Parkinson's disease (PD). The mean ages of the participants were 72.8, 72.9, and 64.0 years, respectively, and the disease duration varied from 3 to 6 years. Each individual underwent blood collection. Morphological and biochemical evaluation of blood samples was performed to analyze the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-high-density lipoprotein ratio (NHR). A single-photon emission computed tomography (SPECT) with technetium-99m hexamethylpropyleneamine oxime ( 99 Tc-HMPAO) tracer was used to assess perfusion in two regions of interest (ROI): the thalamus and insula. Using Pearson correlation to assess the linear relationship between NHR and perfusion in the insula and thalamus for CBS, PSP, and PD patients, the authors intended to verify possible correlations between NLR, PLR, and NHR and perfusion in the indicated ROIs., Results: The study revealed a negative linear correlation between NHR and perfusion of both the left (Insula L; R = -0.59) and right (Insula R; R = -0.58) insula regions. Similar to the insula, a linear correlation between NHR and activity in both the left (Thalamus L) and right (Thalamus R) thalamus regions in CBS subjects with a relatively stronger correlation in the right thalamus (R = -0.64 vs. R = -0.58) was found. These observations were not confirmed in PSP and PD patients., Conclusion: Simultaneously using non-specific parameters for peripheral inflammation (NLR, PLR, and NHR) and perfusion, SPECT may be an interesting beginning point for further analysis of inflammatory disease mechanisms. To the best of our knowledge, this is the first study to address the potential correlation between the peripheral neuroinflammatory markers NLR, PLR, and NHR and perfusion disturbances in particular ROIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chunowski, Migda, Madetko-Alster, Migda, Kutyłowski, Królicki and Alster.)

The aim of this study was to determine the time between the first detection of postural control impairments and the evident manifestation of ataxia in preclinical SCA1 individuals. Twenty five preclinical SCA1 mutation carriers: 13 with estimated disease onset ≤ 6 years (SCA1 +) aged 27.8 ± 8.1 years; 12 with expected disease onset > 6 years (SCA1-) aged 26.6 ± 3.1 years and 26 age and sex matched healthy controls (HCs) underwent static posturography during 5 years of observation. The movements of the centre of feet pressure (COP) during quiet standing with eyes open (EO) and closed (EC) were quantified by calculating the mean radius (R), developed surface area (A) and mean COP movement velocity (V). Ataxia was evaluated by use of the Scale for Assessment and Rating of Ataxia (SARA).SCA1 + exhibited significantly worse quality of stance with EC vs. SCA1- (p < 0.05 for V) and HCs (p < 0.001) even 5 to 6 years before estimated disease onset. There were no statistically significant differences between SCA1- and HCs. A slow increase in Cohen's d effect size was observed for V EO up to the clinical manifestation of ataxia. V EO and A EC recorded in preclinical SCA1 individuals correlated slightly but statistically significantly with SARA (r = 0.47).The study confirms that static posturography detects COP sway changes in SCA1 preclinical gene carriers even 5 to 6 years before estimated disease onset. The quantitative evaluation of stance in preclinical SCA is a sensitive biomarker for the monitoring of the disease progression and may be useful in clinical trials., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m 2 , and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: Pancreatic cancer remains a significant public health challenge, with poor long-term outcomes due to the lack of effective treatment options. Repurposing commonly used clinical drugs, such as ACE inhibitors, ARBs, CCBs, and metformin, may enhance the efficacy of chemotherapy and offer a promising therapeutic strategy for improving patient outcomes., Methods: A retrospective analysis of concomitant treatment with ACE-Is, ARBs, CCBs, and metformin alongside gemcitabine chemotherapy in patients with pancreatic cancer was conducted. Treatment responses were evaluated, with overall survival (OS) estimated using the Kaplan-Meier method. Additionally, the Cox proportional hazards model was employed to assess the impact of these specific agents on patient survival., Results: 4628 patients with various stages of pancreatic cancer were identified in the database between 2007 and 2016. The estimated overall survival (OS) in the analyzed group was 6.9 months (95% CI 6.4-7). The use of any of the analyzed drugs was associated with a significant improvement in mOS of 7.5 months (95% CI 6.8-7.8) vs. 6.7 months (95% CI 6.4-7.0) for patients who did not have additional treatment (p < 0.0001). ARBs, ACE-Is, CCBs, and metformin varied in their effectiveness in prolonging mOS among patients. The longest mOS of 8.9 months (95% CI 7.7-11.6) was observed in patients receiving additional therapy with ARBs, while the shortest mOS of 7.7 months (95% CI 6.5-8.9) was achieved by patients receiving metformin. In the adjusted Cox analysis, metformin was associated with a significantly weaker effect on mOS (p = 0.029). A particularly interesting trend in prolonging 5-year survival was demonstrated by ARBs and CCBs with 14.1% (95% CI 9-22%) and 14.8% (95% CI 11.1-19.6%), respectively, compared to patients not taking these drugs, who achieved a 5-year OS of 3.8% (95% CI 3.2-4.4%)., Conclusion: Our results demonstrate a significant positive impact of ARBs, ACE inhibitors, and CCBs on survival in patients with pancreatic cancer treated with gemcitabine. The addition of these inexpensive and relatively safe drugs in patients with additional comorbidities may represent a potential therapeutic option in this indication. However, prospective clinical trials to evaluate the optimal patient population and further studies to determine the potential impact of these agents on chemotherapy are necessary., (© 2024. The Author(s).)

We report the measurement of impulsive stimulated x-ray Raman scattering in neutral liquid water. An attosecond pulse drives the excitations of an electronic wavepacket in water molecules. The process comprises two steps: a transition to core-excited states near the oxygen atoms accompanied by transition to valence-excited states. Thus, the wavepacket is impulsively created at a specific atomic site within a few hundred attoseconds through a nonlinear interaction between the water and the x-ray pulse. We observe this nonlinear signature in an intensity-dependent Stokes Raman sideband at 526 eV. Our measurements are supported by our state-of-the-art calculations based on the polarization response of water dimers in bulk solvation and propagation of attosecond x-ray pulses at liquid density.

