Differences In Progression Research Articles

Progressively differentiated TFH13 cells are stabilized by JunB to mediate allergen germinal center responses.

Allergic diseases are common and affect a large proportion of the population. Interleukin-13 (IL-13)-expressing follicular helper T (TFH13) cells are a newly identified population of TFH cells that have been associated with high-affinity IgE responses. However, the origins, developmental signals, transcriptional programming and precise functions of TFH13 cells are unknown. Here, we examined the developmental signals for TFH13 cells and found a direct and progressive differentiation pathway marked by the production of IL-21. These two pathways differed in kinetics and extrinsic requirements. However, both pathways converged, forming transcriptionally similar TFH13 cells that express the transcription factor JunB as a critical stabilizing factor. Using an intersectional genetics-based TFH13-diphtheria toxin receptor model to perturb these cells, we found that TFH13 cells were essential to drive broad germinal center responses and allergen-specific IgG and IgE. Moreover, we found that IL-21 is a broad positive regulator of allergen germinal center B cells and synergizes with IL-13 produced by TFH13 cells to amplify allergic responses. Thus, TFH13 cells orchestrate multiple features of allergic inflammation.

Modernizing Neuro-Oncology: The Impact of Imaging, Liquid Biopsies, and AI on Diagnosis and Treatment

Advances in neuro-oncology have transformed the diagnosis and management of brain tumors, which are among the most challenging malignancies due to their high mortality rates and complex neurological effects. Despite advancements in surgery and chemoradiotherapy, the prognosis for glioblastoma multiforme (GBM) and brain metastases remains poor, underscoring the need for innovative diagnostic strategies. This review highlights recent advancements in imaging techniques, liquid biopsies, and artificial intelligence (AI) applications addressing current diagnostic challenges. Advanced imaging techniques, including diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS), improve the differentiation of tumor progression from treatment-related changes. Additionally, novel positron emission tomography (PET) radiotracers, such as 18F-fluoropivalate, 18F-fluoroethyltyrosine, and 18F-fluluciclovine, facilitate metabolic profiling of high-grade gliomas. Liquid biopsy, a minimally invasive technique, enables real-time monitoring of biomarkers such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), circulating tumor cells (CTCs), and tumor-educated platelets (TEPs), enhancing diagnostic precision. AI-driven algorithms, such as convolutional neural networks, integrate diagnostic tools to improve accuracy, reduce interobserver variability, and accelerate clinical decision-making. These innovations advance personalized neuro-oncological care, offering new opportunities to improve outcomes for patients with central nervous system tumors. We advocate for future research integrating these tools into clinical workflows, addressing accessibility challenges, and standardizing methodologies to ensure broad applicability in neuro-oncology.

Transcriptional Integration of Meiotic Prophase I Progression and Early Oocyte Differentiation.

Female reproductive senescence results from the regulated depletion of a finite pool of oocytes called the ovarian reserve. This pool of oocytes is initially established during fetal development, but the oocytes that comprise it must remain quiescent for decades until they are activated during maturation in adulthood. In order for developmentally competent oocytes to populate the ovarian reserve they must successfully initiate both meiosis and oogenesis. As the factors that regulate the timing and fidelity of these early events remain elusive, we assessed the precise function and timing of the transcriptional regulator TAF4b during meiotic prophase I progression in mouse fetal oocytes. Compared to matched controls, E14.5 Taf4b-deficient oocytes enter meiosis I in a timely manner however, their subsequent progression through the pachytene-to-diplotene transition of meiotic prophase I is compromised. Moreover, this disruption of meiotic progression is associated with the reduced ability of Taf4b-deficient oocytes to repair double-strand DNA breaks. Transcriptional profiling of Taf4b-deficient oocytes reveals that between E16.5 and E18.5 these oocytes fail to coordinate the reduction of meiotic gene expression and the induction of oocyte differentiation genes. These studies reveal that TAF4b promotes the formation of the ovarian reserve in part by orchestrating the timely transition to meiosis I arrest and oocyte differentiation, which are often perceived as separate events.

