Ferroelectric materials are crucial for today’s technological society, and nanostructured ferroelectric materials are important for downscaling of devices. Controlled and reproducible synthesis of these materials are therefore of immense importance. Hydrothermal synthesis is a well-established synthesis route, with a large parameter space for optimization, but a better understanding of nucleation and growth mechanisms is needed for full utilization and control. Here we use in situ X-ray diffraction to follow the nucleation and growth of BaTiO₃ formed by hydrothermal synthesis using two different titanium precursors, an amorphous titania precipitate slurry and a Ti-citric acid complex solution. Sequential Rietveld refinement was used to extract the time dependency of lattice parameters, crystallite size, strain and atomic displacement parameters. Phase pure BaTiO₃ nanoparticles 10 - 15 nm in size were successfully synthesized at different temperatures (100, 125, and 150 °C) from both precursors after reaction times ranging from a few seconds, to several hours. The two precursors resulted in phase pure BaTiO₃ with similar final crystallite size. Finally, two different growth mechanisms were revealed, where the effect of surfactants present during hydrothermal synthesis is discussed as one of the key parameters.

To make low-cost catalytic materials that mimic the activity of tyrosinase enzymes (Catechol oxidase) is an exciting challenge of biochemical technology. Herein, we report the synthesis of a series of acylhydrazone-pyrazoles based biomolecule materials (L1-L7) with superior catecholase activity. These biomolecules were synthesized by a one pot chemical condensation between 5-methyl-1H-pyrazole-3-carbohydrazide and benzaldehyde derivatives. The X-ray single crystal diffraction (XRD) for two ligands L1 and L2 have been studied and the molecular structures were optimized and confirmed using the density functional theory (DFT/B3LYP) method. Copper (II) complexes of the biomolecules (L1-L7), generated in-situ, and were studied for their catalytic activities towards the oxidation reaction of catechol to ortho-quinone according to two parameters: the nature of the ligand and the nature of counter anion. The L7-CuSO4 was found to have an excellent catalytic activity (105.42 μmol·L−1·min−1) among the catalysts recently reported in the existing literature.

In this paper new upper limits on the parameters of the Continuous Spontaneous Localization (CSL) collapse model are extracted. To this end the X-ray emission data collected by the IGEX collaboration are analyzed and compared with the spectrum of the spontaneous photon emission process predicted by collapse models. This study allows to obtain the most stringent limits within a relevant range of the CSL model parameters, with respect to any other method. The collapse rate $\lambda$ and the correlation length $r_C$ are mapped, thus allowing to exclude a broad range of the parameter space.

We investigate the cosmological evolution of the universe for a spatially flat FLRW background space within the context of $f(T,B)$ gravity, which is a recently formulated teleparallel theory that connects both $f(T)$ and $f(R)$ gravity under suitable limits. The analysis has been done by focusing on four different $f(T,B)$ cosmological models corresponding to various choices of scale factor, namely emergent, logamediate, and intermediate. In addition to this, we also assume a power-law-like function of $f(T,B)$ gravity. The reconstruction of $f(T,B)$ gravity has been done by considering the Holographic Ricci Dark Energy(HRDE) (a particular case of a highly generalized holographic dark energy given in Nojiri et al. in General Relativity and Gravitation, 38, pp.1285-1304,2006) as the background fluid. We analyze the equation of state parameters and the squared speed of sound for the reconstructed models. Finally, we conducted the thermodynamical analysis for each reconstructed model. The generalised second law of thermodynamics(GSLT) is valid for the four different $f(T,B)$ cosmological models.

Intercellular adhesion molecule 1 (ICAM-1/CD54), a transmembrane glycoprotein, has been considered as one of the most important adhesion molecules during leukocyte recruitment. It is encoded by the ICAM1 gene and plays a central role in inflammation. It’s crucial role in many inflammatory diseases such as ulcerative colitis and rheumatoid arthritis are well established. Given that neuroinflammation, underscored by microglial activation, is a key element in neurodegenerative diseases such as Parkinson’s disease (PD), we investigated whether ICAM-1 has a role in this progressive neurological condition and if so, elucidate the underpinning mechanisms. Specifically, we were interested in potential interaction between ICAM-1, glial cells and ferroptosis, an iron-dependent form of cell death that has recently been implicated in PD. We conclude that there exist direct and indirect (via glial cells and T cells) influences of ICAM-1 on ferroptosis and that further elucidation of these interactions can suggest novel intervention for this devastating disease.

One of the main objectives of developing new anti-cancer vaccine strategies is to effectively induce CD8+ T cell-mediated anti-tumor immunity. Live recombinant vectors, notably Listeria mono-cytogenes, have been shown to elicit a robust in vivo CD8+ T cell response in preclinical settings. Significantly, it has been demonstrated that Listeria induces inflammatory/immunogenic cell death mechanisms such as pyroptosis and necroptosis in immune cells that favorably control immunological responses. Therefore, we postulated that the host's response to Listeria-based vec-tors and the subsequent induction of CD8+ T cell-mediated immunity would be compromised by the lack of regulatory or effector molecules involved in pyroptosis or necroptosis. To test our hy-pothesis, we used recombinant L. monocytogenes carrying the ovalbumin gene (LM.OVA) to vac-cinate wild-type (WT), caspase-1/11-/-, gsdmd-/-, ripk3-/-, and mlkl-/- C57Bl/6 mice. We performed an in vivo cytotoxicity assay to assess the efficacy of OVA-specific CD8+ T lymphocytes in eliminat-ing target cells in wild-type and genetically deficient backgrounds. Furthermore, we evaluated the specific anti-tumor immune response in mice inoculated with B16F0 and B16F0.OVA mela-noma cell lines. Our findings demonstrated that while caspase-1/11 and GSDMD deficiencies in-terfere with the rapid control LM.OVA infection, of the KO seems to contribute to the early acti-vation of OVA-specific CTL responses. In contrast, individual deficiency of each one of these pro-teins negatively impact the generation of long-lasting effector CD8+ T cells.

While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T cell responses against the transgene product upon vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8+ T cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1>MyD88 and TLR9>MyD88>IFN I>IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. We further provide evidence that CpG depletion of vector genomes and inclusion of TLR9 inhibitory sequences can have a synergistic effect. However, even low-frequency CD8+ T cell responses could eliminate transgene expression. Thus, innate immune avoidance/blockade strategies, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of redundancy of immune activating pathways.

Fusarium species are agriculturally important fungi with a broad host range and can be found as endophytic, pathogenic, or opportunistic parasites in many crop plants. This study aimed to identify Fusarium species in bare-rooted, dormant plants in Turkish grapevine nurseries using molecular identification methods and assess their pathogenicity. Asymptomatic dormant plants were sampled from grapevine nurseries (43) in different regions of the country, and fungi were isolated from plant roots and internal basal tissues. The Fusarium isolates were identified by performing gene sequencing (TEF1-α, RPB2) and phylogenetic analyses. Pathogenicity tests were carried out by inoculating mycelial agar pieces of isolates onto the stem or conidial suspensions into the rhizosphere of vines (1103 Paulsen rootstock). Laboratory tests revealed that Fusarium species were highly prevalent in Turkish grapevine nurseries (41 out of 43). Gene sequencing and phylogenetic analyses unraveled that 12 Fusarium species (F. annulatum, F. brachygibbosum, F. clavum, F. curvatum, F. falciforme, F. fredkrugeri, F. glycines, F. nanum, F. nematophilum, F. nirenbergiae, F. solani, and Fusarium spp.) existed in the ready-to-sale plants. Some of these species (F. annulatum, F. curvatum and F. nirenbergiae) consistently caused wood necrosis of seedling stems, rotting of the basal zone and roots, and reduced root biomass. Although the other nine species also caused some root rot and root reduction, their virulence was not as severe as the pathogenic ones, and they were considered opportunistic parasites or endophytic species. This study is the first detailed investigation of Fusarium species in grapevine nurseries in Türkiye and emphasizes the need to consider pathogenic species in producing healthy grapevine seedlings.

Public transportation scheduling aims to optimize the allocation of transportation resources, enhance transportation efficiency, and increase passenger satisfaction, which is crucial for building a sustainable urban transportation system. As a complement to public transportation, shared bikes provide users with a solution for the last mile of travel, compensating for the lack of flexibility in public transportation and helping to improve its utilization rate. Due to the characteristics of shared bikes, such as peak usage periods in the morning and evening and significant fluctuations in demand across different areas, the optimization of shared bike dispatch can better meet user needs, thereby reducing vehicle vacancy rates and increasing operating revenue. Addressing this issue, this paper designs a comprehensive decision-making approach for spatio-temporal demand prediction and bike dispatch optimization. For demand prediction, we designed a T-GCN based bike demand prediction model. In terms of dispatch optimization, we considered factors such as dispatch capacity, distance restrictions, and dispatch costs, and designed an optimization solution based on genetic algorithms. Finally, this paper validates the approach using shared bike operating data, shows that T-GCN can effectively predict short-term demand for shared bikes. Meanwhile, the optimization model based on genetic algorithms provides a complete dispatch solution verifying the model’s effectiveness. The shared bike dispatch approach proposed in this paper, which combines demand prediction with resource scheduling. This scheme can also be extended to other transportation scheduling problems with uncertain demand, such as store replenishment delivery and intercity inventory dispatch.

The allosteric SERCA (Sarcoplasmic/Endoplasmic Reticulum Ca2+-ATPase) activator CDN1163 has been recently added to the group of pharmacological tools for probing SERCA function. We chose to investigate the effects of the compound on T lymphocyte Ca2+ stores, using the well-described Jurkat T lymphocyte as a reliable cell system for Ca2+ signaling pathways. Our study identified the lowest concentrations of the SERCA inhibitors thapsigargin (TG) and 2,5-di-(tert butyl)-1,4-benzohydroquinone (tBHQ) capable of releasing Ca2+, permitting the differentiation of the TG-sensitive SERCA 2b Ca2+ store from the tBHQ-sensitive SERCA 3 Ca2+ store. We proceeded to test the effects of CDN1163 on Ca2+ stores, examining specific actions on the SERCA 2b and SERCA 3 Ca2+ pools using our low dose SERCA blocker regimen. In contrast to previous work, we find CDN1163 exerts complex time-sensitive and SERCA isoform-specific actions on Ca2+ stores. Surprisingly, short-term exposure (0-30 minutes) to CDN1163 perturbs T cell Ca2+ stores by suppressing Ca2+ uptake with diminished Ca2+ release from the SERCA 2b-controlled store. Concomitantly, we find evidence for a SERCA-activating effect of CDN1163 on the SERCA 3 regulated store, given the observation of increased Ca2+ release inducible by low dose tBHQ. Intriguingly, longer-term (>12 hours) CDN1163 exposure reversed this pattern, with increased Ca2+ release from SERCA 2b-regulated pools, yet decreased Ca2+ release responses from tBHQ-sensitive SERCA 3 pool. Our results reveal differential effects of CDN1163 on Ca2+ stores regulated by distinct SERCA isoforms, prompting the need for careful interpretation of the compound’s effects, particularly in cells expressing multiple SERCA isoforms.

Here we explore the emerging role of NKG2D CAR-T cell therapy in the realm of solid tumor treatment. Unique capabilities of NKG2D CAR-T cells to recognize stress-induced ligands on cancer cells are discussed, highlighting the therapy's potential for targeted and precise antitumor responses. We also examine the challenges and opportunities associated with NKG2D CAR-T cell therapy, emphasizing the ongoing advancements and clinical trial progress shaping its future. Ultimately, the discussion underscores the transformative promise of NKG2D CAR-T cell therapy in revolutionizing the landscape of solid tumor treatment and enhancing the prospects for improved patient outcomes.

We investigated the potential genetic variants using whole exome sequencing (WES) and evalu-ated the disease course using T cell receptor (TCR) repertoire analysis in rheumatoid arthritis (RA). Fourteen patients with RA and five healthy controls (HCs) were enrolled. For patients with RA, only naïve patients were recruited before treatment, and data were collected at baseline and 6 and 12 months after the initiation of disease-modifying antirheumatic drug (DMARD) treatment. Laboratory data and disease parameters were also collected. Genetic variants were detected using WES, and the diversity of the TCR repertoire was assessed using Shannon-Weiner diversity. Some variants were detected by WES, but their clinical significance should be confirmed by further studies. The diversity of the TCR repertoire in patients with RA was lower than that in HCs; however, after DMARD treatment, it increased significantly. The diversity was negatively cor-related with laboratory findings and disease measures with statistical significance. Variants with a potential for RA pathogenesis were identified and the clinical significance of TCR repertoire was evaluated in Korean patients with RA. Further studies are required to confirm the findings of the present study.

Claudins are a family of 27 proteins that have an important role in the formation of tight junc-tions. They also have an important function in ions exchange, cell mobility, and in in the epitheli-al-to-mesenchymal transition, the latter being very important in cancer invasion and metastasis. Therapeutic targeting of claudins has been investigated to improve cancer outcomes. Recent evi-dence shows improved outcomes when combining monoclonal antibodies against Claudin 18.2 with chemotherapy for patients with gastroesophageal junction cancer. Currently Chimeric anti-gen receptor T-cells targeting Claudin 18 are under investigation.