The implementation of a new intermediate-Hamiltonian Fock-space coupled-cluster (IHFSCC) scheme for the (3,0) sector of the Fock space is reported. In this IHFSCC approach, the three-body contributions in the cluster operator S (3,0) corresponding to the (3,0) sector of the Fock space are considered, while S (1,0) and S (2,0) at the (1,0) and (2,0) level only include one- and two-body operators. By introducing a suitable partition of the wave operator, the intermediate Hamiltonian, which only depends on the two-body operator of S (1,0) , is obtained. S (2,0) and S (3,0) are not required within this new IHFSCC scheme, and a large reference space can be possibly employed. The performance of this (3,0) IHFSCC method in calculating triple ionization potentials and excitation energies for atoms and cations with a ground p 3 configuration as well as adiabatic excitation energies for some molecules is investigated. The effect of the number of active virtual orbitals and three different types of orbitals, i.e., reference orbitals, restricted open-shell Hartree-Fock orbitals (ROHF) of the target systems, and canonicalized ROHF orbitals, on IHFSCC results, is also studied. Our calculations indicate that reasonable results can be achieved with this (3,0) IHFSCC method when a minimal reference space is employed. Further increasing the number of active orbitals does not necessarily improve the results. In addition, the IHFSCC results using canonicalized ROHF orbitals generally agree well with reference values, and they are not very sensitive to the number of active orbitals compared with results using the reference orbitals. The new (3,0) IHFSCC method can be applied to open-shell systems with three unpaired electrons with reasonable accuracy at a relatively low computational cost.

The presence of Demodex spp. mites on the skin is a common phenomenon in the human population. In most people, it is an asymptomatic infestation, but in some patients, it can contribute to the occurrence of diseases such as demodicosis, rosacea, or blepharitis, as well as non-specific symptoms. In this study, the results of tests assessing the presence of Demodex spp. by direct microscopic examination (DME) in 2508 patients from northern Poland with the suspicion of demodicosis were retrospectively analyzed. A total of 3684 tests were performed. Among them, only 1585 (43.02%) revealed the presence of Demodex spp., while 2099 (56.98%) were negative. It was shown that in the analyzed population of patients with clinical suspicion of demodicosis, the degree of confirmation of the presence of Demodex spp. positively correlated with the patient's age ( p = 0.001) and the mite was mainly found on the edges of eyelids and on the facial skin. Additionally, in men, the presence of Demodex was more often confirmed than in women ( p = 0.004). In conclusion, the proper diagnosis of demodicosis still constitutes an important clinical problem due to the non-specificity of symptoms and the low confirmation of clinical suspicions of infestation by DME, especially in lower age groups.

Purpose: The aim of this study was to analyze treatment outcomes and their predictors in children hospitalized due to varicella complicated by bacterial superinfections after pandemic of COVID-19., Methods: This retrospective study analyzed data collected in a multicenter, nationwide, observational database dedicated for children aged 0-17 years hospitalized due to bacterial complications of varicella in 9 Polish tertiary healthcare inpatient centers. The primary endpoint of this study was the treatment outcome established after the end of hospital management assessed at a 4-point scale. The secondary endpoint was defined as the necessity of surgical intervention., Results: There were 458 patients with a median age of 4 (IQR 2-6) years. After the completed treatment, 319 (69%) participants were found fully recovered; 132 (29%) had transient complications; 2 (0.5%) had persistent complications; and 1 child (0.5%) died. Multivariate analysis revealed that implementation of ibuprofen in pre-treatment management of a child with varicella was associated with a 4.07-fold (2.50-6.60) increase in risk of complications after the treatment and it was associated with 2.87 times (1.39-5.89) higher risk of surgical intervention necessity. For other pre-hospital interventions (implementation of acyclovir, antibiotics or antihistaminics) no significant impact was observed. GAS infection increased the necessity of surgical intervention by 7.51 (3.64-15.49) times., Conclusions: One-third of patients treated for bacterial complications of varicella have post-treatment complications, most of them transient. GAS infection increases the need for surgical intervention. The use of ibuprofen in the treatment of varicella significantly increases the risk of complications and the need for surgical intervention., (© 2024. The Author(s).)

Hydrogen-atom tunneling leading to spontaneous tautomeric conversion in monomeric heterocyclic molecules without intramolecular hydrogen bonds has been experimentally detected for the first time. For monomers of 2-thiouracil, 6-aza-2-thiouracil and 1-methyl-2-thiouracil isolated in low-temperature matrices, higher-energy thiol forms were generated upon UV ( λ = 305 nm) excitation of the most stable thione tautomers. When the matrices were subsequently kept in the dark and at low temperature, hydrogen-atom tunneling occurred, leading to the thiol → thione conversion. During this process, the photoproduced thiol form spontaneously converted into the lowest energy thione tautomer.

The presence of valence coding neurons in the basolateral amygdala (BLA) that form distinct projections to other brain regions implies functional opposition between aversion and reward during learning. However, evidence for opponent interactions in fear learning is sparse and may only be apparent under certain conditions. Here we test this possibility by studying the roles of the BLA→central amygdala (CeA) and BLA→nucleus accumbens (Acb) pathways in fear learning in male rats. First, we assessed the organization of these pathways in the rat brain. BLA→CeA and BLA→Acb pathways were largely segregated in the BLA but shared overlapping molecular profiles. Then we assessed activity of the BLA→CeA and BLA→Acb pathways during two different forms of fear learning-fear learning in a neutral context and fear learning in a reward context. BLA→CeA neurons were robustly recruited by footshock regardless of where fear learning occurred, whereas recruitment of BLA→Acb neurons was state-dependent because footshock only recruited this pathway in a reward context. Finally, we assessed the causal roles of activity in these pathways in fear learning. Photoinhibition of the BLA→CeA pathway during the footshock US impaired fear learning, regardless of where fear learning occurred. In contrast, photoinhibition of the BLA→Acb pathway augmented fear learning, but only in the reward context. Taken together, our findings show circuit- and state-dependent opponent processing of fear. Footshock activity in the BLA→Acb pathway limits how much fear is learned., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Yau et al.)

In this work, a laminate based on bioresin and natural fibers was produced. Flax fabric was selected as the natural fiber. The biocomposite was subjected to strength tests. Stress-strain characteristics and strength indicators were determined. The workability of the laminate produced was also tested using milling technology. The tests were carried out using five carbide shank cutters for different purposes. The cutters with the geometry used in the processing of polymer materials and composites, general purpose cutters, and cutters with the geometry for aluminum and with different numbers of blades were analyzed. In order to obtain information on the workability of the prepared material, machining tests with different configurations of technological parameters were carried out. For each cutter, the effect of cutting speed and feed rate on the quality of the machined surface was tested. Due to the small thickness of the laminate, the machining was carried out in one pass, as a result of which the cutting depth in each case was constant. Changes in cutting speed and feed were evenly distributed over five levels. The quality of machining was assessed in two stages. The first stage included a visual assessment of the machined surface, involving a preliminary qualification of the machining parameters. The criterion was the amount of chips, frays, burrs, etc., remaining after machining that adhered to the surface. The next stage was the measurement of the geometric structure of the surface, during which the roughness parameters were analyzed using an optical microscope with a roughness analysis attachment. Quantitative analysis was performed for the best quality composite surfaces from each measurement series. The studies showed a dependence of the quality of machining on the technological parameters used. High tool speed, regardless of the type, especially at low feed, led to the sticking of chips, which had a very delicate form. In turn, low tool speed and high feed, due to the chip thickness, favored the formation of burrs. Machining with different types of tools showed that the process progresses better for tools with sharp blade geometry. Machining with a regular and polished cutter did not show any differences in the scope of the process progress.