NIMG-14. HEAD-TO-HEAD COMPARISON OF18F-FET PET AND68GA-PSMA-11 PET IN DISTINGUISHING SMALL VOLUME TUMOR PROGRESSION VS TREATMENT-RELATED CHANGE IN POST-STANDARD OF CARE TREATMENT OF HIGH-GRADE GLIOMA USING DYNAMIC ACQUISITION AND KINETIC MODELING

Abstract BACKGROUND The inability to accurately distinguish between tumor progression and treatment-related changes in patients with high-grade glioma on routine imaging can negatively impact patient management and in some cases, outcome. Various imaging methods have been used to address this issue, including 18F-fluoro-ethyl-tyrosine (FET) PET and MR perfusion. However, these methods may not provide reliable results in cases of small lesion size or hemorrhage within the treatment site. The prostate-specific membrane antigen (PSMA) has been observed to be expressed by neovasculature in brain tumors. Since PSMA cannot cross the blood brain barrier, uptake of PSMA in the brain carries high-level of suspicion for residual tumor. Still, further work is needed to better understand PSMA uptake in the tumor bed following standard of care (SOC) treatment and to compare to currently available neuro-oncologic radiotracers, such as FET. We hypothesize that PSMA imaging of glioma neovasculature will provide unique diagnostic information that will aid in the differentiation of small volume tumor progression from treatment-related changes in the post-SOC treatment setting. METHODS Patients who underwent clinical Expanded Access PET/MR imaging with 18F-FET were re-imaged in a research protocol that collected a brain 68Ga-PSMA-11 PET/CT scan, as well as a repeat 18F-FET PET/CT. Kinetic modeling of dynamic radiotracer uptake was performed. Scans were assessed for correlation with subsequent imaging and changes in clinical management. RESULTS All PSMA scans that were performed were concordant with the initial clinical FET scan, subsequent imaging follow up and appropriate changes in clinical management. The PSMA-detected site was confirmed to be tumor in a single case with subsequent tissue sampling. One patient who was started on bevacizumab after their clinical FET demonstrated a significant decrease in uptake on the research FET scan, but persistent uptake on PSMA. CONCLUSION PSMA may effectively show tumor recurrence in post-SOC treatment high-grade glioma patients.

TMIC-04. SPATIAL SEQUENCING OF MEDULLOBLASTOMA REVEALS BIOLOGICAL NICHES CORRELATED WITH HIGH-RISK FEATURES AND RELAPSE

Abstract Medulloblastoma (MB) defines a heterogeneous set of neuroepithelial cancers of the posterior fossa. The MB tumor microenvironment (MB-TME) influences tumor progression and therapy response and has emerged as a growing target for novel therapeutic approaches. Prior single-cell analysis has characterized the MB-TME composition but does not reveal the spatial orientation of components. To address this gap, we performed 10X Visium spatial sequencing on sixteen pediatric MB samples obtained at surgical resection with samples representing the four molecular subtypes (WNT, N=1; SHH, N=6; Group 3, N=2; Group 4, N=5) and two matching samples at diagnosis and relapse. Spatial voxel clustering yielded clusters corresponding to malignant, immune, and stromal components of the TME, including tumor-associated astrocytes (TAAs), macrophages (TAMs), and vascular endothelium. Ten distinct clusters emerged representing malignant cell states, defined primarily by programs of cell cycle progression and neuronal differentiation. Notably, these MB cell clusters were differentially abundant between the MB subgroups, highlighting heterogeneity between disease subtypes. Moreover, examining the patterns of cellular spatial distribution in high-risk (HR) patients revealed dense regions of quiescent MB progenitors, while standard-risk patients showed greater heterogeneity within their TME. Proximity-dependent intercellular signaling further highlighted increased signaling by TAAs and vascular endothelium with decreased heat shock response signaling in HR patients. Comparing samples from relapse to diagnosis, TAMs, TAAs, and vascular endothelium were found to constitute a greater proportion of the TME. Subsequent niche-dependent gene expression and pathway analysis for TAAs localized near tumor vasculature in relapsed samples revealed increased expression of metastasis-associated pathways. Collectively, the results of our study enable new insight into the heterogeneity of the MB-TME, with close spatial association of quiescent MB progenitors correlating with high-risk clinical features. Quiescent MB progenitors have been documented to confer resistance through cellular dormancy, and identifying its molecular drivers may reveal potential targets for anticancer therapy.

Constructing organoid-brain-computer interfaces for neurofunctional repair after brain injury.