The T cell composition of the tumor microenvironment (TME) of esophageal adenocarcinoma (EAC) in comparison to the T cell composition of the TME of Barrett esophagus (BE) and in the context of clinicopathologic features and patient survival is unknown. To help fill these knowledge gaps, we used a multiplex immunofluorescence platform to study adaptive T cells and T cell subtypes based on costimulatory/inhibitory markers in EAC (n=54) and matched BE (n=21) samples from 54 patients with EAC and correlated the T cell phenotype distribution with clinicopathologic features and disease-free survival. We observed significant enrichment of cytotoxic T cells (CTCs), memory T cells, effector memory T cells, memory T regulatory cells (MTregs), and T cells expressing costimulatory/inhibitory markers LAG3, TIM3, and ICOS in EAC compared to BE, in the stroma. In EAC, increased TIM3 expression on T cells significantly correlated with increased CTCs but not T regulatory cells (Tregs). In EAC, higher densities of Tregs and MTregs correlated with pT1 disease, low pathologic stage, and absence of lymphovascular invasion. In EAC, patients with higher density of TIM3-expressing T cells had shorter disease-free survival by univariate and multivariate analyses. Our results identify T cell subtypes that are relevant to EAC biology and patient outcome. Furthermore, our results identify TIM3 as a potential target for optimization of immunomodulatory therapy in EAC.

Trichothecene mycotoxin T-2 toxin is an important environmental pollutant and poses a global threat to human and animal health. T-2 toxin could induce nephrotoxicity, however, the precise molecular mechanism remains unclear. In this study, the mice were intraperitoneally administrated with a single dose of 2 mg/kg T-2 toxin. The kidney function and ultrastructural observation were also assessed and found T-2 toxin exposure could cause kidney damage. Transmission electron microscopy showed a significant swelling and vacuolization of the mitochondria of renal cell. A total of 1122, 58, and 391 differential expression genes (DEGs) that were predominantly expressed in kidney tissues at 1 d, 3 d, and 7 d after T-2 toxin exposure, respectively. Early transcriptomic changes at 1 d after exposure were down-regulation of DEGs involved in the cell cycle, p53 signaling pathway, and cellular senescence, while up-regulation of DEGs referred to the ribosome pathway. The temporal variations in gene expression pattern in T-2 toxin exposure in mice kidney were presented and cellular metabolism was disturbed at the exposure recovery period with 7 d. In conclusion, this study, for the first time, provided a comprehensive comparative transcriptomic analysis of gene regulation in T-2 toxin exposure-induced nephrotoxicity at different temporal periods and explored the nephrotoxicity mechanism of T-2 toxin at the mRNA level.

Tumors are complex tissues of malignant cells surrounded by a diverse cellular micro-environment with which they interact. The molecular and cellular underpinnings of cancer cells have been increasingly understood during the last few decades. Nonetheless, a great deal remains unknown regarding the ways in which tumour cells modify their surroundings and impact the organisation and makeup of cells. This review aims to concentrate on recent advancements in molecular characterization of tumor cells and its immunology, provides recent and general insight into cancer immunity and immunotherapy, and discusses the immunobiology of human adaptive and innate immunity to malignant growth of cancer cells, the mechanisms that support human immune response from beneath, an up-to-date scientific development to cancer immunotherapy, and how tumor and host responses can Encircle as a military tactic effective anti-cancer immunity.

CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor c-Met (c-Met+ CTLs) that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met+ CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met+ CTLs in a three-dimensional (3D) setting, we studied their function within B16 melanoma spheroids and examined the impact of cell-cell contact on the modulation of inhibitory checkpoint molecules expression such as KLRG1, PD-1 and CTLA-4. Additionally, we evaluated the cytolytic capacity of human CTLs clones expressing c-Met (c-Met+) and compared it to c-Met− CTLs clones. Our results indicated that, similar to their murine counterparts, c-Met+ human CTLs clones exhibited increased cytolytic activity compared to c-Met− CTLs clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, our findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promises for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer.

The landscape of therapeutic measures to treat multiple myeloma has undergone a seismic shift since the dawn of the current century. This has been driven largely by the introduction of new classes of small molecules, such as proteasome blockers (e.g., bortezomib) and immunomodulators (e.g., lenalidomide), as well as by immunotherapeutic agents starting with the anti-CD38 monoclonal antibody daratumumab in 2015. Recently, other immunotherapies have been added to the armamentarium of drugs available to fight this malignancy. These include the bispecifics teclistamab, talquetamab, and elranatamab, and the chimeric antigen receptor (CAR) T-cell products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). While the accumulated benefits of these newer agents have resulted in a more than doubling of the disease’s five-year survival rate to nearly 60% and improved quality of life, the disease remains incurable, as patients become refractory to the drugs and experience relapse. This review covers the current scope of anti-myeloma immunotherapeutic agents, both those in clinical use and in development. Included in the discussion are additional monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), bi- and multi-targeted mAbs, and CAR T-cells and emerging natural killer (NK) cells, including products intended for “off-the-shelf” (allogeneic) applications. Emphasis is placed on the benefits of each along with the challenges that need to be surmounted if MM is to be cured.

Systemic autoimmune diseases (SAIDs) such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and rheumatoid arthritis (RA) are fully related to the unregulated innate and adaptive immune systems involved in their pathogenesis. They have similar pathogenic characteristics including the interferon signature, loss of tolerance to self-nuclear antigens, and enhanced tissue damage like necrosis and fibrosis. Glucocorticoids and immunosuppressants, which have limited specificity and are prone to tolerance, are used as the first-line therapy. A plethora of novel immunotherapies have been developed including monoclonal and bispecific antibodies, and other biological agents to target cellular and soluble factors involved in disease pathogenesis such as B cells, co-stimulatory molecules, cytokines or their receptors, and signalling molecules. Many of these have shown encouraging results in clinical trials. CAR-T cell therapy is considered the most promising technique for curing autoimmune diseases, with recent successes in the treatment of SLE and SSc.

miRNAs are major regulators of eukaryotic gene expression, host immunity, and play an important role in the inflammation-mediated pathways in periodontal disease (PD) pathogenesis. Expanding our previous observation with the global miRNA profiling using partial human mouth microbes and lack of in vivo studies involving oral spirochete Treponema denticola induced miRNAs, this study was designed to delineate the global miRNA expression kinetics during progression of periodontitis in mice infected with T. denticola by using NanoString nCounter® miRNA panels. All the T. denticola-infected male and female mice at 8- and 16 weeks demonstrated bacterial colonization (100%) on the gingival surface, and an increase in alveolar bone resorption (p < 0.0001). A total of 70 miRNAs with at least 1.0-fold differential expression/regulation (DE) miRNAs (26 upregulated and 44 downregulated) were identified. nCounter miRNA expression profiling identified 13 upregulated miRNAs (e.g. miR-133a, miR-378) and 25 downregulated miRNAs (e.g. miR-375, miR-34b-5p) in T. denticola-infected mice mandibles during 8-weeks infection whereas 13 upregulated miRNAs (e.g. miR-486, miR-126-5p) and 19 downregulated miRNAs (miR-2135, miR-142-3p) were observed during 16- weeks of infection. One miRNA (miR-126-5p) showed significant difference between 8-and 16-weeks of infection. Interestingly, miR-126-5p has been presented as a potential biomarker in patients with periodontitis and coronary artery disease. Among the 13 upregulated miRNAs, miR-486, miR-126-3p, miR-126-5p were reported in human gingival plaques samples with periodontitis. KEGG analysis revealed various functional pathways of DE miRNAs such as bacterial invasion of epithelial cells, Ras signaling, Fc gamma R- mediated phagocytosis, osteoclast differentiation, adherens signaling and ubiquitin mediated proteolysis. This is the first study of DE miRNAs in mice mandibles at different time-points of T. denticola infection and the combination of three specific miRNAs miR-486, miR-126-3p, miR-126-5p may serve as an invasive biomarker of T. denticola in PD. These miRNAs may have significant role in PD pathogenesis and establishes a link between miRNA, periodontitis, and systemic diseases.

Background: Sulforaphane (SFN) is an isothiocyanate of vegetables origin with potent antioxidant and immunomodulatory properties. The pleiotropic activities characterization in human dendritic cells (DCs) is poorly summarized. The aim of this work was the study of the immunomodulatory power of SFN in response to an inflammatory microenvironment on human monocyte derived DCs (moDCs). Methods: The immunological response induced by SFN was studied, evaluating apoptosis and autophagy assays by flow cytometry in moDCs and cancer cell line (THP-1), including moDCs maturation, lymphocyte proliferation and cytokines production under different experimental conditions associated or not with an inflammatory microenvironment, which was induced by lipopolysaccharide (LPS). Results: Our results demonstrated that SFN can interact with moDCs, significantly reducing autophagy process and enhancing apoptosis, such as THP-1 cells, in chronic inflammatory microenvironment. Under this chronic inflammation, SFN modulated the phenotypical characteristics of moDCs, which reduction the expression of all markers (CD80, CD83, CD86, HLA-DR and PD-L1), and significantly reduced the Th2 proliferative response together with the reduction of the IL-9 and IL-13 levels. Although we did not find changes in the regulatory proliferative response, we observed an increase in IL-10 levels. Conclusion: These findings demonstrate that SFN exerts protective effects against LPS-induced inflammation through moDCs/T-cells modulation towards a regulatory profile. Therefore, SFN may be a potential candidate for use in the treatment of pathologies with an inflammatory profile.

Controlling CD4+ immune cells infiltration of the brain is a leading aim in designing therapeutic strategies for a range of neuropathological disorders such as; multiple sclerosis, Alzheimer and depression. CD4+ T cells are a highly heterogeneous and reprogrammable family, that includes various distinctive cell types such as Th17, Th1, and Tregs. Interestingly Th17 and Tregs share a related transcriptomic profile, where the TGFβ-SMADS pathway plays a fundamental role in regulating the differentiation of both of these cell types. However, Th17 could be highly pathogenic and was shown to promote inflammation in various neuropathological disorders. Conversely, Treg is anti-inflammatory and is known to inhibit Th17. It could be noticed that Th17 frequencies of infiltration of the blood-brain barrier (BBB) in various neurological disorders are significantly upregulated. However, Treg infiltration numbers are significantly low. The reasons behind these contradicting observations are still unknown. In this perspective, we propose that the difference in the TCR repertoire diversity, diapedesis pathways, chemokine expression and mechanical properties of these two cell types could be contributing to answering this intriguing question.

This manuscript provides a new integrated view of the development of allergen-specific TH2 and the lack of their associated Treg cells in a unified model, justifying the need for IL-2 to correct allergy conditions.

To detect aberrant human behaviors from large volume of passive data collected by smartphones in real time, we propose an online anomaly detection method using Hotelling’s T-squared test. The test statistic is a weighted average, with more weight on the between-individual component when there are little data available for the individual and more weight on the within-individual component when the data are adequate. The algorithm takes only O(1) run time in each update and the required memory usage is fixed after a pre-specified number of updates. The performance of the proposed method, in terms of accuracy, sensitivity and specificity, is consistently better than or equal to the offline method that it builds upon depending on the sample size of the individual data.

Findings of new targeted treatments with adequate safety evaluations is essential for better cancer cures and mortality rates. Immunotherapy holds promise for patients with relapsed disease, with the ability to elicit long-term remissions. Emerging promising clinical results in B-cell malignancy using gene-altered T-lymphocytes uttering chimeric antigen receptors have sparked a lot of interest. This treatment could open the path for a major difference in the way we treat tumors that are resistant or recurring. Genetically altered T cells used to produce tumor-specific chimeric antigen receptors are resurrected field of adoptive cell therapy by demonstrating remarkable success in the treatment of malignant tumors. Because of the molecular complexity of chimeric antigen receptors -T cells, a variety of engineering approaches to improve safety and effectiveness are necessary to realize larger therapeutic uses. In this study, we investigate at new strategies for enhancing chimeric antigen receptors-T cell therapy by altering chimeric antigen receptors proteins, T lymphocytes, and their relations with other solid tumor microenvironment (TME) aspects.