In recent years, nanopore direct RNA sequencing (DRS) became a valuable tool for studying the epitranscriptome, due to its ability to detect multiple modifications within the same full-length native RNA molecules. While RNA modifications can be identified in the form of systematic basecalling 'errors' in DRS datasets, N6-methyladenosine (m6A) modifications produce relatively low 'errors' compared to other RNA modifications, limiting the applicability of this approach to m6A sites that are modified at high stoichiometries. Here, we demonstrate that the use of alternative RNA basecalling models, trained with fully unmodified sequences, increases the 'error'signal of m6A, leading to enhanced detection and improved sensitivity even at low stoichiometries. Moreover, we find that high-accuracy alternative RNA basecalling models can show up to 97% median basecalling accuracy, outperforming currently available RNA basecalling models, which show 91% median basecalling accuracy. Notably, the use of high-accuracy basecalling models is accompanied by a significant increase in the number of mapped reads -especially in shorter RNA fractions- and increased basecalling error signatures at pseudouridine (Ψ) and N1-methylpseudouridine (m1Ψ) modified sites. Overall, our work demonstrates that alternative RNA basecalling models can be used to improve the detection of RNA modifications, read mappability, and basecalling accuracy in nanopore DRS datasets., (Published by Cold Spring Harbor Laboratory Press.)

Positronium is abundantly produced within the molecular voids of a patient's body during positron emission tomography (PET). Its properties dynamically respond to the submolecular architecture of the tissue and the partial pressure of oxygen. Current PET systems record only two annihilation photons and cannot provide information about the positronium lifetime. This study presents the in vivo images of positronium lifetime in a human, for a patient with a glioblastoma brain tumor, by using the dedicated Jagiellonian PET system enabling simultaneous detection of annihilation photons and prompt gamma emitted by a radionuclide. The prompt gamma provides information on the time of positronium formation. The photons from positronium annihilation are used to reconstruct the place and time of its decay. In the presented case study, the determined positron and positronium lifetimes in glioblastoma cells are shorter than those in salivary glands and those in healthy brain tissues, indicating that positronium imaging could be used to diagnose disease in vivo.

Background: Understanding the multifactorial nature of major depressive disorder (MDD) is crucial for tailoring treatments. However, the complex interplay of various factors underlying the development and progression of MDD poses significant challenges. Our previous study demonstrated improvements in cognitive functions in MDD patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) supplemented with Lactobacillus plantarum 299v (LP299v)., Methods: To elucidate the biochemical mechanisms underlying cognitive functions improvements, we explored underlying metabolic changes. We employed multi-platform metabolomics, including LC-QTOF-MS and CE-TOF-MS profiling, alongside chiral LC-QqQ-MS analysis for amino acids., Results: Supplementation of SSRI treatment with LP299v intensified the reduction of long-chain acylcarnitines, potentially indicating improved mitochondrial function. LP299v supplementation reduced N-acyl taurines more than four times compared to the placebo, suggesting a substantial impact on restoring biochemical balance. The LP299v-supplemented group showed increased levels of oxidized glycerophosphocholine (oxPC). Additionally, LP299v supplementation led to higher levels of sphingomyelins, L-histidine, D-valine, and p-cresol., Limitations: This exploratory study suggests potential metabolic pathways influenced by LP299v supplementation. However, the need for further research hinders the ability to draw definitive conclusions., Conclusions: Observed metabolic changes were linked to mitochondrial dysfunction, inflammation, oxidative stress, and gut microbiota disruption. Despite the subtle nature of this alterations, our research successfully detected these differences and connected them to the metabolic disruptions associated with MDD. Our findings emphasise the intricate relationship between metabolism, gut microbiota, and mental health prompting further research into the mechanisms of action of probiotics in MDD treatment., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

To improve the translation of preclinical cancer research data to successful clinical effect, there is an increasing focus on the use of primary patient-derived cancer cells with limited growth in culture to reduce genetic and phenotype drift. However, these primary lines are less amenable to standardly used methods of exogenous DNA introduction. Adeno-associated viral (AAV) vectors display tropism for a wide range of human tissues, avidly infect primary cells and have a good safety profile. In the present study, we therefore used a next-generation sequencing (NGS) barcoded AAV screening method to assess transduction capability of a panel of 36 AAVs in primary cell lines representing high-grade glioma (HGG) brain tumours including glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG). As proof of principle, we created a reporter construct to analyse activity of the transcriptional co-activators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Transcriptional activation was monitored by promoter-driven expression of the Timer fluorescent tag, a protein that fluoresces green immediately after transcription and transitions to red fluorescence over time. As expected, attempts to express the reporter in primary HGG cells from plasmid expression vectors were unsuccessful. Using the top candidate from the AAV screen, we demonstrate successful AAV-mediated transduction of HGG cells with the YAP/TAZ dynamic activity reporter. In summary, the NGS-screening approach facilitated screening of many potential AAVs, identifying vectors that can be used to study the biology of primary HGG cells., (© 2024 The Author(s). FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Autoimmune thyroid disease (AIT) is the most frequently linked autoimmune condition to type 1 diabetes (T1D). The analysis of immune profiles could provide valuable insights into the study of these diseases. This knowledge could play a crucial role in understanding the relationship between immune profiles and microcirculation structures and functions. The present study aimed to test the hypothesis that cytokine levels in T1D patients without and those with comorbid Hashimoto's disease differ significantly. The total study group (total T1D) consisted of 62 diabetic young patients: 43 T1D and 19 T1D + AIT matched for age, age at onset, and duration of diabetes. The control group consisted of 32 healthy young subjects. The levels of cytokines (including TNF-α, IL-35, IL-4, IL-10, IL-18, IL-12, VEGF, and angiogenin) were quantified throughout this investigation. A comparative assessment of the cytokines profiles between the control group and total T1D revealed a statistically significant elevation in the levels of IL-4, TNF-α, IL-18, VEGF, and angiogenin, accompanied by a notable decline in IL-10. However, IL-35 and IL-12 exhibited comparable levels between the two groups. A comparison of cytokine levels between T1D + AIT and T1D groups revealed that only angiogenin levels were statistically significantly higher in T1D + AIT. The results of our study indicated that the alterations in cytokine levels associated with AIT did not correspond to the observed changes in T1D-related outcomes. The sole notable observation was the elevation of angiogenin expression, an angiogenic factor.

