Stromal architecture and fibroblast subpopulations with opposing effects on outcomes in hepatocellular carcinoma.

Dissecting the spatial heterogeneity of cancer-associated fibroblasts (CAFs) is vital for understanding tumor biology and therapeutic design. By combining pathological image analysis with spatial proteomics, we revealed two stromal archetypes in hepatocellular carcinoma (HCC) with different biological functions and extracellular matrix compositions. Using paired single-cell RNA and epigenomic sequencing with Stereo-seq, we revealed two fibroblast subsets CAF-FAP and CAF-C7, whose spatial enrichment strongly correlated with the two stromal archetypes and opposing patient prognosis.

Genetic coupling of enhancer activity and connectivity in gene expression control.

Gene enhancers often form long-range contacts with promoters, but it remains unclear if the activity of enhancers and their chromosomal contacts are mediated by the same DNA sequences and recruited factors. Here, we study the effects of expression quantitative trait loci (eQTLs) on enhancer activity and promoter contacts in primary monocytes isolated from 34 male individuals. Using eQTL-Capture Hi-C and a Bayesian approach considering both intra- and inter-individual variation, we initially detect 19 eQTLs associated with enhancer-eGene promoter contacts, most of which also associate with enhancer accessibility and activity.

Targeting glycolytic reprogramming by tsRNA-0032 for treating pathological lymphangiogenesis.

Lymphangiogenesis is vital for tissue fluid homeostasis, immune function, and lipid absorption. Abnormal lymphangiogenesis has been implicated in several diseases such as cancers, inflammatory, and autoimmune diseases. In this study, we elucidate the role of tsRNA-0032 in lymphangiogenesis and its molecular mechanism.

Splicing accuracy varies across human introns, tissues, age and disease.

Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigate splicing accuracy using RNA-sequencing data from >14k control samples and 40 human body sites, focusing on split reads partially mapping to known transcripts in annotation.

Transcription enhanced associate domain factor 1 (TEAD1) predicts liver regeneration outcome of ALPPS-treated patients.

Background: The two-stage surgical technique of associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) enables extensive liver resection and promotes future liver remnant regeneration (FLR), in part by inhibiting the Hippo signalling pathway. Its main effector, Yes-associated protein (YAP), has low intrinsic transcriptional activity and requires the transcription enhanced associated domain factor (TEAD) family members as cofactors for target gene transcription. We evaluated the intracellular localization and expression of TEAD1-4, hypothesized to regulate the activity of YAP and, consequently, liver regeneration.

A role for mitochondria-ER crosstalk in amyotrophic lateral sclerosis 8 pathogenesis.

Protein aggregates in motoneurons, a pathological hallmark of amyotrophic lateral sclerosis, have been suggested to play a key pathogenetic role. ALS8, characterized by ER-associated inclusions, is caused by a heterozygous mutation in VAPB, which acts at multiple membrane contact sites between the ER and almost all other organelles. The link between protein aggregation and cellular dysfunction is unclear.

Comparative impact of tertiary lymphoid structures and tumor-infiltrating lymphocytes in cholangiocarcinoma.

Background: Cholangiocarcinoma is a challenging malignancy with limited responses to conventional therapies, particularly immune checkpoint inhibitor therapy. Tumor-infiltrating lymphocytes (TILs) and tertiary lymphoid structures (TLSs) are key components of the tumor microenvironment (TME) and have been implicated in the immune response to cancer. However, the role and difference of TLSs and TILs in patients with cholangiocarcinoma remains unclear.

Strengthening advanced therapy for sickle cell disease in Africa: experience from sickle cell disease centre in Dar es Salaam, Tanzania.

Despite progress in healthcare services for individuals living with sickle cell disease (SCD) in Africa, substantial gaps remain in advanced treatments for SCD. To help address this burden, Tanzania has established one of the largest single-centre SCD programmes in the world and developed an advanced therapy programme for SCD focused on patient engagement and advocacy, clinical activities involving exchange blood transfusion (ExBT) and haematopoietic stem cell transplant (HSCT), gene therapy (GT) preparedness, and enabling partnerships. This report describes the programme's genesis, structure and progress achieved.

Structural analysis of human ADAR2-RNA complexes by X-ray crystallography.

