Discovery Potential Research Articles

Two new species of Parastagonospora and a new species of Phaeoseptoriella (Phaeosphaeriaceae, Pleosporales) from grasslands in Yunnan Province, China.

During our investigation of microfungi on grasslands in Yunnan Province, China, three new fungal taxa associated with grasses were collected. Morphological observations and phylogenetic analyses of the combined SSU, LSU, ITS, tef1-α, and rpb2 loci based on maximum likelihood and Bayesian inference were used to reveal the taxonomic placement of these fungal taxa. This study introduces Parastagonosporayunnanensis, Para.zhaotongensis, Phaeoseptoriellapoaceicola. Parastagonosporayunnanensis is characterized by ampulliform or globose to subglobose conidiogenous cells, with conidia that are cylindrical to subcylindrical, 0-1-septate, rounded at the apex and slightly truncate at the base. Parastagonosporazhaotongensis features similar globose to subglobose conidiogenous cells but with 0-3-septate, cylindrical to subcylindrical conidia. Phaeoseptoriellapoaceicola is distinguished by its globose to subglobose conidiogenous cells and phragmosporous conidia that are initially hyaline, turn pale yellowish at maturity, and are 7-septate, cylindrical to subcylindrical, either straight or slightly curved. These discoveries underscore the significance of exploring and accurately identifying fungal taxa within Ascomycota, highlighting the species richness and potential for new species discoveries in grass-based habitats. The findings from this study expand our understanding of the taxonomy and phylogeny of grassland-associated Ascomycota, providing a foundation for further ecological and taxonomic studies of these fungi within their natural environments.

Modern Chinese Oil Painting on “Tibetan Themes”

Chinese fine art has undergone a long and painstaking history of the formation of classical writing techniques. However, the globalization processes, which also affected the spheres of artistic activity, influenced the themes of works, techniques and techniques of oil painting in China. Meanwhile, the existential and religious flavor of Tibetan painting, untouched by world trends, has preserved many unique traditional principles of existentialism and worldview concepts that have absorbed the virginity of the spiritual and semantic identity of the people. This phenomenon has attracted a lot of attention from professional artists and collectors of fine art. At the same time, the storehouse of unique Buddhist values and the foundations of the existence of the people of historical Tibet began to attract researchers and artists relatively recently. Namely, since the middle of the last century, eminent masters of the brush have only discovered this “art residence”, instantly capturing the market of connoisseurs of high culture and lovers of painting with their works, gaining their love for Tibetan chronography reflected in modern Chinese oil paintings. The canvases represent the value potential for the historiography of the ancient people, conglomerating the foundations of ontological, ethnic, regional, national and religious traditions of the original style, which determine the semantic value-forming core of Chinese culture. This phenomenon contributes to its continuity and self-identity, despite the influence of Western artists. The development of Chinese oil painting has undergone many collisions, ranging from Westernization, Russification and the consequences of the war with Japan, ending with the discovery of the value potential of the worldview system of the Tibetan people. The recognition of Chinese sovereignty over Tibet allowed China to integrate into its “art workshop” the spiritual and social perspectives of the national identical Tibetan culture, which conquered the art world with its identity. In the process of the formation of oil painting, artists subjected it to nationalization and Sinification, which, through the prism of depicting the realities of Tibetan life, allowed to form an original style of creating works.

G protein-coupled receptor-biased signaling: potential drug discovery to facilitate treatment of metabolic diseases

G protein-coupled receptors (GPCRs) are important, potential drug targets for the treatment of metabolic disorders, such as obesity. GPCRs crosstalk with several transducers, including heterotrimeric G proteins, GPCR kinases (GRKs), and β-arrestins. GPCR-biased agonism has raised the potential of novel drug development to preferentially activate therapeutic signaling pathways over pathways that lead to unwanted side effects. The obesity epidemic and its metabolic complications continue to be a major global public health threat but effective treatments are limited. The accelerated development of structural techniques, like X-ray crystallography and cryo-electron microscopy, has paved the way to understanding how biased agonism measured at GPCRs results in specific downstream physiologic responses. Herein some well-validated GPCR targets are briefly summarized and several new and promising receptors for obesity treatment are outlined. This review highlights the significance of deciphering the role of GPCRs in obesity pathology and biased signaling for drug development. We anticipate the review will facilitate the development of novel GPCR-targeted anti-obesity drugs that lead to heightened therapeutic efficacy with decreased side effect profiles.