Background Context: Our recent studies indicated that a high-riding vertebral artery (HRVA) is a common variant posing a risk of injuring the vessel during C2 instrumentation. However, several different types fit in the current definition of HRVA, which may require a different strategy for C2 screw placement., Purpose: To classify HRVA and provide a clinical aid for preoperative planning of C2 instrumentation. A secondary goal was to estimate coexistence of each HRVA type with the ipsilateral narrow C2 pedicle (NP)., Study Design: A retrospective observational study involving radiologic measurements of the estimated number of anonymized cervical computed tomography (CT) scans. STROBE checklist was applied., Patient Sample: A total of 908 potential screw insertion sites (PSIS) of 454 consecutive cervical CT scans were analyzed. The sample size was estimated using ScalaR SP function in RStudio., Outcome Measures: Three types of HRVA based on a series of C2 vertebral morphological parameters including the C2 isthmus height (C2IsH) and C2 internal height (C2InH). Also, the prevalences of each HRVA type and coexisting NP based on the C2 pedicle width (C2PW)., Methods: HRVA was defined as C2IsH of ≤5 mm and/or C2InH of ≤2 mm measured 3 mm lateral to the lateral border of the spinal canal. A narrow pedicle was defined as C2PW of ≤4 mm. Measurements were done using Syn.govia software. Interobserver, intraobserver, and inter-software agreement coefficients for C2IsH, C2InH, and C2PW parameters were adopted from our previous study. K-means cluster analysis was applied., Results: Prevalence of at least 1 HRVA was 24.9% (n=113 subjects) and 16.2% of PSIS (n=147 sites). Based on the measurements and K-means clustering, the following 3 types of HRVA have been distinguished: type 1-isthmic with only C2IsH being reduced and normal C2InH; type 2-internal with only C2InH being reduced and C2IsH within normal limits; type 3-isthmo-internal with both C2IsH and C2InH being reduced. Kruskal-Wallis test followed by unadjusted and Bonferroni-adjusted post-hoc multiple comparison analysis detected significant differences across the types. The prevalences of the newly identified types were as follows: 78.2%, 8.8%, and 12.9% for type 1, type 2, and type 3, respectively. 73.9% of type 1 HRVA, 53.8% of type 2 HRVA, and 100% of type 3 HRVA had a concomitant ipsilateral NP. Prediction of the HRVA types by the K-means clustering has been evaluated. Screw placement techniques for each type are proposed and discussed., Conclusion: We present the first classification system for the high-riding vertebral artery distinguishing 3 types based on the large homogenous cohort, which may serve as an adjunct to preoperative planning of C2 instrumentation. External validation of this classification scheme shall determine its further clinical utility., Competing Interests: Declaration of competing interest One or more of the authors declare financial or professional relationships on ICMJE-TSJ disclosure forms., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The intimate mechanism of N 2 O decomposition on bare and redox-tuned Co 3 O 4 nanocubes (achieved by single (Li or K) and double (Li and K) doping) was elucidated. The catalysts synthesized by the hydrothermal method were characterized by X-ray electron absorption fine structure measurements, X-ray diffraction, Raman spectroscopy, scanning electron microscopy, transmission electron microscopy, and Kelvin Probe techniques. TPSR and steady-state isothermal catalytic tests reveal that the N 2 O turnover frequencies are critically sensitive to the work function of the catalysts, adjusted purposely by doping. For the catalysts obtained by one-pot hydrothermal synthesis, lithiation of the Co 3 O 4 nanocubes leads to the formation of {Li' 8a , Co· 16d } species, decreasing steadily the work function and the activity, while for the catalysts prepared by postsynthesis impregnation, formation of {Li' 8a , Co' 16d, Co·· 16c } species leads to a volcano-type dependence of the catalytic activity and the work function in parallel. The beneficial effect of potassium was discussed in terms of mitigation of surface potential buildup due to the accumulation of ionosorbed oxygen intermediates (surface electrostatics), which hinders the interfacial electron transfer. Analysis of the catalytic activity response to the redox tuning of Co 3 O 4 , substantiated by DFT calculations, allowed for a straightforward conceptualization of the redox nature of the N 2 O decomposition in terms of the lineup of frontier orbitals of the N 2 O/N 2 O - and O 2 - /O 2 reactants with the surface DOS structure and the resultant molecular orbital interactions. The positions of the virtual bonding 3π g 0 (N 2 O)-α-3d z 2 and the occupied 2π g 1 (O 2 - )-α-3d z 2 states relative to the Fermi energy level play a crucial role in the regulation of the forward and backward interfacial electron transfer events, which drive the redox process.

