Possible compensatory role of cerebellum in bipolar disorder. A cortical thickness study.

Recent studies suggested that structural changes in the cerebellum are implicated in the pathophysiology of bipolar disorder (BD). Here, we aimed to characterize the structural alterations of cerebellar lobules in BD, evaluating their possible relation with those occurring in the rest of the brain. One-hundred-fifty-five type I BD patients were recruited and compared with one-hundred-nineteen controls subjects.

Interleukin 1 β suppresses bile acid-induced BSEP expression via a CXCR2-dependent feedback mechanism.

Inflammation-induced cholestasis is a common problem in septic patients and results from cytokine-mediated inhibition of bile acid export including impaired expression of the bile salt export pump (BSEP) with a consecutive increase in intracellular bile acids mediating cell damage. The present study focuses on the mechanisms by which interleukin 1 β (IL-1β), as a critical mediator of sepsis-induced cholestasis, controls the expression of BSEP in hepatocytes. Notably, the treatment of hepatocytes with IL-1β leads to the upregulation of a broad chemokine pattern.

Metagenomic study of lake microbial mats reveals protease-inhibiting antiviral peptides from a core microbiome member.

In contrast to the large body of work on bioactive natural products from individually cultivated bacteria, the chemistry of environmental microbial communities remains largely elusive. Here, we present a comprehensive bioinformatic and functional study on a complex and interaction-rich ecosystem, algal-bacterial (microbial) mats of Lake Chilika in India, Asia's largest brackish water body. We report the bacterial compositional dynamics over the mat life cycle, >1,300 reconstructed environmental genomes harboring >2,200 biosynthetic gene clusters (BGCs), the successful cultivation of a widespread core microbiome member belonging to the genus , heterologous reconstitution of two silent biosynthetic pathways, and new compounds with potent protease inhibitory and antiviral activities.

Capsules for Automated Azide-Alkyne Click Reactions.

The development of an automated and reproducible process for copper-mediated click reactions of alkynes and azides into 1,4-disubstituted 1,2,3-triazole products is described. This method utilizes prepacked capsules that contain all necessary reagents and materials for the reaction and purification processes. The reaction and product isolation steps are fully automated with no further user involvement, resulting in the triazole products in high purity.

Thrombin receptor PAR4 cross-activates the tyrosine kinase c-met in atrial cardiomyocytes.

Thrombin supports coagulation-independent inflammation via protease-activated receptors (PAR). PAR4 is specifically increased in obese human atria, correlating with NLRP3 inflammasome activation. PAR4-mediated NLRP3 inflammasome activation in atrial cardiomyocytes is not known, nor have signaling partners been identified.

Trajectories and predictive significance of inflammatory parameters for clinical outcome in COVID-19 patients treated with tocilizumab.

Purpose: The IL-6 receptor inhibitor tocilizumab reduces mortality and morbidity in severe cases of COVID-19 through its effects on hyperinflammation and was approved as adjuvant therapy. Since tocilizumab changes the levels of inflammatory markers, we aimed to describe these changes in patients treated with tocilizumab, analyse their value in predicting death and bacterial superinfection and determine their influence on mortality rates.

Methods: A retrospective analysis of 76 patients who were treated with tocilizumab for severe COVID-19 in 2020 and 2021 was conducted.

Dynamics of Virological and Clinical Response Parameters of Bulevirtide Treatment for Hepatitis D: Real-World Data.

Background And Aims: The entry inhibitor bulevirtide represents the first specific treatment for hepatitis-D virus (HDV)-infected patients. In clinical trials, around 80% of patients achieve normalization of alanine aminotransferase (ALT) with about 60% virological response after 1 year, but little is known about the dynamics of responses and clinical predictors of treatment outcomes. We report our single-center data from 15 patients and describe response dynamics, clinical outcomes, and predictive factors for treatment response.

Development of radiofluorinated MLN-4760 derivatives for PET imaging of the SARS-CoV-2 entry receptor ACE2.