Epstein-Barr Virus: Human Interactome Reveals New Molecular Insights into Viral Pathogenesis for Potential Therapeutics and Antiviral Drug Discovery.

Host-virus Protein-Protein Interactions (PPIs) play pivotal roles in biological processes crucial for viral pathogenesis and by extension, inform antiviral drug discovery and therapeutics innovations. Despite efforts to develop the Epstein-Barr virus (EBV)-host PPI network, there remain significant knowledge gaps and a limited number of interacting human proteins deciphered. Furthermore, understanding the dynamics of the EBV-host PPI network in the distinct lytic and latent viral stages remains elusive. In this study, we report a comprehensive map of the EBV-human protein interactions, encompassing 1752 human and 61 EBV proteins by integrating data from the public repository HPIDB (v3.0) as well as curated high-throughput proteomic data from the literature. To address the stage-specific nature of EBV infection, we generated two detailed subset networks representing the latent and lytic stages, comprising 747 and 481 human proteins, respectively. Functional and pathway enrichment analysis of these subsets uncovered the profound impact of EBV proteins on cancer. The identification of highly connected proteins and the characterization of intrinsically disordered and cancer-related proteins provide valuable insights into potential therapeutic targets. Moreover, the exploration of drug-protein interactions revealed notable associations between hub proteins and anticancer drugs, offering novel perspectives for controlling EBV pathogenesis. This study represents, to the best of our knowledge, the first comprehensive investigation of the two distinct stages of EBV infection using high-throughput datasets. This makes a contribution to our understanding of EBV-host interactions and provides a foundation for future drug discovery and therapeutic interventions.

Spectroscopic Imaging of the Sun with MeerKAT: Opening a New Frontier in Solar Physics

Solar radio emissions provide several unique diagnostics to estimate different physical parameters of the solar corona, which are otherwise simply inaccessible. However, imaging the highly dynamic solar coronal emissions spanning a large range of angular scales at radio wavelengths is extremely challenging. At gigahertz frequencies, MeerKAT radio telescope is possibly globally the best-suited instrument at present for providing high-fidelity spectroscopic snapshot solar images. Here, we present the first published spectroscopic images of the Sun made using the observations with MeerKAT in the 880–1670 MHz band. This work demonstrates the high fidelity of spectroscopic snapshot MeerKAT solar images through a comparison with simulated radio images at MeerKAT frequencies. The observed images show extremely good morphological similarities with the simulated images. Our analysis shows that below ∼900 MHz MeerKAT images can recover essentially the entire flux density from the large angular-scale solar disk. Not surprisingly, at higher frequencies, the missing flux density can be as large as ∼50%. However, it can potentially be estimated and corrected for. We believe once solar observation with MeerKAT is commissioned, it will enable a host of novel studies, open the door to a large unexplored phase space with significant discovery potential, and also pave the way for solar science with the upcoming Square Kilometre Array-Mid telescope, of which MeerKAT is a precursor.

Skin emitted volatiles analysis for noninvasive diagnosis: the current advances in sample preparation techniques for biomedical application.

Human skin emits a series of volatile compounds from the skin due to various metabolic processes, microbial activity, and several external factors. Changes in the concentration of skin volatile metabolites indicate many diseases, including diabetes, cancer, and infectious diseases. Researchers focused on skin-emitted compounds to gain insight into the pathophysiology of various diseases. In the case of skin volatolomics research, it is noteworthy that sample preparation, sampling protocol, analytical techniques, and comprehensive validation are important for the successful integration of skin metabolic profiles into regular clinical settings. Solid-phase microextraction techniques and polymer-based active sorbent traps were developed to capture the skin-emitted volatile compounds. The primary advantage of these sample preparation techniques is the ability to efficiently and targetedly capture skin metabolites, thus improving the detection of the biomarkers associated with various diseases. In further research, polydimethyl-based patches were utilized for skin research due to their biocompatibility and thermal stability properties. The microextraction sampling tools coupled with high sensitive Gas Chromatography-Mass Spectrometer provided a potential platform for skin volatolomes, thus emerging as a state-of-the-art analytical technique. Later, technological advancements, including the design of wearable sensors, have enriched skin-based research as it can integrate the information from skin-emitted volatile profiles into a portable platform. However, individual-specific hydration, temperature, and skin conditions can influence variations in skin volatile concentration. Considering the subject-specific skin depth, sampling time standardization, and suitable techniques may improve the skin sampling techniques for the potential discovery of various skin-based marker compounds associated with diseases. Here, we have summarised the current research progress, limitations, and technological advances in skin-based sample preparation techniques for disease diagnosis, monitoring, and personalized healthcare applications.

Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target.

Pancreatic ductal adenocarcinoma (PDAC) poses significant challenges in terms of prognosis and treatment. Recent research has identified splicing deregulation as a new cancer hallmark. Herein, we investigated the largely uncharacterized alternative splicing profile and the key splicing factor SF3B1 in PDAC pancreatic cells and tissues as a potential discovery source of plausible drug targets and new predictive biomarkers of clinical outcome. The research involved a transcriptome-wide analysis, comparing profiles of splicing profiles in PDAC primary cells with normal ductal cells. This revealed more than 400 significant differential splicing events in genes involved in regulation of gene expression, primarily related to mRNA splicing, and metabolism of nucleic acids. PDAC cultures were highly sensitive to the SF3B1 modulators, E7107 and Pladienolide-B, showing IC50s in the low nanomolar range. These compounds induced apoptosis, associated to induction of the MCL-1/S splice variant. and reduced cell migration, associated to RON mis-splicing. In an orthotopic mouse model, E7107 showed promising results. Furthermore, we evaluated SF3B1 expression in specimens from 87 patients and found a significant association of SF3B1 expression with progression-free and overall survival. In conclusion, SF3B1 emerges as both a potential prognostic factor and therapeutic target in PDAC, impacting cell proliferation, migration, and apoptosis. These findings warrant future studies on this new therapeutic strategy against PDAC.

ISOLATION, IDENTIFICATION, AND CHARACTERIZATION OF MICROORGANISMS FROM INDUSTRIAL DAIRY WASTE AND EVALUATION OF ITS BIODEGRADABILITY

Microscopic organisms, commonly referred to as microbes, are organisms that are not visible to the naked eye. While some of these microorganisms can lead to diseases, numerous beneficial ones play essential roles in various domains. These advantageous microorganisms are pivotal in ecological systems, contributing to processes like biodegradation and bioremediation. They also find significant applications in diverse industries such as agriculture, food production, and the development of probiotics. This research aims to investigate the potential discovery of various biodegradable microorganisms capable of breaking down organic waste and similar materials. The focus is on finding effective ways to manage these materials in the context of global warming and related environmental concerns. The isolation of microorganisms involved the collection of samples from dairy industry effluents from dairy farms of Dehradun, Uttarakhand. Six isolates were screened following sample collection and examination. To distinguish the gathered microorganisms, various analyses were conducted. These included testing the isolates on nutrient agar at room temperature for 24 hours, with observations made on characteristics such as size, shape, color, margin, height, opacity, and stability. Morphological features like gram nature and motility were also examined. Subsequent to physical-biochemical characterization, tests for catalase, oxidase, and indole citrate were conducted. Biochemical tests were carried out to assess extracellular enzymatic activities, including caseinase and starch hydrolysis. Additionally, carbohydrate utilization tests were performed for lactose, maltose, inositol, xylose, among others. Out of the 06 isolates, two exhibited protease production and were selected for further investigation. Furthermore, two isolates demonstrated effective antibacterial activity and susceptibility to different antibiotics.