Background: The registry-based randomized VALIDATE-SWEDEHEART trial (NCT02311231) compared bivalirudin vs. heparin in patients undergoing percutaneous coronary intervention (PCI) for myocardial infarction (MI). It showed no difference in the composite primary endpoint of death, MI, or major bleeding at 180 days. Here, we report outcomes at two years., Methods: Analysis of primary and secondary endpoints at two years of follow-up was prespecified in the study protocol. We report the study results for the extended follow-up time here., Results: In total, 6006 patients were enrolled, 3005 with ST-segment elevation MI (STEMI) and 3001 with Non-STEMI (NSTEMI), representing 70 % of all eligible patients with these diagnoses during the study. The primary endpoint occurred in 14.0 % (421 of 3004) in the bivalirudin group compared with 14.3 % (429 of 3002) in the heparin group (hazard ratio [HR] 0.97; 95 % confidence interval [CI], 0.85-1.11; P = 0.70) at one year and in 16.7 % (503 of 3004) compared with 17.1 % (514 of 3002), (HR 0.97; 95 % CI, 0.96-1.10; P = 0.66) at two years. The results were consistent in patients with STEMI and NSTEMI and across major subgroups., Conclusions: Until the two-year follow-up, there were no differences in endpoints between patients with MI undergoing PCI and allocated to bivalirudin compared with those allocated to heparin., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02311231., Competing Interests: Declaration of competing interest Elmir Omerovic reports grants from Astra Zeneca, personal fees from Astra Zeneca, MSD, Bayer, Janssen outside the submitted work. Stefan James reports grants from Astra Zeneca, grants from The Medicines Company, grants from Swedish Heart and Lung Foundation, and grants from Swedish Research Council during the conduct of the study; personal fees from Bayer and grants from Jansen outside the submitted work. Truls Råmunddal reports personal fees from Boston Scientific and personal fees from Abbot outside the submitted work. Ole Fröbert reports personal fees from GE Medical and from Astra Zeneca outside the submitted work. Pontus Lindroos reports personal fees from Astra Zeneca outside the submitted work. Anders Ulvenstam reports personal fees from Boston Scientific outside the submitted work. Matthias Götberg reports grants and personal fees from Volcano Corporation, personal fees from Boston Scientific, and personal fees from Medtronic Corporation outside the submitted work. Oskar Angerås Dr. reports personal fees from Astra Zeneca outside the submitted work. Olie Östlund reports grants from AstraZeneca, grants from The Medicines Company. Cleas Held reports grants and personal fees from AstraZeneca, grants from GlaxoSmithKline, grants from BristolMyers Squibb, and grants from Merck outside the submitted work. Sasha Koul reports personal fees from Pfizer, personal fees from BMS, and personal fees from Astra Zeneca outside the submitted work. David Erlinge reports personal fees from Astrazeneca and The Medicines Company outside the submitted work. All others co-authors have nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this paper, we present the results of mechanical measurement of single nanowires (NWs) in a repeatable manner. Substrates with specifically designed mechanical features were used for NW placement and localization for measurements of properties such as Young's modulus or tensile strength of NW with an atomic force microscopy (AFM) system. Dense arrays of zinc oxide (ZnO) nanowires were obtained by one-step anodic oxidation of metallic Zn foil in a sodium bicarbonate electrolyte and thermal post-treatment. ZnO NWs with a hexagonal wurtzite structure were fixed to the substrates using focused electron beam-induced deposition (FEBID) and were annealed at different temperatures in situ. We show a 10-fold change in the properties of annealed materials as well as a difference in the properties of the NW materials from their bulk values with pre-annealed Young modulus at the level of 20 GPa and annealed reaching 200 GPa. We found the newly developed method to be much more versatile, allowing for in situ operations of NWs, including measurements with different methods of scanning probe microscopy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Reaching beyond the commonly used spherical atomic electron density model allows one to greatly improve the accuracy of hydrogen atom structural parameters derived from X-ray data. However, the effects of atomic asphericity are less explored for electron diffraction data. In this work, Hirshfeld atom refinement (HAR), a method that uses an accurate description of electron density by quantum mechanical calculation for a system of interest, was applied for the first time to the kinematical refinement of electron diffraction data. This approach was applied here to derive the structure of ordinary hexagonal ice (I h ). The effect of introducing HAR is much less noticeable than in the case of X-ray refinement and it is largely overshadowed by dynamical scattering effects. It led to only a slight change in the O-H bond lengths (shortening by 0.01 Å) compared with the independent atom model (IAM). The average absolute differences in O-H bond lengths between the kinematical refinements and the reference neutron structure were much larger: 0.044 for IAM and 0.046 Å for HAR. The refinement results changed considerably when dynamical scattering effects were modelled - with extinction correction or with dynamical refinement. The latter led to an improvement of the O-H bond length accuracy to 0.021 Å on average (with IAM refinement). Though there is a potential for deriving more accurate structures using HAR for electron diffraction, modelling of dynamical scattering effects seems to be a necessary step to achieve this. However, at present there is no software to support both HAR and dynamical refinement., (open access.)

Due to their small size and high anthropogenic pressure, small watercourses are particularly prone to severe siltation and are densely overgrown with macrophytes. Many of these watercourses are subject to regular maintenance works (RMW), consisting of seasonal desilting and vegetation clearance, in order to ensure unobstructed water flow. The aim of the study was to assess the impact of three types of maintenance works: dredging and mud removal (DMR), river channel vegetation removal (RCVR) and river bank vegetation removal (RBVR) on taxa species richness, macroinvertebrate density and the Shannon-Wiener diversity index, as well as their changes and long-term benthic recolonization one and two years after completion of the works. The study was carried out in 21 habitats on eight rivers in the European Central Plains Ecoregion. A total of 107 zoobenthic taxa were found at all sites, and their species composition was characteristic of highly hydrophytic waters with low hydrological and hydrochemical quality parameters. A significant decrease in macroinvertebrate taxa richness was observed one year after the works, as the average number of taxa had dropped from thirteen to eight, with a further fall to seven taxa two years after the RMW. The same was true for density, which had decreased from an average of 2496 to 786 individuals per square meter one year after the RMW, while, a gradual recolonization was recorded two years after the RMW, with an average density of 1295 individuals per square meter. The Shannon-Wiener index, which had averaged 2.528 before the RMW, also decreased, falling to 1.982 and 1.832 one and two years after. BACI statistical analyses showed that of the three types of maintenance work, desilting and bottom sediment removal had the largest negative impact, significantly reducing taxonomic composition (by an average of 53%), density (by an average of 43%), and ecological index values (by an average of 40%). Over-frequent maintenance can prevent macroinvertebrate populations from recovering, thus depleting the environment of valuable taxa, including those that provide food for fish and other vertebrates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neuropsychiatric conditions represent a major medical and societal challenge. The etiology of these conditions is very complex and combines genetic and environmental factors. The latter, for example, excessive maternal or early postnatal inflammation, as well as various forms of psychotrauma, often act as triggers leading to mental illness after a prolonged latent period (sometimes years). Matrix metalloproteinase-9 (MMP-9) is an extracellularly and extrasynaptic operating protease that is markedly activated in response to the aforementioned environmental insults. MMP-9 has also been shown to play a pivotal role in the plasticity of excitatory synapses, which, in its aberrant form, has repeatedly been implicated in the etiology of mental illness. In this conceptual review, we evaluate the experimental and clinical evidence supporting the claim that MMP-9 is uniquely positioned to be considered a drug target for ameliorating the adverse effects of environmental insults on the development of a variety of neuropsychiatric conditions, such as schizophrenia, bipolar disorder, major depression, autism spectrum disorders, addiction, and epilepsy. We also identify specific challenges and bottlenecks hampering the translation of knowledge on MMP-9 into new clinical treatments for the conditions above and suggest ways to overcome these barriers., (© 2023 Nencki Institute. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

The increasing global incidence of obesity and type 2 diabetes mellitus (T2D) underscores the urgency of addressing these interconnected health challenges. Obesity enhances genetic and environmental influences on T2D, being not only a primary risk factor but also exacerbating its severity. The complex mechanisms linking obesity and T2D involve adiposity-driven changes in β-cell function, adipose tissue functioning, and multi-organ insulin resistance (IR). Early detection and tailored treatment of T2D and obesity are crucial to mitigate future complications. Moreover, personalized and early intensified therapy considering the presence of comorbidities can delay disease progression and diminish the risk of cardiorenal complications. Employing combination therapies and embracing a disease-modifying strategy are paramount. Clinical trials provide evidence confirming the efficacy and safety of glucagon-like peptide 1 receptor agonists (GLP-1 RAs). Their use is associated with substantial and durable body weight reduction, exceeding 15%, and improved glucose control which further translate into T2D prevention, possible disease remission, and improvement of cardiometabolic risk factors and associated complications. Therefore, on the basis of clinical experience and current evidence, the Eastern and Southern Europe Diabetes and Obesity Expert Group recommends a personalized, polymodal approach (comprising GLP-1 RAs) tailored to individual patient's disease phenotype to optimize diabetes and obesity therapy. We also expect that the increasing availability of dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists will significantly contribute to the modern management of the cardiometabolic continuum., (© 2024. The Author(s).)