Carboxypeptidase A4 (CPA4) has shown the potential possibility as a biomarker in the early diagnosis for certain cancers. However, no previous research has linked CPA4 to therapeutic or prognostic significance in bladder cancer. Using data from The Cancer Genome Atlas (TCGA) database, we set out to determine the full extent of the link between CPA4 and BLCA. We further analyzed the interacting proteins of CPA4 and infiltrated immune cells via TIMER2，STRING and GEPIA2 databases. The expression of CPA4 in tumor and normal tissues was compared using the TCGA+GETx database. The connection between CPA44 expression and clinicopathologic characteristics and overall survival (OS) was investigated using multivariate methods and Kaplan-Meier survival curves. The potential functions and pathways were investigated via gene set enrichment analysis. Furthermore, we analyze the associations between CPA4 expression and infiltrated immune cells with their respective gene marker sets using the ssGSEA, TIMER2, and GEPIA2 databases. Compared to matching normal tissues, human CPA4 was found to be substantially expressed. We confirmed that overexpression of CPA4 is linked with shorter OS, DSF, PFI, and increased diagnostic potential using Kaplan-Meier and ROC analysis. The expression of CPA4 is related to T-bet, IL12RB2, CTLA4, and LAG3, among which T-bet and IL12RB2 are Th1 marker genes, while CTLA4 and LAG3 are related to T cell exhaustion, which may be used to guide the application of checkpoint blockade and the adoption of T cell transfer therapy.

Superantigens are unconventional antigens which recognise immune receptors outside the usual binding sites e.g. complementary determining regions (CDRs), to elicit a response within the target cell. T-cell superantigens crosslink T-cell receptors and MHC Class II molecules on antigen-presenting cells, leading to lymphocyte recruitment, induction of cytokine storms and T-cell anergy or apoptosis among many other effects. B-cell superantigens, on the other hand, bind immunoglobulin receptors on B-cells affecting opsonisation, IgG-mediated phagocytosis, and drive B-cells into apoptosis. Here, through a review of the structural basis for recognition of immune receptors by superantigens, we show that their binding interfaces share specific physicochemical characteristics when compared with other protein-protein interaction complexes. Given that antibody-binding superantigens have been exploited extensively in industrial antibody purification, these observations could facilitate further protein engineering to optimize the use of superantigens in this and other areas of biotechnology.

Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG⁺ memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, though how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation; specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.

Extracellular vesicles (EVs) released by different cell types play significant role in many physiological and pathophysiological processes. In physiological conditions red blood cells (RBCs) derived EVs compose 4 - 8% of all circulating EVs, and oxidative stress (OS) as a consequence of different pathophysiological conditions significantly increases the amount of circulated RBC-derived EVs, however the mechanisms of EV formation are not fully defined yet. To analyze OS-induced EV formation and RBCs transformations we used flow cytometry to evaluate cell esterase activity, caspase-3 activity, and band 3 clustering. Band 3 clustering was additionally analyzed by confocal microscopy. Two original laser diffraction-based approaches were used for analysis of cell deformability and band 3 activity. Hemoglobin species were characterized spectrophotometrically. We showed that cell viability in tert-butyl hydroperoxide-induced OS directly correlated with oxidant concentration to cell count ratio, RBCs-derived EVs contained hemoglobin oxidized to hemichrome (HbChr). OS induced caspase-3 activation and band 3 clustering in cells and EVs. Importantly, we showed that OS-induced EV formation is independent from calcium. Presented data indicated that during OS RBCs eliminate HbChr by vesiculation, in order to sacrifice the cell itself thereby prolonging lifespan and delaying the untimely clearance of in all other respects healthy RBCs.

Existing approaches to identifying predictive T-cell epitopes have traditionally utilized either 2-digit HLA super-families or more commonly autologous HLA alleles to facilitate the predictions, but frequently they may not consider their representation within a population. Here we propose a modification to this concept whereby subsets of individuals are selected for their specific HLA allele profiles and the representation they provide within a given population. Using this targeted approach to HLA selection and the linkages to specific individuals may enable the design of restricted experimental strategies.

It has been demonstrated that a decrease in cellular adenosine triphosphate (c-ATP) causes cellular dysfunction. T-cells are not an exception. One of their roles is to properly detect and eliminate cancer cells. These processes occur at the expense of ATP. Therefore, it can be concluded that a decrease in c-ATP can defect T-cell function and promote cancer evolution. In this article, we provide a hypothesis to describe the correlation between the expression of PD-1 protein on T-cells and their c-ATP levels. Moreover, we present the possible predictive factors of Anti–PD(L)-1 therapy which has not yet been determined definitely.

In this work, we have studied microstructure and unusual ferromagnetic behavior in cobalt (Co)-implanted epitaxial tin dioxide (SnO2) films. The study was aimed to provide a comprehensive understanding of the interplay between cobalt implant distribution, crystal defects, such as oxygen vacancies, and magnetic properties in Co-implanted SnO2 films, which has potential applications in spintronics and memristor devices. The scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), vibrating sample magnetometry (VSM), differential thermo-magnetic analysis (DTMA), and ferromagnetic resonance (FMR) were employed for investigations of SnO2 films implanted with 40 keV Co+ ions at room or the elevated temperatures of substrate. The experimental data showed that the Co ion implantation with high fluence of 1.0 1017 ions/cm2 induces significant changes in the microstructure of SnO2 films, leading to the appearance of ferromagnetism with the Curie temperature significantly above room temperature. Strong influence of implantation temperature and subsequent high-temperature annealing in air or in vacuum on magnetic properties of Co-implanted SnO2 films were established. Moreover, the chemical effect of ethanol on FMR spectra were observed. The obtained results are discussed within the model of two magnetic layers with different concentration and valence states of the implanted cobalt and with high content of oxygen vacancies.

(1) Background: Stereological estimations significantly contributed to our anatomical and physiological understanding of the lung by providing an average distribution of measured parameters over the entire lung parenchyma. However, most structural lung diseases show a very inhomogeneous pattern of alterations. (2) Methods: We developed a novel protocol for the analysis of all pulmonary airspaces. Our pipeline starts with high-resolution synchrotron radiation-based X-ray tomographic microscopy (SRXTM) and consists of (i) image segmentation with the combination of the free machine-learning tool Ilastik and ImageJ and (ii) calculation of the airspace diameter distribution of an entire lung using a diameter map function. To evaluate the new pipeline, lungs from adult mice with cystic fibrosis (CF)-like lung disease (ENaC-transgenic mice) or mice with elastase-induced emphysema were compared to healthy controls. (3) Results: We were able to show the distribution of airspace diameters throughout the entire lung, as well as separately for the conducting airways and the gas-exchange area. In the pathobiological context, we observed an irregular widening of parenchymal airspaces in mice with CF-like lung disease and elastase-induced emphysema. Comparable results were obtained when analyzing lungs imaged with μCT, suggesting that our pipeline is applicable to different kinds of imaging modalities. (4) Conclusions: We conclude that the airspace diameter map is well suited for a detailed analysis of unevenly distributed structural alterations in chronic muco-obstructive lung diseases such as cystic fibrosis and COPD.

The role of γδ T cells in vertebrate immunity is still an unsolved puzzle. Species such as humans and mice display a low percentage of these T lymphocytes (i.e., “γδ low species”) with a restricted diversity of γδ T cell receptors (TR). Conversely, artiodactyl species (i.e., “γδ high species”) ac-count for a high proportion of γδ T cells with large γ and δ chain repertoires. The genomic organisation of the TR γ (TRG) and δ (TRD) loci has been determined in sheep and cattle, noting that a wide number of germline genes that encode for γ and δ chains characterise their genomes. Taking advantage from the current improved version of the genome assembly, we have investigated the genomic structure and gene content of the dromedary TRD locus, which, as in the other mammalian species, is nested within the TR alpha (TRA) genes. The most remarkable finding was the identification of a very limited number of variable germline genes (TRDV) compared to sheep and cattle, which supports our previous expression analyses for which the somatic hypermutation mechanism is able to enlarge and diversify the primary repertoire of dromedary δ chains. Furthermore, the comparison between genomic and expressed sequences reveals that D genes, up to four incorporated in a transcript, greatly contribute to the increased diversity of the dromedary δ chain antigen binding-site.

At INFN-LNS, and in collaboration with the ATOMKI laboratories, an innovative multi-diagnostic system with advanced analytical methods has been designed and implemented. This is based on several detectors and techniques (Optical Emission Spectroscopy, RF systems, Interfero-polarimetry, X-ray detectors) and here we focus on high resolution spatially-resolved X-ray spectroscopy, performed by means of a X-ray pin-hole camera setup operating in the 0.5−20 keV energy domain. The diagnostic system was installed at a 14 GHz Electron Cyclotron Resonance (ECR) ion source (ATOMKI, Debrecen), enabling high precision X-ray spectrally-resolved imaging of ECR plasmas heated by hundreds of Watts. The achieved spatial and energy resolution were 0.5 mm and 300 eV at 8 keV, respectively. We here present the innovative analysis algorithm that we properly developed for obtaining Single Photon-Counted (SPhC) images providing the local plasma emitted spectrum in a High-Dynamic-Range (HDR) mode, by distinguishing fluorescence lines of the materials of the plasma chamber (Ti, Ta) from plasma (Ar). This method allows a quantitative characterization of warm electrons population in the plasma (and its 2D distribution) which are the most important for ionization, and also to estimate local plasma density and spectral temperatures. The developed post-processing analysis is also able to remove the readout noise, that is often observable at very low exposure times (msec). The setup is now under update including fast shutters and trigger systems in order to allow simultaneously space and time-resolved plasma spectroscopy during transients, stable and turbulent regimes.

Antimicrobial peptides provide a powerful toolkit for combating multidrug resistance. Combatting eukaryotic pathogens is complicated by the fact, the intracellular drug targets in the eukaryotic pathogen are frequently homologs of cellular structures of vital importance in the host organism. The entomopathogenic bacteria, (symbionts of entomopathogenic nematode species), release a series of non-ribosomal templated antimicrobial peptides, some may be potential drug candidates. The ability of an entomopathogenic nematode /entomopathogenic bacterium symbiotic complex to survive in a given polyxenic milieu is a coevolutionary product, explaining that those gene complexes which are responsible for the biosynthesis of different non-ribosomal templated antimicrobial protective peptides (including those which are potently capable to inactivate the protist mammalian -pathogen Leishmania and the gallinaceous bird pathogen Histomonas) are co-regulated. Our approach is based on comparative antimicrobial bioassays of the culture media of the wild-type and regulatory mutant strains. We concluded that Xenorhabdus budapestensis and X. szentirmaii are excellent sources of non-ribosomal templated antimicrobial peptides, that are efficient antagonists of the mentioned pathogens. Data on selective cytotoxicity of different cell-free culture media encourages us to forecast that the recently discovered “easy-PACId” research strategy is suitable for constructing EPB strains producing and releasing single, harmless, non-ribosomal templated antimicrobial peptides with considerable drug, (probiotic) -candidate potential.

Bone fractures are common injuries that require quick and accurate diagnosis to provide the right medical care. The “convolutional neural network” technique relies mostly on manual inspection, by radiologists and can be laborious and prone to error. The objective of this work was to increase the efficiency and accuracy of fracture identification by automating the examination of X-ray images using convolutional neural networks. A “convolutional neural network” model created to detect bone fractures in X-ray images was used in the present study. The model was trained and validated using an extensive dataset of X-ray images, which included both fractured and nonfractured bones. Multiple convolutional layers were used in the “convolutional neural network” architecture for feature extraction, and pooling and fully connected layers were added for classification. The main measures used to assess the model's performance were sensitivity, specificity, and accuracy. In regard to identifying bone fractures, the “convolutional neural network”-based model outperformed the conventional technique. With significant gains in sensitivity and specificity, this approach achieved a high accuracy rate and decreased the frequency of false positives and false negatives. We used “convolutional neural network” tool in PyTorch for bone fracture detection and we outlined the important considerations that must be considered when attempting to achieve this goal Additionally, we contrasted every study with our baseline. Here our maximum accuracies were 99.05%, 98.60%, 99.45% and 99.74% for epochs 8, 9, 10 and 11, respectively. These findings highlight the model's ability to improve the diagnostic efficiency and accuracy in clinical settings. Using “convolutional neural network” to identify bone fractures from X-ray images is a promising development in medical imaging. In the end, our method improves patient outcomes by ensuring faster and more reliable fracture diagnosis while also lessening the diagnostic burden on radiologists. Subsequent investigations will focus on incorporating this system into clinical procedures and investigating its utilization in real-time emergency situations. Since there was no medical intervention on human subjects in this investigation, trial registration regulations were not applied.

Background: Bioelectrical impedance (BIA) and ultrasound (US) have become popular for estimating body fat percentage (BF%) due to their low cost and clinical convenience. However, agreement of these devices with gold standard method still require investigation. The aim was to analyze the agreement between a gold standard %BF assessment method with BIA and US devices. Methods: Twenty-three men (age 30.1 ± 7.7 years, 82.5 ± 14.9 kg, 1.77 ± 0.05 m) underwent Dual Energy X-Ray Absorptiometry (DXA), BIA (tetrapolar) and US (three-site method) %BF assessment. Pearson and concordance correlations were analyzed. T-test compared means between methods, and Bland Altman plots analyzed agreement and proportional bias. Alpha was set at < .05. Results: Pearson coefficients between BIA and US with DXA were high (BIA = 0.94; US = 0.89; both p < .001). Concordance coefficient was high for BIA (0.80) and moderate for US (0.49). BF% measured by BIA (24.5 ± 7.5) and US (19.4 ± 7.0) were on average 4.4% and 9.6% lower than DXA (29.0 + 8.5%), respectively (p < .001). Lower and upper agreement limits between DXA and BIA were -1.45 and 10.31, while between DXA and US were 2.01 and 17.14, respectively. There was a tendency of both BIA (p = .09) and US (p = .057) to present proportional bias and underestimate BF%. Conclusions: Despite the correlation, the mean difference between the methods were significant, and the agreement limits are very wide. This indicate that BIA and US, as measured in this study, have limited potential to accurately measure %BF compared to DXA, especially in individuals with higher body fat.