The reconstruction of damaged neural circuits is critical for neurological repair after brain injury. Classical brain-computer interfaces (BCIs) allow direct communication between the brain and external controllers to compensate for lost functions. Importantly, there is increasing potential for generalized BCIs to input information into the brains to restore damage, but their effectiveness is limited when a large injured cavity is caused. Notably, it might be overcome by transplantation of brain organoids into the damaged region. Here, we construct innovative BCIs mediated by implantable organoids, coined as organoid-brain-computer interfaces (OBCIs). We assess the prolonged safety and feasibility of the OBCIs, and explore neuroregulatory strategies. OBCI stimulation promotes progressive differentiation of grafts and enhances structural-functional connections within organoids and the host brain, promising to repair the damaged brain via regenerating and regulating, potentially directing neurons to preselected targets and recovering functional neural networks in the future.

YAP Alleviates Pulmonary Fibrosis Through Promoting Alveolar Regeneration via Modulating the Stemness of Alveolar Type 2 Cells.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with no cure except transplantation. Abnormal alveolar epithelial regeneration is a key driver of IPF development. The function of Yes1 Associated Transcriptional Regulator (YAP) in alveolar regeneration and IPF pathogenesis remains elusive. Here, we first revealed the activation of YAP in alveolar epithelium 2 cells (AEC2s) from human IPF lungs and fibrotic mouse lungs. Notably, conditional deletion of YAP in mouse AEC2s exacerbated bleomycin-induced pulmonary fibrosis. Intriguingly, we showed in both conditional knockout mice and alveolar organoids that YAP deficiency impaired AEC2 proliferation and differentiation into alveolar epithelium 1 cells (AEC1s). Mechanistically, YAP regulated expression levels of genes associated with cell cycle progression and AEC1 differentiation. Furthermore, overexpression of YAP in vitro promoted cell proliferation. These results indicate the critical role of YAP in alveolar regeneration and IPF pathogenesis. Our findings provide new insights into the regulation of alveolar regeneration and IPF pathogenesis, paving the road for developing novel treatment strategies.

Phospho-signaling couples polar asymmetry and proteolysis within a membraneless microdomain in Caulobacter crescentus

Asymmetric cell division in bacteria is achieved through cell polarization, where regulatory proteins are directed to specific cell poles. In Caulobacter crescentus, both poles contain a membraneless microdomain, established by the polar assembly hub PopZ, through most of the cell cycle, yet many PopZ clients are unipolar and transiently localized. We find that PopZ’s interaction with the response regulator CpdR is controlled by phosphorylation, via the histidine kinase CckA. Phosphorylated CpdR does not interact with PopZ and is not localized to cell poles. At poles where CckA acts as a phosphatase, dephosphorylated CpdR binds directly with PopZ and subsequently recruits ClpX, substrates, and other members of a protease complex to the cell pole. We also find that co-recruitment of protease components and substrates to polar microdomains enhances their coordinated activity. This study connects phospho-signaling with polar assembly and the activity of a protease that triggers cell cycle progression and cell differentiation.

High Mitophagy and Low Glycolysis Predict Better Clinical Outcomes in Acute Myeloid Leukemias.

Acute myeloid leukemia (AML) emerges as one of the most common and fatal leukemias. Treatment of the disease remains highly challenging owing to profound metabolic rewiring mechanisms that confer plasticity to AML cells, ultimately resulting in therapy resistance. Autophagy, a highly conserved lysosomal-driven catabolic process devoted to macromolecular turnover, displays a dichotomous role in AML by suppressing or promoting disease development and progression. Glycolytic metabolism represents a pivotal strategy for AML cells to sustain increasing energy needs related to uncontrolled growth during disease progression. In this study, we tested the hypothesis that a high glycolytic rate and low autophagy flux could represent an advantage for AML cell proliferation and thus be detrimental for patient's prognosis, and vice versa. TCGA in silico analysis of the AML cohort shows that the high expression of MAP1LC3B (along with that of BECN1 and with low expression of p62/SQSTM1) and the high expression of BNIP3 (along with that of PRKN and of MAP1LC3B), which together are indicative of increased autophagy and mitophagy, correlate with better prognosis. On the other hand, the high expression of glycolytic markers HK2, PFKM, and PKM correlates with poor prognosis. Most importantly, the association of a low expression of glycolytic markers with a high expression of autophagy-mitophagy markers conferred the longest overall survival for AML patients. Transcriptomic analysis showed that this combined signature correlates with the downregulation of a subset of genes required for the differentiation of myeloid cells, lactate/pyruvate transporters, and cell cycle progression, in parallel with the upregulation of genes involved in autophagy/lysosomal trafficking and proteolysis, anti-tumor responses like beta-interferon production, and positive regulation of programmed cell death. Taken together, our data support the view that enhanced autophagy-mitophagy flux together with low glycolytic rate predisposes AML patients to a better clinical outcome, suggesting that autophagy inducers and glucose restrictors may hold potential as adjuvant therapeutics for improving AML management.