Adenosine deaminases acting on RNAs (ADARs) are a class of RNA editing enzymes found in metazoa that catalyze the hydrolytic deamination of adenosine to inosine in duplexed RNA. Inosine is a nucleotide that can base pair with cytidine, therefore, inosine is interpreted by cellular processes as guanosine. ADARs are functionally important in RNA recoding events, RNA structure modulation, innate immunity, and can be harnessed for therapeutically-driven base editing to treat genetic disorders.

Mouse models for understanding physiological functions of ADARs.

Adenosine-to-inosine (A-to-I) editing, is a highly prevalent posttranscriptional modification of RNA, mediated by the adenosine deaminases acting on RNA (ADAR) proteins. Mammalian transcriptomes contain tens of thousands to millions of A-to-I editing events. Mutations in ADAR can result in rare autoinflammatory disorders such as Aicardi-Goutières syndrome (AGS) through to irreversible conditions such as motor neuron disease, amyotrophic lateral sclerosis (ALS).

The multifaceted roles of retinoids in eye development, vision, and retinal degenerative diseases.

Vitamin A (all-trans-retinol; at-Rol) and its derivatives, known as retinoids, have been adopted by vertebrates to serve as visual chromophores and signaling molecules, particularly in the eye/retina. Few tissues rely on retinoids as heavily as the retina, and the study of genetically modified mouse models with deficiencies in specific retinoid-metabolizing proteins has allowed us to gain insight into the unique or redundant roles of these proteins in at-Rol uptake and storage, or their downstream roles in retinal development and function. These processes occur during embryogenesis and continue throughout life.

Expanding the phenotypic spectrum of PROS: reclassifying isolated lateralised overgrowth.

Lateralised overgrowth (LO) is characterised by the asymmetric increase in the size of any part of the body exceeding 10% compared with the unaffected contralateral one. LO is a key feature in various syndromic overgrowth disorders, such as Beckwith-Wiedemann spectrum and -related overgrowth spectrum (PROS). However, it can also present as isolated (ILO).

microbiota model recapitulates and predicts individualised sensitivity to dietary emulsifier.

Background: Non-absorbed dietary emulsifiers, including carboxymethylcellulose (CMC), directly disturb intestinal microbiota, thereby promoting chronic intestinal inflammation in mice. A randomised controlled-feeding study (Functional Research on Emulsifiers in Humans, FRESH) found that CMC also detrimentally impacts intestinal microbiota in some, but not all, healthy individuals.

Objectives: This study aimed to establish an approach for predicting an individual's sensitivity to dietary emulsifiers via their baseline microbiota.

The Autonomic Nervous System and Inflammation in Chronic Kidney Disease.

The autonomic nervous system plays a crucial role in regulating physiological processes and maintaining homeostasis through its two branches: the sympathetic nervous system (SNS) and the parasympathetic nervous system. Dysregulation of the autonomic system, characterized by increased sympathetic activity and reduced parasympathetic tone, is a common feature in chronic kidney disease (CKD) and cardiovascular disease. This imbalance contributes to a pro-inflammatory state, exacerbating disease progression and increasing the risk for cardiovascular events.

Optimized Scaffold-Free Human 3D Adipose Tissue Organoid Culture for Obesity and Disease Modeling.

Obesity and type 2 diabetes (T2D) are strongly linked to abnormal adipocyte metabolism and adipose tissue (AT) dysfunction. However, existing adipose tissue models have limitations, particularly in the stable culture of fat cells that maintain physiologically relevant phenotypes, hindering a deeper understanding of adipocyte biology and the molecular mechanisms behind differentiation. Current model systems fail to fully replicate in vivo metabolism, posing challenges in adipose research.

Prospective analysis of biomarkers associated with successful faecal microbiota transplantation in recurrent Clostridioides difficile Infection.

Objectives: Faecal microbiota transplantation (FMT) is an established treatment for recurrent Clostridioides difficile infection (R-CDI). This study aimed to identify calprotectin and microbiome characteristics as potential biomarkers of FMT success.

Methods: We conducted a prospective study of patients who underwent oral FMT (single dose of 4-5 capsules) for R-CDI (January 2018 to December 2022).

The Anti-Neuroinflammatory Effects of Cepharanthine in Uric Acid-Induced Neuroinflammation.

Ethnopharmacological Relevance: Cepharanthine (CEP) is an alkaloid extracted from Stephania cephalantha Hayata, a traditional Chinese medicine (TCM) renowned for its heatclearing and dehumidifying properties. For centuries, Stephania cephalantha Hayata has been employed in the treatment of a wide range of diseases, including pain, edema, inflammation, and fever.