Cyanobacterial community structure and isolation of thermophilic cyanobacteria in the Zharkent geothermal spring

Cyanobacterial biodiversity represents a significant reservoir for the potential discovery of new promising microorganism species. The purpose of this research is to explore the diversity of cyanobacteria and identify thermotolerant species found in the Zharkent geothermal spring situated in the Zhetysu region. At the time of water sampling from the spring, the temperature reached 75-80 °C. Cyanobacterial mats in the form of microbial agglomerations were identified on the stream periphery. Nine cyanobacterial species were found in these cyanobacterial mats, including Synechococcus, Phormidium, Gloeocapsa, Oscillatoria, Fischerella, and Nostoc. Among the cyanobacteria inhabiting the hot spring, 44% were non-heterocystous forms, while the rest exhibited heterocystous characteristics or were present as single-celled organisms. The order Oscillatoriales was the most predominant, including four species, followed by the order Chroococcales with three species. Pure cultures of cyanobacteria, such as Oscillatoria formasa, Nostoc commune, Anabaena cylindrica, and Fischerella thermalis, were isolated from the geothermal spring. These cultures were subjected to thermotolext56rance assessment at different temperatures. All examined strains exhibited a high growth rate at 45-50°C, with a slowdown at 55 and 60°C. The optimal growth temperature was 45-50°C, except for the Fischerella thermalis strain, which showed active growth at 60°C. The obtained results emphasize the potential application of the isolated strains in biotechnology.

Serum-based Comprehensive N-Glycans Profiling Analysis in Different Gastric Disease Stages by Porous Graphitic Carbon Liquid Chromatography-Mass Spectrometry Associated With Potential Marker Discovery.

N-glycans are potential serum biomarkers due to their aberrant structure and abundance alteration during disease progression. Few studies have been associated with relative quantitative N-glycans profiling during different gastric disease stages. In this study, we conducted an investigation on the profiling of N-glycans in patients with gastric disease, as well as in healthy controls. In this study, the porous graphitization carbon chromatography-high resolution Fourier transform mass spectrometry (PGC-FTMS) method was applied to assess comprehensive N-glycans profiling in patients at different stages of gastric disease, including gastritis, atrophic gastritis, gastric ulcer, gastric polyps, and gastric cancer. A total of 45 N-glycans (relative abundance >0.1%) were detected, and 9 N-glycans were found to be potential biomarkers for gastric disease detection. Along with the progression of gastric disease, the abundance of sialylated N-glycans increased, while that of core-fucosylated N-glycans decreased. Multivariate statistical analysis demonstrated that N-glycans profiling between gastritis and healthy controls had significant differences. The characteristic N-glycans distinguished gastric cancer from healthy controls, which had strong clinical diagnostic value. The relative quantitative profile of N-glycans in different gastric disease stages was revealed and serum N-glycans are proposed for distinguishing gastric disease stages in clinical application.

Factors and determinants affecting banking sector stability: empirical evidence from conventional and Islamic banks listed on the Palestine stock exchange

PurposeThis paper aims to investigate the determinants that contribute to the financial stability and banking sector of Palestinian banks listed on the Palestine Stock Exchange (PEX) by using yearly data for the years 2012–2022.Design/methodology/approachPooled ordinary least squares (OLS) and two-stage least squares (2SLS) were used to identify the variables and factors affecting the financial stability and banking sector of Palestinian banks. The study’s data were collected from the banks listed on PEX and from the yearly reports posted on the Palestine Monetary Authority’s (PMA) webpage over the years from 2012–2022. According to this research’s analysis, SMEs loans and capital sufficiency have a statistically significant positive impact on the stability of Palestinian banks. Unobserved heterogeneity, simultaneity and dynamic endogeneity are taken into account when using the 2SLS regression approach to adjust for the study endogeneity factor.FindingsThe study’s findings show that some factors and determinants might have both good and negative effects on financial stability and banking sector. Loans to small and medium-sized businesses (SMEs) and enough capital are two characteristics that statistically have a major favourable impact on the stability of Palestinian banks since they help the banks withstand deficits. A further potential discovery relates to the favourable effects of financial inclusion (FI) and digital financial services (DFS) on the stability of banks.Research limitations/implicationsThis research has faced some limitations, such as the lack of a defined index from the regulatory organizations, this research is based on information from bank annual accounts. It has mostly relied on self-developed or World Bank indexes. Furthermore, the research solely used information from the supply side (banks); demand-side data were not taken into consideration.Practical implicationsThis paper has managerial implications for stability of banking sector. The Palestine Monetary Authority, as the central bank, must increase the percentage of bank loans directed to small and medium-sized companies and oblige bank management to adhere to adequate capital standards, which contributes to strengthening the Palestinian banking sector and increasing its profits. The study findings advise banks that are enjoying financial stability to speed up the pace of FI and DFSs because most of these reliable banks have relatively low FI ratios. PMA is responsible for preserving the stability of the financial system. PMA, decision makers and banks management must retain adequate liquidity in their institutions and raise client collateral expectations to raise credit conditions.Originality/valueThis paper adds some contributions to the literature. To adjust for discrepancies between various types of banks, the authors concentrate on conventional and Islamic banks, which enables us to use a homogenous data set as opposed to depending on dichotomous variables. The authors used Z-scores, which have recently been used in research, to measure stability and FI at the level of specific institutions. This research contributes in some key aspects that no prior research has addressed. Conventional banks are different from Islamic banks, and a number of issues might impact their stability. To evaluate the connection between FI and DFSs, it is important to consider the actions of bank regulators.