Advancements and future directions in single-cell Hi-C based 3D chromatin modeling

Advancements and future directions in single-cell Hi-C based 3D chromatin modeling

739. SIGNIFICANCE OF COX2 INHIBITOR FOR ESOPHAGEAL CANCER FROM THE CLINICAL AND EXPERIMENTAL ESTIMATE

Abstract (Aims) We report experimental and clinical evidence that COX2 represent a potential molecular target for the treatment and prevention of esophageal cancer. (Methods) (A)Experiment: Thirty 8-week male wistar rats were exposed to duodenal content esophageal reflux. All animal underwent an esophagoduodenal anastomosis (EDA) with total gastrectomy in order to produce chronic esophagitis. In ten rats the sham (Control). They were sacrified at 40th week. Their esophagi were examined for HE, COX2,PGE2, PCNA and total bile acids in the esophageal lumen was measured. (B)Clinical: The expression of COX2 was examined for 68 specimens of esophageal squamous cell carcinoma (SCC) and the correlation of COX2 expression with clinicopatholigic features was examined. (Results) (A) After 40 weeks of reflux, columnar dysplasia, squamous cell carcinoma and adenocarcinoma were found. Total bile acid in the esophageal lumen was significantly increased in the EDA group compared with the sham operated rats. PCNA LI and esophageal tissue PGE2 were higher in dysplastic and cancer tissue than that of control. Overexpression of COX2 was shown in dysplastic and cancer tissue. COX2 may play an important role in esophageal cancer by duodenal content reflux.(B) COX2 immunoreactivity was weak in 27(40%) and strong in 41(60%) of the carcinomas. The proportion of poorly differentiated SCC among tumors with a strong expression of COX2 (34%) was significantly higher than among tumors with a weak expression of COX2 (19%, p=0.02). The depth of tumors (p=0.004), lymph node metastasis (p=0.0009) and the stage of the tumors (p=0.001) were advanced significantly more progressively in ECCS with a strong COX2 expression. Moreover, survival was significantly reduced (p=0.02) among patients with strong COX2 expression when compared with the COX2 weak group. This study showed that strong expression of COX2 was correlated with tumor progression and poor differentiation in ESCC. (Conclusion) In this experimental study, we demonstrate that bile reflux of duodenal contents induce COX2 and increase prostaglandin synthesis in dysplastic and cancer tissue. Our study suggests that COX2 may play a role in esophageal carcinoma development and progression, COX2 inhibitors may be potential targets for the prevention or treatment of esophageal carcinoma.

Preventing periprosthetic osteolysis in aging populations through lymphatic activation and stem cell-associated secretory phenotype inhibition

With increases in life expectancy, the number of patients requiring joint replacement therapy and experiencing periprosthetic osteolysis, the most common complication leading to implant failure, is growing or underestimated. In this study, we found that osteolysis progression and osteoclast differentiation in the surface of the skull bone of adult mice were accompanied by significant expansion of lymphatic vessels within bones. Using recombinant VEGF-C protein to activate VEGFR3 and promote proliferation of lymphatic vessels in bone, we counteracted excessive differentiation of osteoclasts and osteolysis caused by titanium alloy particles or inflammatory cytokines LPS/TNF-α. However, this effect was not observed in aged mice because adipogenically differentiated mesenchymal stem cells (MSCs) inhibited the response of lymphatic endothelial cells to agonist proteins. The addition of the JAK inhibitor ruxolitinib restored the response of lymphatic vessels to external stimuli in aged mice to protect against osteolysis progression. These findings suggest that inhibiting SASP secretion by adipogenically differentiated MSCs while activating lymphatic vessels in bone offers a new method to prevent periprosthetic osteolysis during joint replacement follow-up.