Repeated protein folding processes both in vivo and in vitro leading to the same structure for a specific amino acid sequence prove that the amino acid sequence determines protein structuring. This is also evidenced by the variability of structuring, dependent on the introduced mutations. An important phenomenon in this regard is the presence of a differentiated secondary structure for chain fragments of identical sequence representing distinct forms of the secondary-order structure. Proteins termed chameleon proteins contain polypeptide chain fragments of identical sequence (length 6-12 aa) showing structural differentiation: helix versus β-structure. In the present paper, it was shown that these fragments represent components matching the structural status dictated by the physicochemical properties of the entire structural unit. This structural matching is related to achieving the goal of the biological function of the structural unit. The corresponding secondary structure represents a means to achieving this goal, not an end in itself. A selected set of proteins from the ChSeq database have been analyzed using a fuzzy oil drop model (FOD-M) identifying the uniqueness of the hydrophobicity distribution taken as a medium for recording the specificity of a given protein and a given chameleon section in particular. It was shown that in the vast majority, the status of chameleon sections turns out to be comparable regardless of the represented secondary structure., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Directed evolution of viral vectors involves the generation of randomized libraries followed by artificial selection of improved variants. Directed evolution only yielded limited results in adenovirus (AdV) engineering until now, mainly due to insufficient complexities of randomized libraries. Meanwhile, clinical applications of AdVs as gene therapy or oncolytic vectors are still hampered by the predetermined tropism of natural types. To overcome this challenge, we hypothesized that randomized peptide insertions on the capsid surface can be incorporated into the AdV bioengineering toolbox for retargeting. Here we developed AdV-directed EVOlution protocols based on fiber knob peptide display. Human AdV-C5-derived libraries were constructed following three distinct protocols and selected on a panel of cancer cell lines, with the goal of identifying variants able to infect and lyse these tumor cells more efficiently. All protocols enabled the construction of high complexity libraries with up to 9.6 × 10 5 unique variants, an approximate 100-fold improvement compared with previously published AdV libraries. After selection, the most enriched variants, which were robustly selected in various cancer cell lines, did not display enhanced infectivity but rather more efficient replication and cell lysis. Selected inserts also conferred enhanced lysis ability to oncolytic AdVs restricted to telomerase-expressing cell lines., Competing Interests: J.F. and Z.R. are co-inventors in patent application EP20198944 by the Albert Ludwig University of Freiburg that describes the use of CRISPR/Cas-mediated rescue of recombinant AdVs from circular plasmids., (© 2024 The Author(s).)

Aims: The application of conduction system pacing (CSP) in clinical practice is growing, and the need for lead extraction will also increase. The data on outcomes and safety of CSP lead extraction are limited. The aim of this study was to assess procedural outcomes and safety of CSP lead removal., Methods and Results: Forty-seven patients from the EXTRACT Registry with the indication for CSP lead removal were enrolled in the study conducted at the Department of Electrocardiology in Katowice, Poland. Extraction technique, outcomes, safety, and complication were evaluated. Forty-three (91.5%) leads were successfully removed, and 41 (87.2%) were removed with traction only. The dwelling time of 28 extracted leads was longer than 1 year, and the oldest extracted lead was implanted for 89 months. Seven (14.9%) leads were removed from the left bundle branch (LBB) area and 36 from the His bundle (HB). Transient complete atrioventricular block occurred during the procedure in two patients. In 27 out of 31 attempts (87.1%), new CSP leads were implanted: nine (33.3%) HB pacing leads and 18 (66.7%) LBB area pacing leads., Conclusion: The CSP lead extraction is safe and feasible with a low complication rate and high rate of CSP lead reimplantation., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Increased activity of transforming growth factor-beta (TGF-β) is a key factor mediating kidney impairment in diabetes. Glomerular podocytes, the crucial component of the renal filter, are a direct target of TGF-β action, resulting in irreversible cell loss and progression of chronic kidney disease (CKD). Urolithin A (UA) is a member of the family of polyphenol metabolites produced by gut microbiota from ellagitannins and ellagic acid-rich foods. The broad spectrum of biological activities of UA makes it a promising candidate for the treatment of podocyte disorders. In this in vitro study, we investigated whether UA influences the changes exerted in podocytes by TGF-β and high glucose. Following a 7-day incubation in normal (NG, 5.5 mM) or high (HG, 25 mM) glucose, the cells were treated with UA and/or TGF-β1 for 24 h. HG and TGF-β1, each independent and in concert reduced expression of nephrin, increased podocyte motility, and up-regulated expression of b3 integrin and fibronectin. These typical-for-epithelial-to-mesenchymal transition (EMT) effects were inhibited by UA in both HG and NG conditions. UA also reduced the typically elevated HG expression of TGF-β receptors and activation of the TGF-β signal transducer Smad2. Our results indicate that in podocytes cultured in conditions mimicking the diabetic milieu, UA inhibits and reverses changes underlying podocytopenia in diabetic kidneys. Hence, UA should be considered as a potential therapeutic agent in podocytopathies.

Epicardial adipose tissue (EAT) is a fat depot covering the heart. No physical barrier separates EAT from the myocardium, so EAT can easily affect the underlying cardiac muscle. EAT can participate in the development and progression of heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). In healthy humans, excess EAT is associated with impaired cardiac function and worse outcomes. In HFpEF, this trend continues: EAT amount is usually increased, and excess EAT correlates with worse function/outcomes. However, in HFrEF, the opposite is true: reduced EAT amount correlates with worse cardiac function/outcomes. Surprisingly, although EAT has beneficial effects on cardiac function, it aggravates ventricular arrhythmias. Here, we dissect these phenomena, trying to explain these paradoxical findings to find a target for novel heart failure therapies aimed at EAT rather than the myocardium itself. However, the success of this approach depends on a thorough understanding of interactions between EAT and the myocardium., (© 2024 World Obesity Federation.)