Purpose: The angiotensin converting enzyme 2 (ACE2) plays a regulatory role in the cardiovascular system and serves SARS-CoV-2 as an entry receptor. The aim of this study was to synthesize and evaluate radiofluorinated derivatives of the ACE2 inhibitor MLN-4760. [F]F-MLN-4760 and [F]F-Aza-MLN-4760 were demonstrated to be suitable for non-invasive imaging of ACE2, potentially enabling a better understanding of its expression dynamics.

Automated Synthesis for the Safe Production of Organic Azides from Primary Amines.

Described herein is the development of an automated and reproducible process for the conversion of primary amines to organic azides utilizing prepacked capsules containing all the required reagents, including imidazole-1-sulfonyl azide tetrafluoroborate. Apart from manually loading the primary amine into the reaction vessel, the entire reaction and product isolation process can be achieved automatically, with no further user involvement, and delivers the desired organic azide in high purity. This practical and simple automated capsule-based method offers a convenient and safe way of generating organic azides without handling or exposure of potentially explosive reagents.

Soluble urokinase plasminogen activator receptor levels predict survival in patients with portal hypertension undergoing TIPS.

Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective therapy for complications of portal hypertension. However, clinical outcomes following TIPS placement vary widely between patients and identifying ideal candidates remains a challenge. Soluble urokinase plasminogen activator receptor (suPAR) is a circulating marker of immune activation that has previously been associated with liver inflammation, but its prognostic value in patients receiving TIPS is unknown.

The thrombin receptor PAR4 supports visceral adipose tissue inflammation.

Thrombin inhibition suppresses adiposity, WAT inflammation and metabolic dysfunction in mice. Protease-activated receptor (PAR)1 does not account for thrombin-driven obesity, so we explored the culprit role of PAR4 in this context. Male WT and PAR-4 mice received a high fat diet (HFD) for 8 weeks, WT controls received standard chow.

Chemical Synthesis of Secretoglobin 3A2 Covalent Homodimer and Photocaged Monomeric Variants.

Secretoglobin (SCGB) 3A2 belongs to an intriguing family of small, secreted proteins present only in mammals. Although members of the SCGB protein family have distinct amino acid sequences, they share structural similarities. Of particularly interest is the not yet fully understood self-assembly ability of SCGBs, which arise from covalent disulfide dimerization and non-covalent oligomerization.

Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction.

Inhibition of K-RAS effectors like B-RAF or MEK1/2 is accompanied by treatment resistance in cancer patients via re-activation of PI3K and Wnt signaling. We hypothesized that myotubularin-related-protein-7 (MTMR7), which inhibits PI3K and ERK1/2 signaling downstream of RAS, directly targets RAS and thereby prevents resistance. Using cell and structural biology combined with animal studies, we show that MTMR7 binds and inhibits RAS at cellular membranes.

Peptide-Directed Attachment of Hydroxylamines to Specific Lysines of IgG Antibodies for Bioconjugations with Acylboronates.

The role of monoclonal antibodies as vehicles to deliver payloads has evolved as a powerful tool in cancer therapy in recent years. The clinical development of therapeutic antibody conjugates with precise payloads holds great promise for targeted therapeutic interventions. The use of affinity-peptide mediated functionalization of native off-the-shelf antibodies offers an effective approach to selectively modify IgG antibodies with a drug-antibody ratio (DAR) of 2.

Nationwide quality assurance of high-throughput diagnostic molecular testing during the SARS-CoV-2 pandemic: role of the Belgian National Reference Centre.

Since the onset of the coronavirus disease (COVID-19) pandemic in Belgium, UZ/KU Leuven has played a crucial role as the National Reference Centre (NRC) for respiratory pathogens, to be the first Belgian laboratory to develop and implement laboratory developed diagnostic assays for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and later to assess the quality of commercial kits. To meet the growing demand for decentralised testing, both clinical laboratories and government-supported high-throughput platforms were gradually deployed across Belgium. Consequently, the role of the NRC transitioned from a specialised testing laboratory to strengthening capacity and coordinating quality assurance.

T-cell immunophenotype correlations with cortical thickness and white matter microstructure in bipolar disorder.