Osteoclast-derived exosomes influence osteoblast differentiation in osteoporosis progression via the lncRNA AW011738/ miR-24-2-5p/ TREM1 axis

To investigate the molecular mechanism of osteoclast-derived exosomes in osteoporosis. RANKL induced osteoclast model was screened for significantly differentially expressed lncRNAs and mRNAs by whole RNA sequencing. Exosomes were characterized using electron microscopy, western blotting and nanosight. Overexpression or knockdown of AW011738 was performed to explore its function. The degree of osteoporosis in an osteoporosis model was assessed by mirco-CT. The osteoclast model, osteoblast differentiation ability and the molecular mechanism of lncRNA AW011738/miR-24-2-5p/TREM1 axis in osteoporosis were assessed by dual luciferase reporter gene assay, Western blotting (WB), immunofluorescence and ALP staining. Bioinformatics was used to predict interactions of key osteoporosis-related genes with miRNAs, transcription factors, and potential drugs after upregulation of AW011738. To predict the protein-protein interaction (PPI) network associated with key genes, GO and KEGG analyses were performed on the key genes. The ssGSVA was used to predict changes in the immune microenvironment. Osteoclast-derived exosomes containing lncRNA AW011738 decreased the osteogenesis-related markers and accelerated bone loss in OVX mice. Osteoclast (si-AW011738)-derived exosomes showed a significant increase in biomarkers of osteoblast differentiation in vitro compared to the si-NC group. As analyzed by mirco-CT, tail vein injected si-AW011738 OVX mice were less osteoporotic than the control group. AW011738 inhibited osteoblast differentiation by regulating TREM1 expression through microRNA. Meanwhile, overexpression of miR-24-2-5p inhibited TREM1 expression to promote osteoblast differentiation. Osteoclast-derived exosomes containing lncRNA AW011738 inhibit osteogenesis in MC3T3-E1 cells through the lncRNA AW011738/miR-24-2-5p/TREM1 axis and exacerbate osteoporosis in OVX mice.

Fasciola gigantica: Ultrastructural localisation of neoblast recruitment in somatic tissues during growth and development in the hepatic parenchyma of experimentally infected mice

Application of 'omics' technology, and advances in in vitro methods for studying the growth of Fasciola hepatica, have highlighted the central role of migrating neoblasts in driving forward development and differentiation towards the adult-like form. Neoblast populations present molecular heterogeneity, morphological variation and changes associated with recruitment of these stem cells into their final tissue locations. However, terminal differentiation towards function, has received much less attention than has been the case for the free-living Platyhelminths. An actively replicating neoblast population, comprising cells with heterochromatic nuclei consistent with regulation of gene expression, has been identified in the parenchyma of juvenile Fasciola gigantica migrating in the liver of experimentally infected mice. In some of these cells, early cytoplasmic differentiation towards myocyte function was noted. Neoblasts have also been identified close to, and incorporated in, the subtegumental zone, the gastrodermis and the excretory ducts. In these locations, progressive morphological differentiation towards terminal function has been described. This includes the appearance of specific progenitors of type-1, type-2 and type-3 tegumental cells, the latter possibly contributing to tegumental spine development. 'Cryptic' surface molecular differentiation is postulated to account for recognition and 'docking' of migrating neoblasts with their final site for terminal differentiation.

Myeloid‑derived suppressor cells as targets of emerging therapies and nanotherapies (Review).

Breast cancer (BC) is the leading cause of cancer-related mortality among women worldwide. Immunotherapies are a promising approach in cancer treatment, particularly for aggressive forms of BC with high mortality rates. However, the current eligibility for immunotherapy remains limited to a limited fraction of patients with BC. Myeloid-derived suppressor cells (MDSCs), originating from myeloid cells, are known for their dual role in immunosuppression and tumor promotion, significantly affecting patient outcomes by fostering the formation of premetastatic niches. Consequently, targeting MDSCs has emerged as a promising avenue for further exploration in therapeutic interventions. Leveraging nanotechnology-based drug delivery systems, which excel in accumulating drugs within tumors via passive or active targeting mechanisms, are a promising strategy for the use of MDSCs in the treatment of BC. The present review discusses the immunosuppressive functions of MDSCs, their role in BC, and the diverse strategies for targeting them in cancer therapy. Additionally, the present review discusses future advancements in BC treatments focusing on MDSCs. Furthermore, it elucidates the mechanisms underlying MDSC activation, recruitment and differentiation in BC progression, highlighting the clinical characteristics that render MDSCs suitable candidates for the therapy and targeted nanotherapy of BC.