A Genome-Wide Association Study of Metabolic Syndrome in the Taiwanese Population.

The purpose of this study was to investigate genetic factors associated with metabolic syndrome (MetS) by conducting a large-scale genome-wide association study (GWAS) in Taiwan, addressing the limited data on Asian populations compared to Western populations. Using data from the Taiwan Biobank, comprehensive clinical and genetic information from 107,230 Taiwanese individuals was analyzed. Genotyping data from the TWB1.0 and TWB2.0 chips, including over 650,000 single nucleotide polymorphisms (SNPs), were utilized. Genotype imputation using the 1000 Genomes Project was performed, resulting in more than 9 million SNPs. MetS was defined based on a modified version of the Adult Treatment Panel III criteria. Among all participants (mean age: 50 years), 23% met the MetS definition. GWAS analysis identified 549 SNPs significantly associated with MetS, collectively mapping to 10 genomic risk loci. Notable risk loci included rs1004558, rs3812316, rs326, rs4486200, rs2954038, rs10830963, rs662799, rs62033400, rs183130, and rs34342646. Gene-set analysis revealed 22 associated genes: CETP, LPL, APOA5, SIK3, ZPR1, APOC1, BUD13, MLXIPL, TOMM40, GCK, YKT6, RPS6KB1, FTO, VMP1, TUBD1, BCL7B, C19orf80 (ANGPTL8), SIDT2, SENP7, PAFAH1B2, DOCK6, and FOXA2. This study identified genomic risk loci for MetS in a large Taiwanese population through a comprehensive GWAS approach. These associations provide novel insights into the genetic basis of MetS and hold promise for the potential discovery of clinical biomarkers.

Karenia brevis Extract Induces Cellular Entry through Distinct Mechanisms in Phagocytic RAW 264.7 Macrophages versus Non-Phagocytic Vero Cells.

Marine algae extracts are an important area of potential drug discovery; however, nearly all studies to date have used non-fluorescent-based methods to determine changes in target cell activity. Many of the most robust immunological and cellular analyses rely on fluorescent probes and readouts, which can be problematic when the algae extract is fluorescent itself. In this study, we identified the fluorescent spectrum of an isolated extract from the marine dinoflagellate Karenia brevis, which included two fluorescing components: chlorophyll α and pheophytin α. When excited at 405 nm and 664 nm, the extract emitted fluorescence at 676 nm and 696 nm, respectively. The extract and its fluorescing components, chlorophyll α and pheophytin α, entered phagocytic RAW 264.7 macrophages and non-phagocytic Vero kidney cells through distinct mechanisms. When incubated with the extract and its main components, both the RAW 264.7 macrophages and the Vero cells accumulated fluorescence as early as 30 min and continued through 48 h. Vero kidney cells accumulated the K. brevis fluorescent extract through a dynamin-independent and acidified endosomal-dependent mechanism. RAW 264.7 macrophages accumulated fluorescent extract through a dynamin-independent, acidified endosomal-independent mechanism, which supports accumulation through phagocytosis. Furthermore, RAW 264.7 macrophages downregulated cell-surface expression of CD206 in response to extract stimulation indicating activation of phagocytic responses and potential immunosuppression of these immune cells. This study represents the first characterization of the cellular update of K. brevis extracts in phagocytic versus non-phagocytic cells. The data suggest the importance of understanding cellular uptake of fluorescing algae extracts and their mechanism of action for future drug discovery efforts.