(S)-1-Methyl-2-oxoimidazolidine-4-carboxylic acid 1 is an analog of (S)-pyroglutamic acid, a key component of naturally occurring peptide hormones and synthetic pharmaceutical candidates. Reaction of (S)-2-amino-3-(methylamino)propionic acid with COCl2 and aqueous NaHCO3 followed by ion exchange afforded 1, which was recrystallized from acetonitrile and then characterized by IR, 1H NMR, 13C NMR, polarimetry, elemental microanalysis, high resolution mass spectrometry and single crystal X-ray diffraction. The acid 1 crystallized in the orthorhombic chiral space group P212121 with cell constants a = 6.2275(4) Å, b = 8.3963(5) Å, c = 24.9490(14) Å. The X-ray crystal structure reveals that two distinct conformers of 1 occur at alternating positions within helices which are supported by hydrogen-bonding. Each molecule of 1 is linked to its two neighbors in the helix by a total of three hydrogen bonds and four molecules of 1 are contained within each turn of the helix. The pattern of hydrogen bonds illustrates a preference for the carboxylic acid group to act as a hydrogen bond donor and for the urea unit to be a hydrogen bond acceptor.

The atomic structures of Zn and Na borophosphate glasses were studied by X-ray and neutron diffraction. Peaks assigned to the B−O, P−O, and O−O distances confirm that only BO4 units co-exist with the PO4 tetrahedra. The Zn−O and Na−O coordination numbers are found to be a little larger than four. The narrowest peaks of the Zn−O first-neighbor distances exist for the glasses along a line connecting the Zn(PO3)2 and BPO4 compositions (50 mol% P2O5) which is explained by networks of ZnO4, BO4, and PO4 tetrahedra with twofold coordinated oxygens. Calculated amounts of the available oxygen support this interpretation. Broadened peaks occur for glasses with lower P2O5 contents, consistent with the presence of threefold coordinated oxygens. The two distinct P−O peak components of the Zn and Na borophosphate glasses differ in their relative abundances which is interpreted by Na+ cations that coordinate oxygens in some P−O−B bridges, something not seen for the Zn2+ ions.

There are thousands of rare genetic diseases that could be treated with classical gene therapy strategies such as the addition of the defective gene via viral or non-viral delivery or by direct gene editing. However, several genetic defects are too complex for these approaches. These “genomic mutations” include aneuploidies, intra and inter chromosomal rearrangements, large deletions, or inversion and copy number variations. Chromosome Transplantation (CT) refers to the precise substitution of an endogenous chromosome with an exogenous one. By the addition of an exogenous chromosome and the concomitant elimination of the endogenous one, every genetic defect, irrespective of its nature, could be resolved. In the current review, we analyze the state of the art of this technique and discuss its possible application to human pathology. CT might not be limited to the treatment of human diseases. By working on sex chromosomes, we showed that female cells can be obtained from male cells, since chromosome-transplanted cells can lose either sex chromosome, giving rise to 46,XY or 46,XX diploid cells, a modification that could be exploited to obtain female gametes from male cells. Moreover, CT could be used in veterinary biology, since entire chromosomes containing an advantageous locus could be transferred to animals of zootechnical interest without altering their specific genetic background and the need for long and complex interbreeding. CT could also be useful to rescue extinct species if only male cells were available. Finally, the generation of “synthetic” cells could be achieved by repeated CT into a recipient cell. CT is an additional tool for genetic modification of mammalian cells.

Severe combined immunodeficiency disorders (SCID) are a genetically heterogeneous group of inherited defects characterized by severe abnormalities of immune system development and function that lead to a wide spectrum in clinical manifestations. A subgroup of patients presents a disabling and life-threatening clinical course. In these cases, allogeneic hematopoietic stem cell transplant provides a curative approach. The occurrence of SCID-associated lymphoproliferative disorders is rare and occur mostly in adenosine deaminase-deficient severe combined immunodeficiency disorders, after allogeneic hematopoietic stem cell transplant. Epstein Barr virus infection is present in the majority of individuals with primary immunodeficiency developing lymphoma, revealing compromised anti-tumour surveillance of virally transformed cells. Herein, we report a rare case of diffuse large B cell lymphoma occurring in an Epstein Barr virus negative, non-transplanted X-linked severe combined immunodeficiency 4-months-old infant, successfully treated with immunotherapy and allogeneic stem cell transplantation. This case suggests that Epstein Barr virus -independent mechanism of neoplastic transformation must take action in severe combined immunodeficiency associated lymphoma and unveils the curative potential of donor T cells after allogeneic transplantation.

In the context of high-temperature water vapor treatment, Zn-Mg-Al alloy-coated steel sheets exhibit the emergence of a black surface. This study aims to explore the factors and mechanisms contributing to surface blackening by inducing black surfaces on Zn-Mg-Al alloy-coated steel sheets, which were fabricated through molten coating subjected to water vapor treatment at 150 degrees Celsius. The surfaced composition was predominantly identified as ZnO, a zinc oxide film, validated through X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). Morphological analysis of the surface and cross-section post-water vapor treatment revealed a disrupted lamellar structure with diffused features, resulting in the formation of an oxide film. Optical properties analysis demonstrated an increased absorbance and a decreased bandgap energy after water vapor treatment, indicative of an augmented blackening effect. Consequently, the high-temperature water vapor treatment led to the formation of oxides on the surface, with the highly reactive Mg and Al extracting oxygen from the predominantly present ZnO surface. This process resulted in the creation of an oxygen-deficient oxide, ultimately causing surface blackening.

This study assessed the impacts of genotypes, environments, and their interaction on the performance of elite cowpea lines for key adaptive, grain yield, and associated traits across different locations. A total of 42 elite genotypes were evaluated in five Nigerian environments, representing various savanna ecologies during the 2021 growing season. The experimental design employed was an alpha lattice arrangement, replicating each genotype three times. The results revealed significant differences among genotypes, environments, and genotype-by-environment interaction for most traits, including days to maturity, 100 seed weight, and grain yield. GGE biplot showed G21 (IT14K-2111-2) and G25 (IT15K-2386-1) as the most stable genotypes across the five environments, G41(IT1K-61-82) was best adapted to Ibadan and Shika, G5 (245-1) was best adapted to Bagauda and Gumel while G30 (IT16K-2365-1) was best adapted to Bauchi. G21 and G25 could be recommended across the five test environments while G41, G30 and G5 are specific to the adapted environments.

Post-menopausal women are at risk of osteoporotic vertebral fractures (OVFs), which if undetected and untreated, can lead to significant pain and morbidity. However, OVFs are often not reported by radiologists on routine chest radiographs. Artificial Intelligence (AI) is increasingly used in medical applications with improvements in detection and diagnosis. This study aims to investigate the clinical value of a newly developed AI tool, Ofeye 1.0 for automated detection of OVFs on lateral chest radiographs in post-menopausal women (>60 years) who were referred to undergo chest x-rays for other reasons. A total of 510 de-identified lateral chest radiographs from three clinical sites were retrieved and analysed by Ofeye1.0 tool. These images were then reviewed by a consultant radiologist to decide whether there is any fracture present or not with findings served as the reference standard for determining the diagnostic performance of the AI tool. The percentage of radiologist reports which included the OVF was analysed by comparing diagnostic reports with AI findings, while the accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV) of the AI tool were calculated. Out of all the original radiologist reports, missed OVFs were found in 14% images but were detected by the AI tool. The AI tool demonstrated a relatively high specificity 92.8% (95% CI: 89.6, 95.2%), moderate accuracy 80.3% (95% CI: 76,3, 80.4%), PPV 73.7% (95% CI: 65.2, 80.8%) and NPV 81.5% (95%CI: 79, 83.8%), but low sensitivity 49% (95%CI: 40.7, 57.3%). The high false negative results were mainly due to mild OVFs with <20% vertebral height loss. The new AI software tool has high specificity with a low false positive rate of 5.1%, showing that it can be used as a complimentary tool to the routine diagnostic reports for reduction of missed OVF in elderly women. The low sensitivity with high false negative rates indicate the necessity of radiologist’s in identifying and reporting early OVFs.

A digital twin is a virtual representation that serves as the real-time digital counterpart of a physical object or system. Recent advancements have extended the concept of digital twins to humans, incorporating complex biological data such as DNA (Predictiv Care, Inc.) and immune system profiles. These sophisticated models go beyond mere pictorial representations, offering a more holistic digital reflection. However, a significant gap remains. The current human digital twin models are not capable of learning one’s preferences. In this pilot study, we introduce Diginality, a chatbot powered by HyperCLOVA X, a Large Language Model (LLM) developed by NAVER, Inc. Diginality, learns one’s preferences with custom training from data collected by interview-style questions on the user’s topic of interest. Our findings demonstrate that Diginality successfully answers one’s preferences, thereby adding a new dimension to the concept of human digital twins. This work represents a pioneering step towards creating a more comprehensive and psychologically nuanced human digital twin.

Edward syndrome, clinically known as trisomy 18 syndrome, is an autosomal chromosomal disorder characterized by an extra copy of chromosome 18. It belongs to the category of autosomal trisomy syndromes and is the second most common, with trisomy 21 being the only more frequent occurrence. In the context of this research, we present a case study focusing on a 3-month-old female infant admitted to the emergency department due to a complex array of symptoms. The primary clinical manifestations included a persistent cough, cold, and fever lasting for eight consecutive days. Comprehensive clinical evaluations, encompassing radiological and hematological investigations, confirmed the diagnosis of bronchiolitis along with viral bronchopneumonia. Chest X-rays revealed bilateral patchy opacities and diffuse haziness, primarily concentrated in the right hemithorax. Beyond respiratory issues, the infant displayed a range of distinctive physical attributes, including low-set ears, micrognathia, cranial anomalies, flattened nasal bridge, widely spaced nipples, overlapping fingers, abdominal distention, rocker-bottom feet, and recurring limb deformities known as recurvatum. Attempts to correct the limb deformity with a hip spica cast over an extended month-long period proved unsuccessful. Chronic villus sampling (CVS) ultimately confirmed the presence of Edward Syndrome (Trisomy 18), linked to the extra chromosome 18, leading to diverse physiological and developmental abnormalities. This case underscores the critical importance of timely and precise diagnosis, highlighting the challenges involved in addressing complex medical conditions marked by multifaceted clinical phenotypes.

We have recently introduced the possibility of performing operando small-angle X-ray scattering measurements using a novel industrially relevant injection moulding system for plastics. We show that useful time-resolving measurements can be performed with a time-cycle of 1s and we highlight the possible steps to reduce this to 0.5s. We show how we can use the transmission measurements to provide a time-marker when plastic first enters the mould cavity in the region probed by the incident X-ray beam. We show the opportunities provided by this experimental stage mounted on the NCD-SWEET beamline at ALBA to probe the reproducibility of the injection moulding system on different scales. The design of the equipment allows the development of the structure and the morphology to be evaluated in different parts of mould cavity and we evaluate any differences in a rectangular mould cavity. We identify future prospects for this equipment in terms of novel mould heating and cooling systems and the opportunities for quantitatively evaluating radical approaches to injection moulding technology.

The pulse duration in short-pulse schemes for Self-Amplified Spontaneous Emission Free Electron Lasers (SASE FELs) is limited by the FEL coherence time. A recently proposed concept allows to overcome the coherence time barrier and to get much shorter pulses. When the lasing part of an electron bunch is much shorter than the coherence time, one can suppress the radiation in the long main undulator while preserving microbunching within that short lasing slice. Then a short radiation pulse is produced in a relatively short radiator. A possible suppression method, an excessive reverse undulator taper, is discussed and illustrated numerically in this paper. We also performed first experimental tests of this method at the soft X-ray FEL user facility FLASH. The measured pulse duration approaches 1 fs (FWHM) at the wavelength of 5 nm.

The current systematic review examines whether there is an association between the genetic 5-HTTPLR pol-ymorphism and parenting and the mechanisms by which this association operates. The literature was searched in various databases such as PubMed, Scopus and ScienceDirect. In line with our inclusion criteria, nine articles were eligible out of 22. Most of the studies, analysed in this review, found an association between 5HTTLPR and parenting. Four studies found a direct association between 5-HTTLPR and parenting with conflicting findings: two studies found that mothers carrying the short variant were more sensitive to their infants, while two studies found that parents carrying the S allele were less sensitive. In addition, several studies found strong interaction between genetic and environmental factors, such as childhood stress and disruptive child behaviour, quality of early care experiences, poor parenting environment, and quality of environment. Only one study found an association between children’s 5HTTLPR and parenting. Parenting can be described as a highly complex construct influenced by multiple factors, including environmental, parenting and child charac-teristics. According to the studies, maternal 5-HTTLPR polymorphism is most likely associated with sensitive parenting.