Clinical Impact of C-myc Oncogenic Diversity on Solid and Lymphoid Malignancies.

Onset and progression of malignant tumors is a multistep process including a variety of gross chromosomal and specific genes' deregulation. Among oncogenes that are frequently altered in solid and also in hematological malignancies, the C-myc (gene locus: 8q24.21) plays a pivotal role. C-myc is a proto-oncogene encoding for a nuclear phosphoprotein implicated in cell cycle progression, apoptosis and cellular differentiation and transformation. The purpose of the current molecular review was to explore the differences of C-myc oncogenic activity in solid and lymphoid malignancies that modify its clinical impact on them. A systematic review of the literature in the international database PubMed was carried out. The year 2010 was set as a prominent time limit for the publication date of articles in the majority of them, whereas specific references of great importance and historical value in the field of C-myc gene discovery and analysis were also included. The following keywords were used: C-myc, oncogene, signaling pathway, malignancies, carcinoma, lymphoma. A pool of 43 important articles were selected for the present study at the basis of combining molecular knowledge with new targeted therapeutic strategies. C-myc oncogene demonstrates two different mechanisms of deregulation: amplification, mutation and translocation patterns. These particular aspects of gene alteration are unique for solid and non-solid (hematological) malignancies, respectively. C-myc is characterized by diversity regarding its deregulation mechanisms in malignancies derived from different tissues. C-myc translocation is sporadically combined with amplification ("complicon" formation) or mutations creating exotic genetic signatures. This "bi-phasic" C-myc deregulation model in the corresponding malignant tumor categories clinically affects the corresponding patients, also modifying the targeted therapeutic strategies on them.

MiR-744-5p promotes T-cell differentiation via inhibiting STK11

T cells utilized in adoptive T cell immunotherapy are typically activated in vitro. Although these cells demonstrate proliferation and anti-tumor activity following activation, they often face difficulties in sustaining long-term survival post-reinfusion. This issue is attributed to the induction of T cells into a terminal differentiation state upon activation, whereas early-stage differentiated T cells exhibit enhanced proliferation potential and survival capabilities. In previous study, we delineated four T cell subsets at varying stages of differentiation: TN, TSCM, TCM, and TEM, and acquired their miRNA expression profiles via high-throughput sequencing. In the current study, we performed a differential analysis of miRNA across these subsets, identifying a distinct miRNA, hsa-miR-744-5p, characterized by progressively increasing expression levels upon T cell activation. This miRNA is not expressed in TSCM but is notably present in TEM. Target genes of miR-744-5p were predicted, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, revealing that these genes predominantly associate with pathways related to the 'Wnt signaling pathway'. We established that miR-744-5p directly targets STK11, influencing its expression. Further, we investigated the implications of miR-744-5p on T cell differentiation and functionality. Overexpression of miR-744-5p in T cells resulted in heightened apoptosis, reduced proliferation, an increased proportion of late-stage differentiated T cells, and elevated secretion of the cytokine TNF-α. Moreover, post-overexpression of miR-744-5p led to a marked decline in the expression of early-stage differentiation-associated genes in T cells (CCR7, CD62L, LEF1, BCL2) and a significant rise in late-stage differentiation-associated genes (KLRG1, PDCD1, GZMB). In conclusion, our findings affirm that miR-744-5p contributes to the progressive differentiation of T cells by downregulating the STK11 gene expression.