Zebrafish drug screening identifies Erlotinib as an inhibitor of Wnt/β-catenin signaling and self-renewal in T-cell acute lymphoblastic leukemia

The Wnt/β-catenin pathway’s significance in cancer initiation, progression, and stem cell biology underscores its therapeutic potential. However, the clinical application of Wnt inhibitors remains limited due to challenges posed by off-target effects and complex cross-talk of Wnt signaling with other pathways. In this study, we leveraged a zebrafish model to perform a robust and rapid drug screening of 773 FDA-approved compounds to identify Wnt/β-catenin inhibitors with minimal toxicity. Utilizing zebrafish expressing a Wnt reporter, we identified several drugs that suppressed Wnt signaling without compromising zebrafish development. The efficacy of the top hit, Erlotinib, extended to human cells, where it blocked Wnt/β-catenin signaling downstream of the destruction complex. Notably, Erlotinib treatment reduced self-renewal in human T-cell Acute Lymphoblastic Leukemia cells, which rely on active β-catenin signaling for maintenance of leukemia-initiating cells. Erlotinib also reduced leukemia-initiating cell frequency and delayed disease formation in zebrafish models. This study underscores zebrafish’s translational potential in drug discovery and repurposing and highlights a new use for Erlotinib as a Wnt inhibitor for cancers driven by aberrant Wnt/β-catenin signaling.

HUMAN CAPITAL AND INTELLECTUAL POTENTIAL: FEATURES AND TRENDS OF DEVELOPMENT IN KAZAKHSTAN

This article is devoted to the study of human capital, its relationship with intellectual potential. The main factor influencing the formation and accumulation of human capital is education and science. The purpose of the study is to identify the role of education, science and intellectual potential in the formation and reproduction of human capital. The article identifies the distinguishing characteristics of human capital from other types of capital, provides justification of its priority role in the economy of Kazakhstan. Varieties of investments in human capital are described. The article shows the degree of influence of education on successful realisation of professional activity of the person, gives characteristics of sources of formation of human capital, and also describes influence of education and science on process of development of human capital. The research results and conclusion provide recommendations. Their implementation will contribute to the improvement of the system of education and science, increase the quality side and efficiency, which will ultimately lead to the discovery of intellectual potential and the development of human capital as one of the competitive factors of the national economy.

A resilient bunch: stem cell antiviral immunity in plants.

Stem cells are vital for plant development and reproduction. The stem cells within shoot apical meristems are known to possess exceptionally effective antiviral defenses against pathogenic viruses which preclude their infection, yet how this is achieved remains poorly understood and scarcely investigated. In this Tansley Insight, we connect very recent experimental results with previous work to summarize the known molecular mechanisms determining stem cell antiviral immunity. More broadly, we attempt to define the viral features triggering immunity and the global consequences of virus infection in these essential cells. This brief article will highlight how these phenomena are fascinating, complex and often crucial for virus-host interactions, while emphasizing the potential for discovery in their investigation.

Secondary Metabolites of Biscogniauxia: Distribution, Chemical Diversity, Bioactivity, and Implications of the Occurrence.

The genus Biscogniauxia, a member of the family Xylariaceae, is distributed worldwide with more than 50 recognized taxa. Biscogniauxia species is known as a plant pathogen, typically acting as a parasite on tree bark, although certain members of this genus also function as endophytic microorganisms. Biscogniauxia endophytic strain has received attention in many cases, which includes constituent research leading to the discovery of various bioactive secondary metabolites. Currently, there are a total of 115 chemical compounds belonging to the class of secondary metabolites, and among these compounds, fatty acids have been identified. In addition, the strong pharmacological agents of this genus are (3aS,4aR,8aS,9aR)-3a-hydroxy-8a-methyl-3,5-dimethylenedecahydronaphto [2,3-b]furan-2(3H)-one (HDFO) (antifungal), biscopyran (phytotoxic activity), reticulol (antioxidant), biscogniazaphilone A and B (antimycobacterial), and biscogniauxone (Enzyme GSK3 inhibitor). This comprehensive research contributes significantly to the potential discovery of novel drugs produced by Biscogniauxia and holds promise for future development. Importantly, it represents the first-ever review of natural products originating from the Biscogniauxia genus.