Men are more likely to develop cancer than women. In fact, male predominance is one of the most consistent cancer epidemiology findings. Additionally, men have a poorer prognosis and an increased risk of secondary malignancies compared to women. These differences have been investigated in order to better understand cancer and to better treat both men and women. In this review, we discuss factors that may cause this gender difference, focusing on urothelial bladder cancer (UBC) pathogenesis. We consider physiological factors that may cause higher male cancer rates, including differences in X chromosome gene expression. We discuss how androgens may promote bladder cancer development directly by stimulating bladder urothelium and indirectly by suppressing immunity. We are particularly interested in natural killer (NK) cells because they are important, but often overlooked anti-cancer lymphocytes.

We addressed the frequent occurrence of mixed-chain lipids in biological membranes and their impact on membrane structure by studying several chain-asymmetric phosphatidylcholines and the highly asymmetric milk sphingomyelin. Specifically, we report trans-membrane structures of the corresponding fluid lamellar phases using small-angle X-ray and neutron scattering, which were jointly analyzed in terms of a membrane composition-specific model, including a headgroup hydration shell. Focusing on terminal methyl groups at the bilayer center we found a linear relation between hydrocarbon chain length mismatch and the methyl-overlap for phosphatidylcholines, and a non-negligible impact of the glycerol backbone-tilting, letting the sn1-chain penetrate deeper into the opposing leaflet by half a CH2 group. That is, penetration-depth differences due to the ester-linked hydrocarbons at the glycerol backbone, reported previously for gel phase structures also extend to the physiological more relevant fluid phase, but are significantly reduced. Moreover, milk sphingomyelin was found to follow the same linear relationship suggesting a similar tilt of the sphingosine backbone. Complementary performed molecular dynamics simulations revealed that there is always a part of the lipid tails bending back, even if there is a high interdigitation with the opposing chains. This suggests that hydrocarbon chain interdigitation plays only a minor role in transbilayer coupling. For both cases of adaption to chain length mismatch, chain-asymmetry has a large impact on hydrocarbon chain ordering, inducing disorder in the longer of the two hydrocarbons.

The authors present a stereotypical case presentation of x-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact Fibroblast Growth Factor 23 (FGF23) which lead to i) low serum phosphate levels, ii) increased fractional excretion of phosphorus, and iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in XLH patients is due to chronic hypophosphatemia. Additionally, XLH patients experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration’s (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.

Maghemite (γ-Fe2O3) is a mineral formed from magnetite oxidation at low temperatures, an intermediate metastable term of the magnetite to hematite oxidation and could be mixed with both. It has magnetic susceptibility similar to magnetite, crystal structure close to magnetite with which it forms a solid solution, while compositionally it equals hematite. Maghemite is thus easily misidentified as magnetite by X-ray diffraction and/or as hematite by spot chemical analysis in iron ore characterization routines. Nonstoichiometric magnetite could be quantified in samples of Brazilian soils and iron ores by the Rietveld method using a constrained refinement of the X-ray patterns. The results were confirmed by reflected light microscopy and Raman spectroscopy, thus qualitatively validating the method. X-ray diffraction with the refinement of the isomorphic substitution of Fe2+ by Fe3+ along the magnetite-maghemite solid solution could help to suitably characterize maghemite in iron ores, allowing for the evaluation of its ultimate influence on mineral processing, by affecting its surface and breakage properties.

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception, in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome.

To ensure the safety in aircraft flying, we aim use of the deep learning methods of nondestructive examination with multiple defect detection paradigms for X-ray image detection posed. The use of the Fast Region-based Convolutional Neural Networks (Fast R-CNN) driven model seeks to augment and improve existing automated Non-Destructive Testing (NDT) diagnosis. Within the context of X-ray screening, limited numbers insufficient types of X-ray aeronautics engine defect data samples can thus pose another problem in training model tackling multiple detections perform accuracy. To overcome this issue, we employ a deep learning paradigm of transfer learning tackling both single and multiple detection. Overall the achieve result get more then 90% accuracy based on the AE-RTISNet retrained with 8 types of defect detection. Caffe structure software to make networks tracking detection over multiples Fast R-CNN. We consider the AE-RTISNet provide best results to the more traditional multiple Fast R-CNN approaches simpler translate to C++ code and installed in the Jetson™ TX2 embedded computer. With the use of LMDB format, all images using input images of size 640 × 480 pixel. The results scope achieves 0.9 mean average precision (mAP) on 8 types of material defect classifiers problem and requires approximately 100 microseconds.

ZnS-CdS composite nano-powder doped with (0.01 mol %) Cobalt has been collected by a co-precipitation process at 300 K. The sample is characterized by structural, combined spectroscopic methods and magnetic studies. The prepared samples were belonging to cubic structure no impurity phases were observed. Doping of cobalt increase the neighborhood strain assessment and a decreases lattice constants decides from x-ray diffraction data. The crystallite size is 10.42nm. From UV-absorption and EPR studies revealed that the energy band gap of Co2+ doped ZnS-CdS composite nanopowder and extension of sp-d exchange interactions and common d-d transitions. The variation in the energy bandgap varies as a function of cobalt concentration is due to structural modification. Photoluminescence spectrum reveals the defect-related emissions and shows the formation of luminescence. FT-IR spectrum confirmed the feature vibrational manner of Zn, Cd, O–H and sulfide ions are in the host lattice. The doping-induced magnetic properties are studied by vibrating sample magnetometer which matches with the theoretical values besides ferromagnetic nature. Magnetic studies confirm the ferromagnetic nature of the material. Surface morphology and chemical homogeneity studies were carried out by using SEM with EDAX. Transmission electron microscope recommends the crystalline nature of nanoparticles, with average particle size is of the order of 20-100nm.

In this work, the structural, magnetic, and mechanical properties of Nd16Fe76-xCoxB8 alloys varying the Co content at x = 0, 10, 20 and 25, were experimentally investigated by X-Ray Diffraction (XRD), Mössbauer Spectrometry (MS), Vibrating Sample Magnetometry (VSM) at room temperature (RT), and microhardness test were performed too. The system presents the hard Nd2Fe14B and the Nd1.1Fe4B4 phases for samples with x = 0 and 10. When concentration increases to x= 20 and 25, the CoO phase appears. All MS show the ferromagnetic behavior (eight sextets: sites 16k1, 16k2, 8j1, 8j2, 4c, 4e, sb) associated to the hard and soft magnetic phases, and one paramagnetic component (doublet: site d) associated to the minority Nd1.1Fe4B4 phase, which was not identified by XRD. All samples are magnetically hard present a hard magnetic behavior. The increase of Co content in these samples did not improve the hard magnetic behavior, but increased the critical temperature of the system and decrease the crystallite size of the hard phase. The hysteresis loop showed that predominates the Nd2Fe14B hard magnetic phase. There is a general tendency to increase microhardness with cobalt content, attributable to cobalt doping reduces the lattice parameters and porosities in the sample improving it hardness.

Air filtration mechanisms in the composite filter media used in practical applications are important and challenging to understand because the component fibers could have various size scales and morphologies. In this work, a three-dimensional digital model of nanofiber-based filter media was reconstructed for the first time based on the X-ray tomography data for the cellulose substrate and the Focused Ion Beam-Scanning Electron Microscope (FIB-SEM) image analysis for the several microns thick (3.82-7.90 μm) electrospun polyvinylidene fluoride (PVDF) nanofiber membrane. Besides the high-resolution model where the details of the fibrous structures were fully resolved, another low-resolution model with approximated unresolved structures was also established. Filtration simulations utilizing these models were conducted considering the drag force, Brownian diffusion and aerodynamic slip. The simulated filtration efficiencies agreed well with the experiments for particles of 70-400 nm, including the most penetrating particle size (MPPS, 100-200 nm). Moreover, the structure-resolved models had higher accuracy but higher computational costs, while the unresolved simulations saved much running time but over-predicted the filtration efficiency, especially for smaller particles (<100 nm). Our study presents a comprehensive strategy for investigating the composite filter media with multiscale complex structures using a combination of advanced characterization technologies and modular simulation models.

The aim of this study was to clarify degradation characteristics in each tissue of the knee complex of a medial meniscectomy (MMx)-induced knee osteoarthritis (KOA) animal model using classical methods and a new comprehensive evaluation method called contrast-enhanced X-ray micro-computed tomography (CEX-μCT), which was developed in the study. Surgical MMx was performed in the right knee joints of five male Wistar rats to induce KOA. At 4 wk post-surgery, the synovitis was evaluated using qPCR. Degradations of the articular cartilage of the tibial plateau were evaluated using classical methods and CEX-μCT. Evaluation of the synovitis demonstrated significantly increased expression levels of inflammation-associated marker genes in MMx-treated knees compared to that in sham-treated knees. Evaluation of the articular cartilage using classical methods showed that MMx fully induced degradation of the cartilage. Evaluation using CEX-μCT showed that local areas of the medial cartilage of the tibial plateau were significantly reduced in MMx-treated knees compared to that in sham-treated knees. On the other hand, total cartilage volumes were significantly increased in MMx-treated knees. Based on the findings of this study, the researchers in KOA research could be helped to select an optimal KOA model to discover new drugs.

Contrary to optical images, Synthetic Aperture Radar (SAR) images are in different electromagnetic spectrum where the human visual system is not accustomed to. Thus, with more and more SAR applications, the demand for enhanced high-quality SAR images has increased considerably. However, high-quality SAR images entail high costs due to the limitations of current SAR devices and their image processing resources. To improve the quality of SAR images and to reduce the costs of their generation, we propose a Dialectical Generative Adversarial Network (Dialectical GAN) to generate high-quality SAR images. This method is based on the analysis of hierarchical SAR information and the “dialectical” structure of GAN frameworks. As a demonstration, a typical example will be shown where a low-resolution SAR image (e.g., a Sentinel-1 image) with large ground coverage is translated into a high-resolution SAR image (e.g., a TerraSAR-X image). Three traditional algorithms are compared, and a new algorithm is proposed based on a network framework by combining conditional WGAN-GP (Wasserstein Generative Adversarial Network - Gradient Penalty) loss functions and Spatial Gram matrices under the rule of dialectics. Experimental results show that the SAR image translation works very well when we compare the results of our proposed method with the selected traditional methods.

Herein, we present preparation of solid polymer electrolyte (SPE) comprising of PEO, NaPF₆ and varying fraction of Succinonitrile (SN) by standard solution cast technique. The morphological features and structural properties were studied by the FESEM, XRD, respectively. FTIR was performed to study the interactions between polymer host, salt, and SN. Impedance spectroscopy, Transference number measurements, LSV and CV were used to examine the electrochemical properties. The complex permittivity/conductivity & modulus were studied to understand the dielectric properties by evaluating the dielectric strength, relaxation time, hopping frequency and dc conductivity. Based on the experimental results an interaction mechanism is presented.

Retinoid X receptor (RXR) antagonists are not only useful as chemical tools for biological research, but also are candidate drugs for treatment of various diseases, including diabetes and allergy, although no RXR antagonist has yet been approved for clinical use. In this review, we describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research.

In order to enhance the accuracy of the relative velocity measurement for the Mars explorer formation flight, we develop a relative velocity measurement method. In this method, the spectrometers at two Mars explorers are adopted to measure the starlight frequency shift and to estimate the velocity with respect to the star. Unfortunately, the instantaneous velocity of star can not be predicted accurately, which results in a large error in the velocity measurement. The difference of these two velocities, which does not include the proper motion of star, is the relative velocity between a pair of Mars explorers at the direction of the star. However, this navigation method can not work alone because of unobservability. To make the navigation system observable and improve the accuracy of both absolute and relative navigation for the Mars explorer formation flight, we combine it with X-ray pulsar navigation and the inter-satellite links, and propose an autonomous integrated navigation method with observability. In this integrated navigation scheme, the extended Kalman filter is adopted to deal with the relative velocity, the inter-satellite links and the pulse time-of-arrival, and estimate the absolute and relative navigation information for the Mars explorer formation flight. The simulation results demonstrate that both absolute and relative navigation accuracy of the proposed method are higher than that of the pulsar navigation, especially the relative one.