Red scalp is a common complaint that may constitute a diagnostic and therapeutic challenge in daily clinical practice. Among the numerous diseases to cause diffuse scalp erythema are psoriasis, seborrhoeic dermatitis, contact dermatitis, diffuse lichen planopilaris, dermatomyositis and scalp rosacea. Accurate diagnosis is crucial for optimal treatment outcomes. Histology most frequently discriminates the underlying condition, but it requires scalp biopsy. In many cases, the combination of clinical examination and trichoscopy is sufficient for establishing the correct diagnosis. The main trichoscopic features of psoriasis are silver-white scaling, regularly distributed dotted (glomerular) vessels or twisted red loops, and punctate haemorrhages. Yellowish-white scaling and thin arborizing vessels are typical features of seborrhoeic dermatitis. Contact dermatitis is characterized by the presence of yellow exudate and polymorphic vessels, while perifollicular scaling and erythema with the lack of follicular openings are typical findings in lichen planopilaris. In scalp dermatomyositis, tortuous and arborizing vessels with interfollicular and perifollicular pigmentation may be detected. The most characteristic features of scalp rosacea are perifollicular scaling and polygonal/arborizing vessels. This review also summarizes histological features and therapeutic options for these conditions., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dendrimers are covalently bonded globular nanostructures that may be used in the treatment of Alzheimer's disease (AD). Nowadays, AD therapies are focused on improving cognitive functioning and not causal treatment. However, this may change with the use of dendrimers, which are being investigated as a drug-delivery system or as a drug per se. With their ability to inhibit amyloid formation and their anti-tau properties, they are a promising therapeutic option for AD patients. Studies have shown that dendrimers may inhibit amyloid formation in at least two ways: by blocking fibril growth and by breaking already existing fibrils. Neurofibrillary tangles (NFTs) are abnormal filaments built by tau proteins that can be accumulated in the cell, which leads to the loss of cytoskeletal microtubules and tubulin-associated proteins. Cationic phosphorus dendrimers, with their anti-tau properties, can induce the aggregation of tau into amorphous structures. Drug delivery to mitochondria is difficult due to poor transport across biological barriers, such as the inner mitochondrial membrane, which is highly negatively polarized. Dendrimers may be potential nanocarriers and increase mitochondria targeting. Another considered use of dendrimers in AD treatment is as a drug-delivery system, for example, carbamazepine (CBZ) or tacrine. They can also be used to transport siRNA into neuronal tissue and to carry antioxidants and anti-inflammatory drugs to act protectively on the nervous system.

Many machine learning problems can be formulated as non-convex multi-player games. Due to non-convexity, it is challenging to obtain the existence condition of the global Nash equilibrium (NE) and design theoretically guaranteed algorithms. This paper studies a class of non-convex multi-player games, where players' payoff functions consist of canonical functions and quadratic operators. We leverage conjugate properties to transform the complementary problem into a variational inequality (VI) problem using a continuous pseudo-gradient mapping. We prove the existence condition of the global NE as the solution to the VI problem satisfies a duality relation. We then design an ordinary differential equation to approach the global NE with an exponential convergence rate. For practical implementation, we derive a discretized algorithm and apply it to two scenarios: multi-player games with generalized monotonicity and multi-player potential games. In the two settings, step sizes are required to be O(1/k) and O(1/√k) to yield the convergence rates of O(1/ k) and O(1/√k), respectively. Extensive experiments on robust neural network training and sensor network localization validate our theory. Our code is available at https://github.com/GuanpuChen/Global-NE.

Although therapies based on mesenchymal stromal cells (MSCs) are being implemented in clinical settings, many aspects regarding these procedures require further optimization. Domestic dogs suffer from numerous immune-mediated diseases similar to those found in humans. This study aimed to assess the immunomodulatory activity of canine (c) Wharton jelly (WJ)-derived MSCs and refer them to human (h) MSCs isolated from the same tissue. Canine MSC(WJ)s appeared to be more prone to in vitro aging than their human counterparts. Both canine and human MSC(WJ)s significantly inhibited the activation as well as proliferation of CD4+ and CD8+ T cells. The treatment with IFNγ significantly upregulated indoleamine-2,3-dioxygenase 1 (IDO1) synthesis in human and canine MSC(WJ)s, and the addition of poly(I:C), TLR3 ligand, synergized this effect in cells from both species. Unstimulated human and canine MSC(WJ)s released TGFβ at the same level ( p > 0.05). IFNγ significantly increased the secretion of TGFβ in cells from both species ( p < 0.05); however, this response was significantly stronger in human cells than in canine cells. Although the properties of canine and human MSC(WJ)s differ in detail, cells from both species inhibit the proliferation of activated T cells to a very similar degree and respond to pro-inflammatory stimulation by enhancing their anti-inflammatory activity. These results suggest that testing MSC transplantation in naturally occurring immune-mediated diseases in dogs may have high translational value for human clinical trials.

Background: Normative data on hand and precision grip strengths are essential for evaluating the level of development, the efficacy of rehabilitation, and treatment results. The need for established norms of grip strength in Polish children is one of the problems that Polish physiotherapists and physicians face when treating upper limbs. The aim was to establish normative values of hand and precision grips strengths in Polish children and adolescents aged 3-19. Methods: In the years 2012-2023, a sample of 358 children and adolescents with no history of upper limb injuries or congenital upper extremity defects were randomly chosen from kindergartens, primary schools, middle schools, and high schools. They were living in urban agglomerations and in smaller towns or villages. Hand and precision grips like the pincer, three-point, side, and opposition grip strength were assessed using a hand dynamometer and pinchmeter in standard positions. Results: The strength in all types of examined hand grips increases with chronological age in both genders. The grip strength was higher in the boys' group than in the girls' and it was higher in the right hand than in the left, but the difference was no more greater than 10%. Detailed data with standard deviation were presented in the form of a table, divided by age and sex. Conclusions: Norms for grip strength were provided for Polish children and adolescents aged 3-19, allowing therapists and physicians to compare Polish patients with that of normally developed, healthy children of the same age and sex.

In this study, we introduce a novel advancement in the field of theoretical exploration. Specifically, we investigate the transfer and trapping of electronic excitations within a two-component disordered system confined to a finite volume. The implications of our research extend to energy transfer phenomena on spherical nanoparticles, characterized by randomly distributed donors and acceptors on their surface. Utilizing the three-body Padé approximant technique, previously employed in single-component systems, we apply it to address the challenge of trapping within our system. To validate the robustness of our model, we conduct Monte Carlo simulations on a donor-acceptor system positioned on a spherical nanoparticle. In particular, very good agreement between the model and Monte Carlo simulations has been found for donor fluorescence intensity decay., (© 2024. The Author(s).)