Bioprinted Organoids Platform with Tumor Vasculature for Implementing Precision Personalized Medicine Targeted Towards Gastric Cancer

AbstractAccurate prediction of treatment response for cancer patients is essential for overcoming intrinsic therapy resistance that results from genetic heterogeneity, varying tumor growth kinetics, and the complex tumor microenvironment. To achieve this goal, there is an urgent need for effective preclinical in vitro models that recapitulate the molecular–pathologic features and intricate ecology of native tumors for precision medicine. In this study, a vascularized organoid model (VOM) composed of patient‐derived gastric cancer organoids (PDOs), perfusable endothelium, and stomach decellularized extracellular matrix is presented that enables the prediction of clinical response to VEGFR2‐targeted therapy in gastric cancer patients. The results indicate that VOMs are dependent on the PDO molecular subtype. Moreover, VOMs accurately reproduce the clinically observed responses of patients treated with VEGFR2 inhibitor. Therefore, VOMs represent a valuable platform for providing clinical predictions for personalized testing and potential discovery of therapeutic drugs in various cancers that lack standardized regimens.

IMBAS-MS Discovers Organ-Specific HLA Peptide Patterns in Plasma

Distinction of non-self from self is the major task of the immune system. Immunopeptidomics studies the peptide repertoire presented by the human leukocyte antigen (HLA) protein, usually on tissues. However, HLA peptides are also bound to plasma soluble HLA (sHLA), but little is known about their origin and potential for biomarker discovery in this readily available biofluid. Currently, immunopeptidomics is hampered by complex workflows and limited sensitivity, typically requiring several mL of plasma. Here, we take advantage of recent improvements in the throughput and sensitivity of mass spectrometry (MS)-based proteomics to develop a highly sensitive, automated, and economical workflow for HLA peptide analysis, termed Immunopeptidomics by Biotinylated Antibodies and Streptavidin (IMBAS). IMBAS-MS quantifies more than 5000 HLA class I peptides from only 200μl of plasma, in just 30min. Our technology revealed that the plasma immunopeptidome of healthy donors is remarkably stable throughout the year and strongly correlated between individuals with overlapping HLA types. Immunopeptides originating from diverse tissues, including the brain, are proportionately represented. We conclude that sHLAs are a promising avenue for immunology and potentially for precision oncology.

A brain‐seeded fibril amplification models the aggregation process of tau in Alzheimer’s disease for drug discovery

AbstractBackgroundThe microtubule‐associated protein tau is implicated in the development of a class of diverse neurodegenerative disorders, referred to as tauopathies, with symptoms of dementia and parkinsonism. Tauopathies comprise more than 20 clinicopathological entities, including Alzheimer’s disease, which accounts for 70% of dementia cases worldwide. In combination with clinical diagnosis and neuropathology, the reconstruction of different tau filaments by cryogenic electron microscopy (cryo‐EM) further points to the presence of distinct tau folds. The knowledge of these disease‐specific aggregate conformers provides a platform for the establishment of novel diagnostic methods and more tailored therapeutic approaches.MethodIn order to investigate this problem, this project aims to selectively amplify tau in vitro from human brain homogenates affected by Alzheimer’s disease (AD) and Pick’s diseases (PiD). Kinetic analysis for drug discovery for the specific process of tau aggregation that takes place in Alzheimer’s disease was performed.ResultStrain discrimination was achieved, with a significant acceleration relative to the off‐target control, suggesting formation of two different fibril structures. Cryo‐EM was performed to confirm whether the in vitro AD‐like tau aggregates resembled those extracted from brains.We identify specific tau aggregation inhibitors, through in silico docking to binding sites on the surface of the cryo‐EM structure of tau fibrils adopting an AD fold.ConclusionThe application of this line of research is illustrated by a study of the aggregation kinetics of AD‐like tau fibrils, and of its potential in drug discovery. In perspective, the approach that we present offer novel opportunities for the systematic in vitro study of the tau aggregation process as it may happen in the human brain.References(WHO), W. H. O. et al. (2019). Dementia fact sheet.Alzheimer’s disease facts and figures. Alzheimer’s and Dementia 18, 700‐789 (2022).Chia, S. et al. Structure‐Based Discovery of Small‐Molecule Inhibitors of the Autocatalytic Proliferation of alpha‐Synuclein Aggregates. Mol Pharm (2022).