Fragile X syndrome (FXS) is the most frequent monogenic form of autism spectrum disorder (ASD). Autistic FXS is caused by loss of the fmr1 gene product, the fragile X mental retardation protein (FMRP), triggering physiological and behavioral abnormalities. It is correlated with clock components for behavioral circadian rhythm. Mutation of this gene causes the disturbances in sleep patterns and circadian behavior commonly observed in patients with autistic FXS, accompanied by frequent dysregulation of melatonin synthesis and melatonin-dependent signaling. These changes impair vigilance, learning and memory, and are also linked to autistic behavior including the abnormal anxiety response. However, although several possible causes, symptoms, and clinical features of ASD have been investigated, the correlation between an altered circadian rhythm and autistic FXS has not been extensively studied. Recent works have highlighted the impact of melatonin on the nervous, immune, and metabolic systems. Even though utilization of melatonin for sleep disorder in ASD has been considered in clinical research, further studies should be aimed at its neuroprotective role in ASD during developmental period. In this review, we focus on the regulatory circuits involved in melatonin dysregulation and circadian system disruption in those with autistic FXS. Additionally, we discuss the neuroprotective effect of melatonin intervention. This may improve neuroplasticity and physical capability. We also review the underlying molecular mechanisms, and suggest that melatonin may be a useful novel treatment for autistic FXS, countering the adverse effects of circadian variation.

The objective of this study was to investigate the concentration and spatial distribution patterns of six potentially toxic heavy metal elements (Mn, Zn, Cr, Pb, Cu and Ni) in bus station dusts in the Xifeng district of Gansu province, NW China. The contents were analyzed for Mn, Zn, Cr, Pb, Cu and Ni by using S8 TIGER Brochures wavelength dispersive X-ray fluorescence spectrometry. Geoaccumulation index (Igeo ), enrichment factor (EF), pollution index (PI) and integrated pollution index(IPI) were calculated to evaluate the heavy metal contamination level of bus station dusts. The results indicate that, in comparison with the background values of local soil, bus station dusts in Xifeng have elevated metal concentrations as a whole. The concentrations of heavy metals investigated in this paper are compared with the reported data of other cities. The results show that the arithmetic means of Mn, Zn, Cr, Pb, Cu and Ni are 440.8, 137.9, 60.0, 42.8, 33.5 and 19.8mg kg−1 respectively. The mean values of Igeo reveal the order of Ni<Mn<Cr<Cu<Zn<Pb. The high Igeo and EF for Cu, Zn and Pb in bus station dusts indicate that there is a considerable Cu, Zn and Pb pollution, which mainly originate from traffic and industry activities. The Igeo and EF of Ni, Mn and Cr are low and the assessment results indicate an absence of distinct Ni, Mn and Cr pollution in bus station dusts. The assessment results of PI also support Cu, Zn and Pb in bus station dusts presented middle pollution, and IPI indicates heavy metals of bus station dusts polluted seriously.

We have previously demonstrated that receptor-interacting serine threonine kinase 1 (RIPK1) is expressed in hair follicle and regulates hair cycle. RIPK1 inhibitors also accelerated the telogen-to-anagen transition and elongated the anagen period in the mouse model. Here, we first investigated the involvement of RIPK1 in alopecia areata (AA). mRNA and protein expression of RIPK1 was increased in the skin of AA mouse model. Single cell RNA sequencing and immunohistochemistry showed that RIPK1 is highly increased in dendritic cells (DCs) and CD8+ T cells. RIPK1 inhibitors (i.e., Necrostatin-1s and GSK2982772) delayed the onset of AA in mouse model, and reduced the DCs and CD8+ T cells in AA skin. RIPK1 inhibitors also increased the hair length in the mouse hair organ culture mimicking AA. Collectively, these results suggest that RIPK1 is involved in AA onset via modulating immune cells, and RIPK1 inhibitors could prevent AA onset.

We developed a protein to rapidly and accurately diagnose Chagas disease, a life-threatening illness identified by the WHO as a critical worldwide public health risk. Complicating the current health situation are serological test limitations that contribute to most infected persons being unaware of their condition and therefore untreated. To improve diagnostic testing, we developed an immunological mimic of the etiological agent, Trypanosoma cruzi, by combining ten pathogen specific epitopes within the beta-barrel protein structure of Thermal Green Protein. The resulting multi-epitope protein, DxCruziV3, displayed high specificity and sensitivity as the antibody capture reagent in an ELISA platform with an analytical sensitivity that exceeds WHO recommendations. Within an immunochromatographic platform, DxCruziV3 showed excellent performance for the point of application diagnosis in a region endemic for multiple diseases, the municipality of Barcelos in the state of Amazonas, Brazil. In total, 167 individuals were rapidly tested using whole blood from a finger stick. As recommended by the Brazilian Ministry of Health, venous blood samples were laboratory tested by conventional assays for comparison. Test results suggest utilizing DxCruziV3 in different assay platforms can confidently diagnosis chronic infections by T. cruzi. Rapid and more accurate results will benefit everyone but will have the most noticeable impact in resource-limited rural areas where the disease is endemic.

Because we observed a reduced humoral immune response to the COVID-19 vaccine and subsequently discovered a lower susceptibility to COVID-19 in individuals carrying the ALDH2 rs671 variant, we hypothesized that rs671 is beneficial for cellular immunity against COVID-19. Using the IFN-γ enzyme-linked immunospot (ELISPOT) assay, we evaluated cellular immunity before and after COVID-19 vaccination in two subcohorts of a previously reported cohort. Subcohort 1 (26 participants) had six repeated observations at baseline and after one to three doses, whereas subcohort 2 (19 participants) had two observations, before and after the third dose. ELISPOT counts at six months after the second dose increased from baseline in carriers of the rs671 variant, but not in non-carriers. A positive effect of rs671 on ELISPOT counts was estimated using a mixed model, including the random effect of subcohort, repeated measures, and fixed effects of vaccine type, age, sex, height, lifestyle, steroid use, and allergic disease. There was no association between ELISPOT counts and specific IgG levels, suggesting a limitation in estimating protective potential by humoral response. There is lower humoral and higher cellular immunity against SARS-CoV-2 in rs671 variant carriers compared to non-carriers, providing a potential basis for optimizing preventive measures and drug discovery.

Infection with the Chikungunya virus (CHIKV) manifests as a febrile illness known as chikungunya fever (CHIKF). CHIKF is characterized by sudden-onset high fever, rash, polyarthritis, and polyarthralgia. Alt-hough the infection typically resolves within two weeks, many patients experience recurrent joint pain and inflammation that can outlast the other symptoms for many months. CHIKF has been previously linked to rheumatoid arthritis (RA) due to similar inflammatory processes. This study aimed to identify molecular markers in the blood of CHIKV-infected individuals associated with joint pain and chronicity of CHIKF. Sequencing of B and T cell receptors (BCR and TCR) revealed that CHIKV infection reduces CDR3 diver-sity. Lower BCR diversity was linked to increased expression of genes involved in osteoclast differentiation and activation through RANK/RANKL signaling. If osteoclast involvement in CHIKF pathogenesis is con-firmed, existing therapeutic approaches could be used as alternative treatments for CHIKF patients.

Multiple sclerosis is an autoinflammatory condition that results in damage of myelinated neurons in affected patients. While disease-modifying treatments have been successful in slowing the progression of relapsing remittent disease, most patients still progress to secondary progressive disease that is largely unresponsive to disease-modifying treatments. Similarly, there is currently no effective treatment for patients with primary progressive MS. Innate and adaptive immune cells in the CNS play a critical role in initiating an autoimmune attack and in maintaining the chronic inflammation that drives disease progression. In this review, we will focus on recent insights into the role of T cells with regulatory function in suppressing the progression of MS, and, more importantly, in promoting the remyelination and repair of MS lesions in the CNS. We will discuss the exciting opportunity to genetically reprogram regulatory T cells to achieve immune suppression and enhance repair locally at sites of tissue damage, while retaining a fully competent immune system outside the CNS. In the future, reprogramed regulatory T cells with defined specificity and function may provide life medicines that can persist in patients and achieve lasting disease suppression after one cycle of treatment.

Chimeric antigen receptor (CAR) T-cell therapy has greatly improved outcomes for patients with relapsed or refractory hematological malignancies. However, challenges such as treatment resistance, relapse, and severe toxicity still hinder its widespread clinical application. Traditional transcriptome analysis has provided limited insights into the complex transcriptional landscape of both leukemia cells and engineered CAR-T cells, as well as their interactions within the tumor microenvironment. However, with the advent of single-cell sequencing techniques, a paradigm shift has occurred, providing robust tools to unravel the complexities of these factors. These techniques enable unbiased analysis of cellular heterogeneity and molecular patterns. These insights are invaluable for precise receptor design, guiding gene-based T cell modification, and optimizing manufacturing conditions. Consequently, this review utilizes modern single-cell sequencing techniques to clarify the transcriptional intricacies of leukemia cells and CAR-Ts. The aim of this manuscript is to discuss the potential mechanisms that contribute to the clinical failures of CAR-T immunotherapy. We will examine the biological characteristics of CAR-Ts, the mechanisms that govern clinical responses, and the intricacies of adverse events. By exploring these aspects, we hope to gain a deeper understanding of CAR-T therapy, which will ultimately lead to improved clinical outcomes and broader therapeutic applications.

Trypanosomosis is a global animal issue, causing significant economic losses, particularly in Africa. In Spain, only one pathogenic species, Trypanosoma evansi, has been identified so far. It was first detected in a dromedary camel in the Canary Islands in 1997. Since then, numerous cases of the disease, known as surra, have been diagnosed, prompting various studies and efforts in control and surveillance. Given the lack of a comprehensive database that consolidates the most relevant data in this area, the development of a national atlas, with focus on the Canary Islands, to incorporate all available information on T. evansi in Spain became a necessity. For the development of the atlas, a repository was constructed, encompassing a range of datasets and documents spanning from 1997 to 2022. Information from each source, and in particular georeferenced locations and results of blood tests on animals, were extracted and integrated into a comprehensive database. A total of 31 sources were analysed, providing a total of 99 georeferenced locations and 12,433 animal samples. Out of these samples, 601 (mostly from dromedaries) were found to be positive for T. evansi. The Card Agglutination Test for T. evansi (CATT/T. evansi), a serological test, was the most commonly used diagnostic method, and it showed higher prevalence for all tested animal species. Positive cases were mainly concentrated in the Canary Islands, specifically in the eastern islands, with isolated cases found in the province of Alicante (Iberian Peninsula). This atlas provides an overview of the history and occurrence of surra in Spain, and it represents a valuable tool for future control initiatives and for research. Still, the need for more studies remains, especially for further testing of potential hosts other than camelids and for the examination of their potential transmission vectors.

Mesothelioma is a cancer arising from mesothelial cells lining the thoracic (pleura) or the abdominal (peritoneum) cavities, and more rarely from transformed mesothelial cells of pericardium or tunica vaginalis testis. The development of mesothelioma has been related to the exposure to carcinogenic mineral fibers, mainly asbestos. Malignant mesothelioma is an aggressive disease with diffuse nature, low median survival, and prolonged latency presenting difficulty in prognosis, diagnosis, and treatment. We here review all these aspects to underline the progress being made in investigation and to emphasise how much work remains to be done to improve prognosis and treatment.

The new class of mRNA vaccines is studied extensively, leading to many novel prospects based on the pivotal success of vaccines against the SARS-Cov-2 virus. Many novel mechanisms of immune response discovered have led to the possibility of mutation-resistant vaccines by combining multiple conserved epitopes as antigens to manipulate the T-cell and B-cell responses; these antigens can also come from different organisms, providing protection against numerous diseases and of most tremendous significance is the utility of mRNA vaccines in preventing and treating more than 100 autoimmune disorders. This is a significant humanitarian breakthrough given the ease and faster and low cost of mRNA vaccines, being a chemical entity. This paper provides a prospective analysis of mRNA vaccines with much broader applications than anticipated when these vaccines entered treating SARS-Cov-2 infections.

The human T-cell leukemia virus type 1 (HTLV-1) is the only known human oncogenic retrovirus. HTLV-1 can cause a cancer called adult T-cell leukemia/lymphoma (ATL). The virus is transmitted through body fluids of infected individuals, primarily breast milk, blood, and semen. At least 5–10 million people in the world are infected with HTLV-1. In addition to ATL, HTLV-1 infection can also cause HTLV-I-associated myelopathy (HAM /TSP). ATL is characterized by low viral ex-pression and poor prognosis. The oncogenesis triggered by HTLV-1 is extremely complex and the molecular mechanisms are not fully understood. However, viral regulatory proteins Tax and HTLV-1 bZIP factor (HBZ) have been shown to play key roles in the transformation of HTLV-1-infected T cells. Moreover, several studies have shown that the final fate of HTLV-1-infected transformed T cell clones is the result of a complex interplay of HTLV-1 oncogenic protein expression with cellular transcription factors that subvert the cell cycle and disrupt reg-ulated cell death, thereby exerting their transforming effects. This review provides updated in-formation on the mechanisms underlying the transforming action of HTLV-1 and the potential therapeutic targets to combat ATL.