LEGAL ANALYSIS OF TARGETING AS A BASIS FOR THE PROVISION OF SOCIAL ASSISTANCE

Introduction. The relevance of the chosen topic lies in the fact that the system of social assistance is always based on the main principle - to support those who are unable to take care of themselves. Summary of the main results of the study. At the current stage of transformation of Ukrainian society, given the progressive differentiation of incomes, the most important task of the social security system is to fight poverty. A well-developed social assistance system is an important element of a modern market economy, as people face certain economic risks and other setbacks throughout their lives that can lead to loss of income. Moreover, poverty and its interrelated phenomena such as disease, crime, and social neglect have an impact on society and economic development. However, it is difficult to define who is poor. This is especially difficult in Ukraine because of the existence of a large shadow economy, underreporting of income, and a rather weak administrative system. The problem is that in recent years, as a result of lawmaking activities, many new legal principles have emerged that guide the legal regulation of the social sphere and outline the general directions of the realization of social rights. Some principles faded away, losing their relevance and ceasing to influence the realization of social rights, while others, on the contrary, having barely appeared in social security legislation, are gaining a stronger position in the system of sectoral principles. One of these principles is the principle of targeting. Targeting is a characteristic tool of anti-poverty and cost-cutting programs. The article formulates the main principles of targeted social assistance for the poor. A brief assessment of the Ukrainian social assistance system is made. Conclusion. The article provides a theoretical overview of the targeting of social assistance as a component of the state's social policy, which in turn will have a positive impact on the effectiveness of social protection. It is important to note that in the current conditions of economic development, the problem of overcoming poverty and ensuring decent living conditions for citizens is a priority task for every state. This goal is achieved by allocating funds to the targeted, least well-off categories of the population. Thus, ideally, all those in need and the poor should receive assistance provided by the laws of Ukraine on the basis of targeted social payments. Targeting is a characteristic tool of anti-poverty programs.

The NDR family of kinases: essential regulators of aging.

Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by López-Otin, numerous studies have attempted to identify the main regulators and contributors in the aging process. One interesting group of proteins whose participation has been implicated in several aging hallmarks are the nuclear DBF2-related (NDR) family of serine-threonine AGC kinases. They are one of the core components of the Hippo signaling pathway and include NDR1, NDR2, LATS1 and LATS2 in mammals, along with its highly conserved metazoan orthologs; Trc in Drosophila melanogaster, SAX-1 in Caenorhabditis elegans, CBK1, DBF20 in Saccharomyces cerevisiae and orb6 in Saccharomyces pombe. These kinases have been independently linked to the regulation of widely diverse cellular processes disrupted during aging such as the cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, and stem cell differentiation. However, a comprehensive overview of the state-of-the-art knowledge regarding the post-translational modifications of and by NDR kinases in aging has not been conducted. In this review, we summarize the current understanding of the NDR family of kinases, focusing on their relevance to various aging hallmarks, and emphasize the growing body of evidence that suggests NDR kinases are essential regulators of aging across species.

PI15, a novel secreted WNT-signaling antagonist, regulates chondrocyte differentiation

ABSTRACT Purpose/Aim of Study During the development of the vertebrate skeleton, the progressive differentiation and maturation of chondrocytes from mesenchymal progenitors is precisely coordinated by multiple secreted factors and signaling pathways. The WNT signaling pathway has been demonstrated to play a major role in chondrogenesis. However, the identification of secreted factors that fine-tune WNT activity has remained elusive. Here, in this study, we have identified PI15 (peptidase inhibitor 15, protease Inhibitor 15, SugarCrisp), a member of the CAP (cysteine rich secretory proteins, antigen 5, and pathogenesis related 1 proteins) protein superfamily, as a novel secreted WNT antagonist dynamically upregulated during chondrocyte differentiation. Materials and Methods ATDC5 cells, C3H10T1/2 micromass cultures and primary chondrocyte cells were used as in vitro models of chondrogenesis. PI15 levels were stably depleted or overexpressed by viral shRNA or expression vectors. Chondrogenesis was evaluated by qPCR gene expression analysis and Alcian blue staining. Protein interactions were determined by coimmunoprecipitation assays. Results and Conclusions shRNA-mediated knockdown of PI15 in ATDC5 cells, C3H10T1/2 cells or primary chondrocytes inhibits chondrogenesis, whereas the overexpression of PI15 strongly enhances chondrogenic potential. Mechanistically, PI15 binds to the LRP6 WNT co-receptor and blocks WNT-induced LRP6 phosphorylation, thus repressing WNT-induced transcriptional activity and alleviating the inhibitory effect of WNT signaling on chondrogenesis. Altogether, our findings suggest that PI15 acts as a key regulator of chondrogenesis and unveils a mechanism through which chondrocyte-derived molecules can modulate WNT activity as differentiation proceeds, thereby creating a positive feedback loop that further drives differentiation.