Background: Inflammation and immunological alterations, such as T-cell and cytokine changes, are implicated in bipolar disorder (BD), with some evidence linking them to brain structural changes (e.g., cortical thickness (CT), gray matter (GM) volume and white matter (WM) microstructure).

Perioperative outcome and long-term survival for intrahepatic cholangiocarcinoma after portal vein embolization and subsequent resection: A propensity-matched study.

Introduction: In view of the high therapeutic value of surgical resection for intrahepatic cholangiocarcinomas (ICC), our study addresses the question of clinical management and outcome in case of borderline resectability requiring hypertrophy induction of the future liver remnant prior to resection.

Methods: Clinical data was collected of all primary ICC cases receiving major liver resection with or without prior portal vein embolization (PVE) from a single high-volume center. PVE was performed via a percutaneous transhepatic access.

High-throughput synthesis provides data for predicting molecular properties and reaction success.

The generation of attractive scaffolds for drug discovery efforts requires the expeditious synthesis of diverse analogues from readily available building blocks. This endeavor necessitates a trade-off between diversity and ease of access and is further complicated by uncertainty about the synthesizability and pharmacokinetic properties of the resulting compounds. Here, we document a platform that leverages photocatalytic N-heterocycle synthesis, high-throughput experimentation, automated purification, and physicochemical assays on 1152 discrete reactions.

Biocompatible Lysine Protecting Groups for the Chemoenzymatic Synthesis of K48/K63 Heterotypic and Branched Ubiquitin Chains.

The elucidation of emerging biological functions of heterotypic and branched ubiquitin (Ub) chains requires new strategies for their preparation with defined lengths and connectivity. While enzymatic assembly using expressed E1-activating and E2-conjugating enzymes can deliver homotypic chains, the synthesis of branched chains typically requires extensive mutations of lysines or other sequence modifications. The combination of K48- and K63-biased E2-conjugating enzymes and two new carbamate protecting groups-pyridoxal 5'-phosphate (PLP)-cleavable aminobutanamide carbamate (Abac group) and periodate-cleavable aminobutanol carbamate (Aboc group)-provides a strategy for the synthesis of heterotypic and branched Ub trimers, tetramers, and pentamers.

A surgical strategy for intrahepatic cholangiocarcinoma - the hilar first concept.

Purpose: The present study assesses long-term overall survival (OS) and disease-free survival (DFS) after curative resection for intrahepatic cholangiocarcinoma (ICCA) depending on resection margin (RM) status and lymph node (LN) status.

Methods: Clinical data of all consecutively resected patients with ICCA at a single high-volume center between 2005 and 2018 were collected. Minimum follow-up was 36 months.

Molecular dynamics studies of the solubility behavior of carbon dioxide (CO ), difluoromethane (R-32), 1-chloro-3,3,3-trifluoropropene (R-1233zd(E)) and 2,3,3,3-tetrafluoro-1-propene (R-1234yf) in pentaerythritol tetra(2-ethylhexanoate) (PEB8), pentaerythritol tetrabutyrate (PEC4) and pentaerythritol tetraoctanoate (PEC8).

To reduce the climate impact of thermal engines such as heat pumps or refrigeration machines, refrigerants with a low global warming potential need to be paired with fitting lubricants. As the contamination of those liquid components influences the efficiency and lifetime of these machines, knowledge about their solubility behavior is of great interest. Molecular simulations offer mighty tools to investigate these solubilities while giving structural insight into the systems.

Hepatocytes reprogram liver macrophages involving control of TGF-β activation, influencing liver regeneration and injury.

Background: Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in terms of their activation state and which other liver cell populations may play a role in regulating the same.

Methods: Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy.

A Cellular Ground Truth to Develop MRI Signatures in Glioma Models by Correlative Light Sheet Microscopy and Atlas-Based Coregistration.

Glioblastoma is the most common malignant primary brain tumor with poor overall survival. Magnetic resonance imaging (MRI) is the main imaging modality for glioblastoma but has inherent shortcomings. The molecular and cellular basis of MR signals is incompletely understood.