Environmental concerns, among other causes, are leading to meat replacement in the diet by healthy, nutritious and tasty foods. Alternative protein sources of plant origin can be an alternative to meat, but their low biological value proteins can be a problem. Novel foods, such as insect meals, can meet currently consumer demands. Therefore, this research has developed innovative prototypes of analogue burgers with animal and vegetable proteins. Concerned about health and allergies, a prototype incorporating soya to satisfy coeliacs was developed. An iterative and heuristic process was carried out to test the product development feasibility. The main raw materials used were insect flour (Tenebrio molitor), seitan and soya. In addition, oat and sodium alginate were used as binders. Shelf-life of the new product was evaluated by physicochemical (pH, aw, moisture, colour, acidity and peroxide index) and sensory analysis (quantitative analysis -QDA-). The production of the burger analogues was feasible. Product characterisation showed significant differences (p < 0.05) among samples for organoleptic properties, highlighting texture changes. Using a multivariate model, it was established “The best before date” at 7 days for all developed prototypes, conditioned by microbial growth. Finally, the spoilage model indicated an important contribution to bacterial growth with a notable modification in the pastiness and hardness of the burger analogues developed.

Current COVID-19 vaccines can effectively reduce disease severity and hospitalisation; however, they are not considerably effective in preventing infection and transmission. In this context, mucosal vaccines are pertinent to prevent SARS-CoV-2 infection and spread. In this study, we generated a replication-competent recombinant chimeric influenza A virus (IAV) expressing the receptor-binding domain (RBD) of SARS-CoV-2 prototype in the C-terminus of the neuraminidase (NA) of A/Puerto Rico/08/1934 H1N1 (PR8). The remaining seven segments from A/WSN/1933 H1N1 (WSN) were named PR8NARBD/WSN. We observed that the recombinant virus with the WSN backbone demonstrated improved expression of NA and RBD. A single intranasal dose of PR8NARBD/WSN in mice generated robust mucosal immunity, neutralising antibodies, cellular immunity, and tissue-resident memory T cells specific to SARS-CoV-2 and IAV. Importantly, immunisation with PR8NARBD/WSN viruses effectively protected mice against lethal challenges with H1N1, H3N2 IAV, and SARS-CoV-2 Beta variant and significantly reduced lung viral loads. Overall, our research demonstrates the promising potential of PR8NARBD/WSN as an attractive vaccine against emerging SARS-CoV-2 variants and influenza A virus infections.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 enters the host by infecting nasal ciliated cells. Then, the virus can spread towards the oropharyngeal cavity and the pulmonary tissues. The antiviral adaptive immunity is promptly induced in response to virus detection, with virus-specific T lymphocytes appearing before antiviral antibodies. Both breadth and potency of the antiviral CD8+ T cell immunity have a key role in containing viral spread and disease severity. Current anti-SARS-CoV-2 vaccines do not impede the virus replication in the upper respiratory tract, and there is consensus on the fact that the best potency of the antiviral immune response in both blood and upper respiratory tract can be reached upon infection in vaccinees (i.e., breakthrough infection). However, whether the antiviral CD8+ T cells developing in response to the breakthrough infection in the upper respiratory tract diffuse to the lungs also is still largely unknown. To fill the gap, we checked the CD8+ T cell immunity elicited after infection of K18-hACE2 transgenic mice both 3 weeks and 3 months after anti-Spike vaccination. The virus-specific CD8+ T cell immunity was monitored in both blood and the lungs before and after infection. By investigating the de novo generation of CD8+ T cells specific for SARS-CoV-2 viral proteins, we found that both membrane (M) and/or nucleocapsid (N)-specific CD8+ T cells were induced at comparable levels in blood of both unvaccinated and vaccinated mice. Conversely, N-specific CD8+ T cells were readily found in the lungs of control mice, but were either rare or absent in those of vaccinated mice. These results support the idea that the hybrid cell immunity developing after asymptomatic/mild breakthrough infection strengthens the antiviral cell immunity at lungs only marginally, implying that the direct exposition of the viral antigens is required for the induction of an efficient antiviral cell immunity in the lungs.

COVID-19, the infectious disease caused by SARS-CoV-2, has spread on a pandemic scale. The virus infection can evolve asymptomatically or generate severe symptoms, influenced by the presence of comorbidities. Lymphopenia in patients affected with COVID-19 according to the severity of symptoms is frequent. However, the profile of CD4+ and CD8+ T-cells regarding cytotoxicity and antiviral factor expression has not yet been completely elucidated in acute SARS-CoV-2 infections. The purpose of this study is to evaluate the phenotypic and functional profile of T-lymphocytes in patients with moderate and severe/critical COVID-19. During this pandemic period, we analyzed a cohort of 62 confirmed patients with SARS-CoV-2 (22 moderate cases and 40 severe/critical cases). Albeit lymphopenia, we observed an increase in the expression of CD28, co-stimulator molecule, and activation markers (CD38 and HLA-DR) in T-lymphocytes as well as an increase in the frequency of CD4+ T-cells, CD8+ T-cells, and NK cells that express the immunological checkpoint protein, PD-1, in patients with severe/critical condition compared to healthy controls. Regarding the cytotoxic profile of peripheral blood mononuclear cells, an increase in the response of CD4+ T-cells already at baseline level was observed, scarcely changed upon PMA and Ionomycin stimulation. Meanwhile, CD8+ T-lymphocytes decreased cytotoxic response, evidencing a profile of exhaustion in patients with severe COVID-19. As observed in the t-SNE technique CD4+ T-cytotoxic and CD8+ T with low granzyme production evidencing their dysfunctionality in severe/critical conditions. In addition, purified CD8+ T-lymphocytes from patients with severe COVID-19 showed an increased constitutive expression of differentially expressed genes associated with the caspase pathway, inflammasome, and antiviral factors, and curiously, reduced expression of TNF-α. The cytotoxic profile, by CD4+ T-cells, may compensate for the dysfunction/exhaustion of TCD8+ in acute SARS-CoV-2 infection. These findings may provide an understanding of the interplay of cytotoxicity between CD4+ T-cells and CD8+ T-cells in the severity of acute COVID-19 infection.

Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM. BCMA is primarily produced on mature B cells. Its up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell treatments, ADCs, bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.

Visceral Leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we have designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from 3 previously identified antigen genes of Leishmania donovani from our lab, by immune-informatic approach using IFNepiotpe, NET-MHC-1 and NET MHC-2 webservers. We have tested the protective potential of these three multiepitope proteins as vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th-1 biased protective immune response in-vivo in a hamster model of experimental visceral Leishmaniasis, with one of the candidates inducing a sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of designed candidates.

The analytical method for the calculation of the properties of a bolted connection established by the structural Eurocodes proposes the T-stub as a component for the characterization of the tension and compression zones in moment joints. In this article, a review of the state of the art on the T-stub component is developed, where the works developed since it was initially defined, and from the perspectives of formulation, experimentation and numerical simulation are summarized and discussed. Additionally, possible future lines of work are proposed.

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells and CAR T cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T cells and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load and tumor burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.

The mechanisms involved in immune responses to cancer have been extensively studied for several decades and, considerable attention has been paid to harnessing the immune system's therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell-cancer therapy and immune test therapy have gained prominence through immunotherapy. However, it remains to be accomplished the full potential of cancer immunotherapy. In spite of having startling aspects, the cancer immunotherapies have some difficulties including the inability to effectively targeting the cancer antigens and the abnormalities in patient response. With the advancement of technology, this system has changed the genome-based immunotherapy process in the human body including generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome-editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR-T cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR-T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against the cancer. In this review, we have broadly focused on the use of CRISPR-Cas9 technology for the modification of the T-cell, which can specifically recognize cancer cells and be used as immune therapeutics against cancer. We have also demonstrated the other potential strategies for the treatment of cancer.

Wheat is one of the global strategic crops and ranks third in terms of cereals production. Wheat crop is exposed to many fungal infections during the cultivation stages, some of which have the ability to secrete numbers of toxic secondary metabolites that threaten the quality of grains, consumer health, producer economics and global trade exchange. Fifty-four random samples were collected from wheat which originated from different countries. The samples included 14 of soft wheat to study the extent of their contamination with Deoxynivalenol (DON) and T-2 toxin by auto-ELISA technology and r-biopharm Microtiter plate. All samples were contaminated with DON toxin except one sample, and the contamination average ranged between 40.7 and 1018.8 µg kg-1. The highest contamination rates were in Lithuanian and the lowest in Indian wheat. Meanwhile the highest average level of T-2 toxin contamination was in Lithuanian wheat grains with a rate of 377.4µg kg-1 and the lowest in Polish wheat with an average of 115.3µg kg-1. GC-MS/MS and multiple reaction monitoring mode (MRM), was used to detect 15 triazole derivatives in collected samples, which may be used to combat fungal diseases on wheat during the growing season. Only 9 derivatives were found; Simeconazole, Penconazole, Hexaconazole, Cyproconazole, Diniconazole, Tebuconazole, Metconazole, Fenbuconazole and Difenoconazole. These derivatives varied according to the origin of wheat samples as well as their its concentration whereas, another 6 derivatives were not detected in all samples. A direct inverse relationship was found between the DON concentration in the samples and the residues of Simeconazole, Penconazole, Diniconazole, Tebuconazole, Metconazole, Fenbuconazole and Difenoconazole and the T-2 toxin showed the same relationship except for Tebuconazole. The safe and rational use of some triazole derivatives may be a new approach and a promising strategy not only to reduce plant diseases and their problems, but also to get rid of some mycotoxins as contaminates.

The development and optimization of an effective non-viral gene delivery method for genetic manipulation of primary human T cells is a major challenge in clinical immunotherapy researches. According to the low transfection efficiency of conventional methods in human primary T cells, there is an effort in order to increase the transfection rate in these cells. Protamine is an FDA-approved compound with a documented safety profile that enhances DNA condensation for gene delivery. In this study, the effect of protamine on the transfection efficiency of standard transfection reagents, TurboFect, and Lipofectamine 2000 was evaluated in order to transfect primary human T cells. Results demonstrated that protamine condenses DNA and increases the positive charge of DNA/Cargo complex efficiently without any cytotoxic effect on the primary human T cells. The results also revealed that the DNA/Protamine/Cargo complexes effectively transfect human primary T cells.

The aim of this study is (a) to develop, test, and employ a combined method of unsupervised machine learning to objectively assess the condition of sports facility in primary schools (PSSFC) and (b) examine the examine the geographical and typological association with PSSFC. Based on the Sixth National Sports Facility Census (NSFC), six PSSFC indicators (indoor and outdoor facility included) were selected as the measurements and decomposed by using the t-stochastic neighbor embedding (t-SNE). Thereafter, the Fuzzy C-mean (FCM) algorithm was used to cluster the same type of PSSFC with selecting the optimum numbers of evaluation level. Overall 845 primary schools in Shanghai, China were recruited and tested by this combined approach of unsupervised machine learning. In addition, the two-way analysis of covariance was used to examine the location and types of school associated with PSSFC variables in each level. The combined method was found to have acceptable reliability and good interpretability, differentiating PSSFC into five gradient levels. The characteristics of PSSFC differ by the location and school type of individual school. Our findings are conducive to the regionalized and personalized intervention and promotion on the children’s physical activity (PA) upon the practical situation of particular schools.

Copulas are useful tools for modeling the dependence structure between two or more variables. Copulas are becoming a quite flexible tool in modeling dependence among the components of a multivariate vector, in particular to predict losses in insurance and finance. In this article, we study the dependence structure of some well-known real life insurance data (with two components mainly) and subsequently identify the best bivariate copula to model such a scenario via VineCopula package in R. Associated structural properties of these bivariate copulas are also discussed.

The objective of this study was to determine the effects of supplementing L-isoleucine (L-Ile) on milk protein synthesis, using an immortalized bovine mammary epithelial (MAC-T) cell line. In this case, the cells were treated with 0, 0.3, 0.6, 0.9, 1.2 and 1.5 mM of supplemental Isoleucine (Ile), and the most efficient time for protein synthesis for each amino acid was determined by measuring the cell, medium and total protein at 0, 24, 48, 72 and 96 h. Confirmatory tests showed that 48h incubation time and 0.6 mM dosage of L-Ile are considered as the optimal time and dosage. The mechanism of milk protein synthesis was elucidated through proteomics analysis to clarify the metabolic pathway. When the L-Ile was supplemented, extracellular protein (medium protein) reached a peak at 48h, whereas in the case of the intracellular cell protein, it was shown to have reached to its peak at 24h in all L-Ile dosage treatments. In total, it is noted that there were 63 upregulated and 52 downregulated proteins. The results of the protein pathway analysis showed that the L-Ile group stimulated insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade, insulin/IGF pathway-protein kinase B signaling cascade, p53 pathway, de novo purine biosynthesis, Wnt signaling pathway, glycolysis, pentose phosphate pathway, and ATP synthesis which are pathways involved and related to protein and energy metabolism. Together, these results demonstrate that L-Ile supplementation was effective in stimulating β-casein synthesis by stimulating genes and pathways which are significantly related to protein and energy metabolism.