Aim Of The Study: Our research aims to investigate the role and mechanism of Cepharanthine in ameliorating uric acid (UA) induced neuroinflammatory responses.

Uncovering the naturally occurring covalent inhibitors of SARS-CoV-2 M from the Chinese medicine sappanwood and deciphering their synergistic anti-M effects.

Ethnopharmacological Relevance: The Chinese medicine sappanwood is primarily sourced from the dried heartwood of the medicinal plant Caesalpinia sappan Linn., which has been found with a variety of valuable properties including anti-inflammatory, anti-oxidant, and anti-viral effects. Preliminary investigations have demonstrated that sappanwood showed strong anti-SARS-CoV-2 M effects, but the key constituents responsible for SARS-CoV-2 M inhibition and their anti-M mechanisms have not been uncovered.

Kinetic and structural investigation of the 4-allyl syringol oxidase from Streptomyces cavernae.

4-Phenol oxidases are proposed to be involved in the utilization of lignin-derived aromatic compounds. While enzymes with selectivity towards 4-hydroxyphenyl and guaiacyl motifs are well described, we identified the first syringyl-specific oxidase from Streptomyces cavernae (Sc4ASO) only very recently. Here, in-depth studies were conducted to unravel the molecular origins of the outstanding selectivity of Sc4ASO.

Biochemical, structural, and cellular characterization of S-but-3-yn-2-ylglycine as a mechanism-based covalent inactivator of the flavoenzyme proline dehydrogenase.

The mitochondrial flavoenzymes proline dehydrogenase (PRODH) and hydroxyproline dehydrogenase (PRODH2) catalyze the first steps of proline and hydroxyproline catabolism, respectively. The enzymes are targets for chemical probe development because of their roles in cancer cell metabolism (PRODH) and primary hyperoxaluria (PRODH2). Mechanism-based inactivators of PRODH target the FAD by covalently modifying the N5 atom, with N-propargylglycine (NPPG) being the current best-in-class of this type of probe.

Folic acid-targeted β-lactoglobulin nanocarriers for enhanced delivery of 5-fluorouracil and sodium butyrate in colorectal cancer treatment.

Colorectal cancer (CRC) remains a significant public health concern, emphasizing the need for innovative therapeutic strategies to improve patient outcomes. This study aimed to develop a highly efficient nanocarrier for targeted drug delivery, enhancing drug efficacy while minimizing concentrations and limiting adverse effects. We synthesized protein-based β-lactoglobulin (βlg) nanoparticles (NPs), loaded with 5-fluorouracil (5-FU) and sodium butyrate (NaB), and further functionalized with folic acid (FA) for specific targeting of folate receptor-positive CRC cells.

Advances in the therapeutic potentials of ligands of the apelin receptor APJ.

Angiotensin II protein J receptor, APJ, is a type A G protein coupled receptor. Endogenous apelin and elabela peptides stimulate APJ via distinct signalling profiles. A complex signalling map of elabela-stimulated APJ was published in 2022.

NKAP: a new m6A RNA binding protein predicts prognosis and immunotherapy response in head and neck squamous cell carcinoma.

Objective: This study aimed to investigate whether NKAP (nuclear factor κB activating protein) serves as a prognostic marker and predictive biomarker for immunotherapy response in head and neck squamous cell carcinoma (HNSCC).

Methods: A retrospective cohort study combined with in vitro analyses was conducted. NKAP mRNA expression levels were assessed in 520 HNSCC tumor tissues and 44 normal tissues from the TCGA dataset and validated in a clinical cohort (n=32).

Assessing the impact of TiO nanomaterials on intestinal cells: new evidence for epithelial translocation and potential pro-inflammatory effects.

Understanding the potential impact of nanomaterials (NMs) on human health requires further investigation into the organ-specific nano-bio interplay at the cellular and molecular levels. We showed increased chromosomal damage in intestinal cells exposed to some of in vitro digested Titanium dioxide (TiO) NMs. The present study aimed to explore possible mechanisms linked to the uptake, epithelial barrier integrity, cellular trafficking, as well as activation of pro-inflammatory pathways, after exposure to three TiO-NMs (NM-102, NM-103, and NM-105).