The clinical significance of B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in pediatric patients remains an area of evolving understanding, particularly regarding their utility in the presence or absence of pre-existing heart conditions. While clear cutoff values and established roles in heart failure are understood in adult patients, pediatric norms vary with age, complicating interpretation. Notably, the emergence of multi-system inflammatory syndrome in children (MIS-C) has highlighted the importance of these markers not only in the detection of acute heart failure but also as a marker of disease severity and even as a differential diagnosis tool. This review summarizes current knowledge on the utility of BNP and NT-proBNP in pediatric patients. Their unique physiology, including circulation and compensation mechanisms, likely influence BNP and NT-proBNP release, potentially even in non-heart failure states. Factors such as dynamic volemic changes accompanying inflammatory diseases in children may contribute. Thus, understanding the nuanced roles of BNP and NT-proBNP in pediatric populations is crucial for the accurate diagnosis, management, and differentiation of cardiac and non-cardiac conditions.

The largest rivers in developed countries have usually been turned into waterways by straightening them and removing large bedforms hampering navigation. For river restoration and their sustainable management it is important to know how large bedforms support biodiversity, whether they could be protected and what potential conflicts in river management they can pose. We have addressed these questions by studying the role of large bedforms in supporting populations of two inland tern species Sternula albifrons and Sterna hirundo. We spatially analysed the behaviour of these two species with reference to the bedform structure mapped over a long semi-natural reach of the River Wisła (Vistula) (S. Poland). The results show that radiotagged terns breed on islands within the aggradation reaches, foraging in the adjacent shallows inhabited by populations of small fish. For Little Terns, the more complex the water line of emergent forms, the greater their foraging intensity. The islands do not pose any flood risk to human settlements. The whole geofeature forms an integral habitat for fish and birds; it is maintained by its geographic settings and so is stable over long periods of time (over 200 years). Protection of such habitats is thus feasible., (© 2024. The Author(s).)

Introduction: The objective of this bovine peripheral blood study was a comparative assessment of the phagocytic activity of neutrophils and monocytes and of the intracellular killing capacity of neutrophils from cows given no probiotic and from cows which were administered a probiotic consisting of Saccharomyces cerevisiae, Lactobacillus acidophilus, Lactobacillus plantarum and Rhodopseudomonas palustris . These activity types were compared during different lactation periods., Material and Methods: A cohort of 20 pregnant dairy cows was divided into two groups of 10. The experimental group consisted of cows fed a ration supplemented with probiotics, and the control group consisted of cows fed an unsupplemented ration. Blood was drawn six times: 7 days before dry off, 14 days before parturition, and 7, 21, 60 and 90 days postpartum (DPP). The phagocytic activity of neutrophils and monocytes and the oxidative burst activity of neutrophils were determined by flow cytometry in the peripheral blood of all examined cows., Results: Phagocytosis testing revealed increased percentages of phagocytic neutrophils and monocytes in the experimental group at 21, 60 and 90 DPP (P-value < 0.01). The mean fluorescence intensity (MFI) values for neutrophils and monocytes were higher on all days of the study (P-value < 0.01). In oxidative burst testing, the percentages of detected neutrophils and their MFI were increased in the experimental group on all days (P-value < 0.01)., Conclusion: The use of probiotics supported dairy cows' immunity throughout the whole experiment. Probiotic supplementation may limit the occurrence of infectious diseases in these animals., Competing Interests: Conflict of Interests Statement: The authors declare that there is no conflict of interests regarding the publication of this article., (© 2024 P. Brodzki et al., published by Sciendo.)

Background: Atopic dermatitis (AD) is the most common chronic inflammatory skin disease. Due to its high prevalence, considerable morbidity, and chronicity, there is a need for the accurate in vivo evaluation of treatment efficacy. Line-field confocal optical coherence tomography (LC-OCT) is a new emerging imaging technique able to perform a non-invasive, real-time examination of the epidermis and the upper dermis. LC-OCT may represent a promising tool in the diagnosis and treatment follow-up of chronic eczematous skin diseases with barrier defects., Objectives: We aimed to investigate the role of LC-OCT in the non-invasive monitoring of the treatment effect on five patients with severe atopic dermatitis during dupilumab treatment., Materials and Methods: LC-OCT imaging was performed on five patients (three women and two men) aged between 14 and 85 years old at the baseline and at 2, 4, and 6 weeks of treatment with dupilumab. The LC-OCT scans were performed at two sites, the lesional skin in the antecubital fossa and the extensor part of the arm, considered a control site on each patient for comparison. The captured images were later evaluated. Descriptive statistics and a t -test were used to compare the analyzed parameters over time and between involved atopic skin and clinically healthy skin., Results: The LC-OCT imaging was able to detect the difference in stratum corneum (SC) thickness and quality and epidermal thickness (ET) and the changes before and after treatment with high accuracy. The main findings include a significant reduction in the epidermal and stratum corneum thickness and decreased epidermal spongiosis and inflammation, with better quality of the stratum corneum indicating restoration of its tightness at both lesional and control sites., Conclusions: This study demonstrates that clinical improvement of affected and unaffected atopic skin under dupilumab treatment correlates with the LC-OCT findings. LC-OCT represents a novel, non-invasive tool examining the in vivo skin barrier and inflammation and can help to monitor the treatment efficacy among patients with atopic dermatitis in daily practice.

Most kidney transplant patients who undergo biopsies are classified as having no rejection based on consensus thresholds. However, we hypothesized that because these patients have normal adaptive immune systems, T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) may exist as subthreshold activity in some transplants currently classified as no rejection. To examine this question, we studied genome-wide microarray results from 5086 kidney transplant biopsies (from 4170 patients). An updated molecular archetypal analysis designated 56% of biopsies as no rejection. Subthreshold molecular TCMR and/or ABMR activity molecular activity was detectable as elevated classifier scores in many biopsies classified as no rejection, with ABMR activity in many TCMR biopsies and TCMR activity in many ABMR biopsies. In biopsies classified as no rejection histologically and molecularly, molecular TCMR classifier scores correlated with increases in histologic TCMR features and molecular injury, lower estimated glomerular filtration rate, and higher risk of graft loss, and molecular ABMR activity correlated with increased glomerulitis and donor-specific antibody. No rejection biopsies with high subthreshold TCMR or ABMR activity had a higher probability of having TCMR or ABMR, respectively, diagnosed in a future biopsy. We conclude that many kidney transplant recipients have unrecognized subthreshold TCMR or ABMR activity, with significant implications for future problems., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. P.F. Halloran holds shares in Transcriptome Sciences Inc., a University of Alberta research company dedicated to developing molecular diagnostics, supported in part by a licensing agreement between Transcriptome Sciences Inc. and Thermo Fisher Scientific, and by a research grant from Natera, Inc. P.F. Halloran is a consultant to Natera, Inc. and Argenx BV. The other authors have declared no conflict of interest exists., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)