The current generation of nuclear reactors are evolutionary in design, mostly based on the technology originally designed to power submarines, and dominated by Light Water Reactors. The aims of the GenIV consortium are driven by sustainability, safety and reliability, economics, and proliferation resistance. The aims are extended here to encompass the ultimate and universal vision for strategic development of energy production, the ‘perpetuum mobile’ – at least as close as possible. We propose to rethink nuclear reactor design with the mission to develop a system which uses no fresh resources and produces no fresh waste during operation as well as generates power safe and reliably in economic way. The results of the innovative simulations presented here demonstrate that, from a theoretical perspective, it is feasible to fulfil the mission through the reuse of spent nuclear fuel from currently operating reactors as the fuel for a new reactor. The produced waste is less burdensome than current spent nuclear fuel which is used as feed to the system. However, safety, reliability and operational economics will need to be demonstrated to create the basis for the long term success of nuclear reactors as a major carbon free, sustainable, and applied highly reliable energy source.

Let  β= (((24!)!)!)!, and let {${\mathcal P}_{n^2+1}$} denote the set of all primes of the form {$n^2+1$}. Let ${\mathcal M}$ denote the set of all positive multiples of elements of the set {${\mathcal P}_{n^2+1} \cap (\beta,\infty)$}. The set {${\mathcal X}=\{0,\ldots,\beta\} \cup {\mathcal M}$} satisfies the following conditions: (1) ${\rm card}({\mathcal X})$ is greater than a huge positive integer and it is conjectured that ${\mathcal X}$ is infinite, (2)} we do not know any algorithm deciding the finiteness of ${\mathcal X}$, (3)~a~known and short algorithm for every {$n \in N$} decides whether or not {$n \in {\mathcal X}$}, (4) a known and short algorithm returns an integer~$n$ such that ${\mathcal X}$ is infinite if and only if ${\mathcal X}$ contains an element greater than $n$. The following problem is open: {\em simply define a set {${\mathcal X} \subseteq N$} such that ${\mathcal X}$ satisfies conditions (1)-(4), and \underline{we do not know any representation of~~${\mathcal X}$~~as a finite union of sets whose definitions are simpler than} \underline{the definition of ${\mathcal X}$}} {\tt (5)}. Let {$f(1)=2$}, {$f(2)=4$}, and let {$f(n+1)=f(n)!$} for every integer {$n \geqslant 2$}. For a positive integer $n$, let {$\Psi_n$} denote the following statement: {\em if a system of equations ${\mathcal S} \subseteq \Bigl\{x_i!=x_k: i,k \in \{1,\ldots,n\}\Bigr\} \cup \Bigl\{x_i \cdot x_j=x_k: i,j,k \in \{1,\ldots,n\}\Bigr\}$ has only finitely many solutions in positive integers \mbox{$x_1,\ldots,x_n$}, then each such solution \mbox{$(x_1,\ldots,x_n)$} satisfies {$x_1,\ldots,x_n \leqslant f(n)$}.} We prove that for every statement $\Psi_n$ the bound {$f(n)$} cannot be decreased. The author's guess is that the statements {$\Psi_1,\ldots,\Psi_9$} are true. We prove that the statement $\Psi_9$ implies that the set ${\mathcal X}$ of all {non-negative} integers $k$ whose number of digits belongs to {${\mathcal P}_{n^2+1}$} satisfies conditions {\tt (1)-(5)}.

In the realm of molecular science, intricate relationships between molecular structures and their biomedical and pharmacological characteristics have been revealed through empirical experiments. This exploration hinges on the application of numerical descriptors, known as Topological Indices, which illuminate the inherent properties of diverse molecular structures. With particular significance in the medical and pharmaceutical domains, these indices facilitate the prediction of biological features for new chemical compounds and drugs by quantifying weighted entropies. In the context of this paper, we delve into the concept of graph entropy, weaving it intricately with the topological properties of the crystalline framework of the copper oxide molecule, denoted as Cu\textsubscript{2}O$[i,j,t]$. Our primary objective is to unravel the mathematical symphony underlying the structural intricacies of Cu\textsubscript{2}O$[i,j,t]$ and to imbue it with the conceptual essence of entropy. We accomplish this through the computation of entropy, leveraging various topological indices, including weight. In addition to our analytical journey, we present a graphical comparison that juxtaposes the computed indices and entropies, shedding light on the interplay between mathematical analysis and the structural elegance of Cu\textsubscript{2}O$[i,j,t]$. This endeavor contributes to a deeper understanding of the material's multifaceted applications, spanning domains from chemical sensors to solar cells, photocatalysis, and batteries, where Cu\textsubscript{2}O's crystallographic structure plays a pivotal role.

We previously reported nano-pulse treatment (NPT), a pulsed power technology, resulted in 4T1-luc mammary tumor elimination and a strong in situ vaccination, thereby completely protecting tumor-free animals against a second live tumor challenge. The mechanism whereby NPT mounts effective antitumor immune responses in the 4T1 breast cancer predominantly immunosuppressive tumor microenvironment (TME) remains unanswered. In this study, orthotopic 4T1 mouse breast tumors were treated with NPT (100 ns, 50 kV/cm, 1000 pulses, 3 Hz). Blood, spleen, draining lymph nodes and tumors were harvested at 4-hour, 8-hour, 1-, 3-, 7-day. Additional studies were conducted over 3-month posttreatment intervals for the analysis of frequencies, death and functional markers of various immune cells in addition to suppressor function of regulatory T cells (Tregs). NPT was verified to elicit strong in situ vaccination (ISV) against breast cancer and promoted both acute and long-term T cell memory. NPT abolished immunosuppressive dominance systemically and in the TME by substantially reducing Tregs, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). NPT induced apoptosis in Tregs and TAMs. It also functionally diminished the Treg suppression capacity, likely explained by the downregulation of activation markers, particularly 4-1BB and TGFβ, and a phenotypic shift from predominantly activated (CD44+CD62L-) to naïve (CD44-CD62L+) Tregs. Importantly, NPT selectively induced apoptosis in activated Tregs and spared effector CD4+ and CD8+ T cells. These changes were followed by a concomitant rise in CD8+CD103+ tissue-resident memory T cells and TAM M1 polarization. These findings indicate that NPT effectively switches the TME and secondary lymphatic systems from an immunosuppressive to an immunostimulatory state allowing cytotoxic T-cell function and immune memory formation to eliminate cancer cells and account for the NPT in situ vaccination.

Modern surface analysis techniques are expanding significantly possibilities in description and attribution of historical artifacts. The present study is aimed to compare analytical ability of the X-ray fluorescent analysis (XRF) typically applied for studies ceramic art items with novel surface analysis methods: time-of-flight secondary ions mass spectroscopy (SIMS) and X-ray photoelectron spectroscopy (XPS) that were applied on measurements of elemental compositions of powder raw materials for porcelain fabrication: pegmatite P-1, Vesco-prima clay, kaolin, bone earth, dolomite, and feldspar. It was shown that SIMS successfully measures light elements unnoticeable for XRF such as lithium, beryllium, boron and heavy impurities not found out by XRF such as cobalt, cerium, copper, rubidium, vanadium. XPS has found thorium in the kaolin sample that was not detected by SIMS and XRF. The paper provides also values of chemical shifts of some XPS lines observed in materials under examination. The obtained information on relations of basic and impurity elements revealed by XRF and SIMS together with XPS chemical shifts data could be used to expose contemporary falsifications of historical porcelain and to attribute porcelain items during conservation process.

Background. The multisystemic features of Down syndrome (DS) in children are accompanied by an immunodeficiency, making them susceptible to infections and immune dysregulation with autoimmune, allergic, inflammatory, and hematological complications. This study was aimed at a better understanding of the abnormalities within the B and T cell compartments and their correlations with clinical immunophenotypes. Methods. Medical records of 35 DS children were retrospectively reviewed, referring to clinical symptomatology including history of infections, immune dysregulation disorders, and humoral and cellular immune response. Results. While the etiology of respiratory tract infections included typical viral and bacterial pathogens, SARS-CoV2-induced inflammatory disease and syndromic immunodeficiency contributed significantly to deterioration of the clinical course. Allergic diseases in the form of asthma, allergic rhinitis, and alimentary allergy were the most frequent manifestations of immune dysregulation and were followed by autoimmune disorders, such as Crohn disease, celiac disease, autoimmune thyroiditis, and alopecia, as well as inflammatory disorders, balanitis xerotica obliterans and lymphadenopathy, and a hematological disorder of myelopoiesis. Deficiency of serum immunoglobulin levels, reduced numbers of naïve B cells, and non-switched memory B cells along with low naïve T helper cells and significantly reduced regulatory T helper cells were the most prominent immune abnormalities. Conclusions. The loss of naïvete in B and T lymphocyte compartments with a deficiency of regulatory T cells may be underpinning pathomechanisms for the skewed immune response. The clinical immunophenotype in DS is complex and represents syndromic inborn error of immunity with immune dysregulation.

Tourism Geographers in Anglo-American geographical departments migrate to teach and research tourism in applied schools and departments such as business, resource and environment, and even cultural and creative industry. Under national research assessment and funding pressures, tourism geographers are not encouraged to keep on undertaking serious theoretical researches related to their mother discipline and transferred to research applied researches and publish in hybrid journals. Such changes in tourism geographers` research behavior have not been tested and reported in Asian academic contexts, especially Taiwan while frequently being discussed internationally. This research aims to investigate the differences in the research behavior of tourism geographers between those who are staffed in geography departments and those who migrate to applies departments such as tourism and recreation, resource and environment, and others in terms of publishing journals, paradigmatic approaches, research types(qualitative, quantitative, and mixed), research methods and geographical scales conducted based on content analysis of articles published by tourism geographers in geography and tourism and recreation departments. This study revealed that there are significant differences in the research behavior of tourism geographers between different department. Finally, this paper explains the differences in terms of Taiwan changing social and economic conditions, academic traditions and politics of geography and applied departments, research habits and preferences of tourism geographers among departments and other aspects. This study can help international tourism geography academic circles to understand the complexity and diversity of tourism geography academic landscape of the Chinese language.

In this paper, we report a comprehensive and consistent annotation of the locus encoding the horse T cell receptor b-chain (TRB), as inferred from the most recent genome assembly. The horse TRB locus spans approximately 1 Mb, making it the largest locus among the mammalian species stud-ied to date, with a significantly higher number of genes related to extensive duplicative events. In the region, 136 TRBV, belonging to 29 subgroups, 2 TRBD, 13 TRBJ and 2 TRBC genes, were iden-tified. The general genomic organization resembles that of other mammals, with a V-cluster of 135 TRBV genes, located upstream of two in-tandem aligned TRBD-J-C clusters, and an inverted TRBV gene at the 3’ end of the last TRBC gene. However, the horse b-chain repertoire would be affected by a high number of non-functional TRBV genes. Thus, we queried a transcriptomic da-taset derived from splenic tissue of a healthy adult horse, using each TRBJ gene as a probe to ana-lyse clonotypes encompassing the V(D)J junction. This analysis provided insights into the usage of the TRBV, TRBD and TRBJ genes and the variability of the juxtaposition region. Our results clearly demonstrated that the horse β-chain constitutes a complex level of variability broadly like that described in other mammalian species.

The Um Ara granites are a suite of granitoid rocks located in the south Eastern Desert of Egypt. The combination of Back Scattered Electron imaging (BSE), X-ray compositional mapping, and the data of the Electron Probe Micro Analyzer (EPMA) has provided valuable insights into the alteration process of zircon in the Um Ara granite. The investigated zircon grains have measurable amount of non-formula elements such as U, Th, Hf, REEs, P, Al, Ca, Fe, and Ti, along with extensive structural features indicative of radiation damage. These characteristics point to significant hydrothermal alteration of the zircon following its initial crystallization. The textural and geochemical evidence suggests the alteration of the Um Ara zircons was driven by coupled dissolution-reprecipitation processes influenced by aqueous fluids. The breakdown of accessory minerals like xenotime, thorite, monazite, and apatite during a major hydrothermal event around 1.8 Ga released the non-formula elements (U, Th, P, Ca, Al, Fe, REEs) that were then incorporated into the zircon structures. Subsequent pluvial periods around 50,000-159,000 years ago may have allowed further uptake of these elements during low-temperature alteration. The shear zones within the Um Ara granites facilitated the mobilization and transport of the non-formula element-bearing fluids, likely as carbonate and fluoride complexes. The temperature regime, with fluids remaining below 300°C, was crucial in preserving the radiation damage features in the zircons despite the extensive chemical changes.

Ab initio density functional theory molecular dynamics extensive calculations were used for the first time to evaluate stability conditions for relevant phases of InN. In particular, thermal decomposition of InN with formation of N2 molecules and pressure induced wurtzite – rocksalt solid-solid phase transition were established. The results consistent with available experimental data allowed a critical evaluation of potential and limitations of the proposed simulation method. The ab initio molecular dynamics as an efficient tool for simulations of phase transformations of InN including solid-solid structural transition and thermal decomposition with formation of N2 molecules has been demonstrated. It is of high interest because InN being important component of epitaxial quantum structures has still not been obtained as a bulk single crystal making difficult a determination of its basic physical properties and designing new applications.