Sepsis pathogenesis and outcome are shaped by the balance between the transcriptional states of systemic inflammation and antimicrobial response.

Patients with sepsis differ in their clinical presentations and immune dysregulation in response to infection, but the fundamental processes that determine this heterogeneity remain elusive. Here, we aim to understand which types of immune dysregulation characterize patients with sepsis. To that end, we investigate sepsis pathogenesis in the context of two transcriptional states: one represents the immune response to eliminate pathogens (resistance, R) and the other is associated with systemic inflammation (SI).

ConfRank: Improving GFN-FF Conformer Ranking with Pairwise Training.

Conformer ranking is a crucial task for drug discovery, with methods for generating conformers often based on molecular (meta)dynamics or sophisticated sampling techniques. These methods are constrained by the underlying force computation regarding runtime and energy ranking accuracy, limiting their effectiveness for large-scale screening applications. To address these ranking limitations, we introduce ConfRank, a machine learning-based approach that enhances conformer ranking using pairwise training.

Entangled and non-modular enhancer sequences producing independent spatial activities.

The modularity of transcriptional enhancers is central to our understanding of morphological evolution, allowing specific changes to a gene expression pattern component, without affecting others. Enhancer modularity refers to physically separated stretches of regulatory sequence producing discrete spatiotemporal transcriptional activity. This concept stems from assays that test the sufficiency of a DNA segment to drive spatial reporter expression resembling that of the corresponding gene.

Screening of Natural Compounds as Inhibitor of Mpro SARS-CoV-2 Protein; A Molecular Dynamics Approach.

Background: New strains of SARS-CoV-2 are continually emerging worldwide. Recently, WHO warned of a severe new wave in Europe. Current vaccines cannot fully prevent reinfection in vaccinated individuals.

The endocannabinoid anandamide mediates anti-inflammatory effects through activation of NR4A nuclear receptors.

Background And Purpose: Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. Tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N-arachidonoyl-ethanolamine (anandamide, AEA), this has been linked to an anti-inflammatory function. In this study, we set out to determine the anti-inflammatory mechanism of action of AEA, specifically focusing on vascular smooth muscle cells.

Health-Related Quality of Life and Experiences of Minor Children With Parental Cancer-A Family-Based Multilevel Analysis of Determinants.

Objective: Children in families with parental cancer may experience emotional, social or physical problems. The aims are to analyze child, parent and family-based determinants of children's health-related quality of life (HRQoL) and their experiences of parental cancer.

Methods: As part of a mixed-methods, multicenter, prospective, interventional non-randomized study "Family-SCOUT," a family-centered intervention in the form of care and case management was developed.

Validation of SSR markers for identification of high-yielding and Phytophthora Capsici root rot resistant chilli genotypes.

The study was designed to validate the previously reported 34 SSR markers using 78 chilli genotypes to detect significant trait specific markers as well as superior genotypes resistant to Phytophthora capsici root rot (PcRR). In this context, the identification of germplasm with higher yield per plant (YPP) leads to hype in stress tolerance index (STI) in genotypes, Chakwal3 (11.98), Greenfire (10.

Identification of phosphatases that dephosphorylate the co-chaperone BAG3.

The co-chaperone BAG3 plays critical roles in maintaining cellular proteostasis. It associates with 14-3-3 proteins during the trafficking of aggregation-prone proteins and facilitates their degradation through chaperone-assisted selective autophagy in cooperation with small heat shock proteins. Although reversible phosphorylation regulates BAG3 function, the involved phosphatases remain unknown.

RNA-Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post-Transcriptional Manner.

Stimulating cardiomyocyte (CM) dedifferentiation and cell cycle activity (DACCA) is essential for triggering daughter CM formation. In addition to transcriptional processes, RNA-binding proteins (RBPs) are emerging as crucial post-transcriptional players in regulating CM DACCA. However, whether post-transcriptional regulation of CM DACCA by RBPs could effectively trigger daughter CM formation remains unknown.

Prediction of the chance of successful immune tolerance induction in persons with severe hemophilia A and inhibitors: a clinical prediction model.

Background: Inhibitor eradication to restore factor (F)VIII efficacy is the treatment goal for persons with severe hemophilia A (HA) and inhibitors. Immune tolerance induction (ITI) is demanding and successful in about 70% of people. Until now, it has remained difficult to quantify the probability of ITI success or failure, complicating the decision to initiate or not initiate ITI.

Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype.

Diffuse pediatric-type high-grade gliomas (pedHGG), H3- and IDH-wildtype, encompass three main DNA-methylation-based subtypes: pedHGG-MYCN, pedHGG-RTK1A/B/C, and pedHGG-RTK2A/B. Since their first description in 2017 tumors of pedHGG-RTK2A/B have not been comprehensively characterized and clinical correlates remain elusive. In a recent series of pedHGG with a Gliomatosis cerebri (GC) growth pattern, an increased incidence of pedHGG-RTK2A/B (n = 18) was observed.

Forecasting the future of smart hospitals: findings from a real-time delphi study.

Background: In concert with other digital technologies, artificial intelligence (AI) is shaping the vision of smart hospitals. The transformation into smart hospitals, however, is all but trivial due to the lack of financial and human resources, digital skills, and supporting policies. Thus, the extent to which the vision of smart hospitals will eventually become reality is uncertain.

Assessment of trace organic chemicals in anaerobically digested sludge and their partitioning behaviour: Simultaneous Soxhlet chemical extraction and quantification via LC-MS/MS analysis.

The increasing number of trace organic contaminants (TrOCs) detected in anaerobically digested sludge (ADS) is triggering increasing concern on its circular-economy reuse practices. A large scientific effort has been performed to define their concentration limits, partition behaviour, and innovative technologies for their removal, which require the definition of versatile and economically sustainable analytical methodologies. In this study, a Soxhlet extraction method coupled with LC-MS/MS analysis was developed to simultaneously determine 32 TrOCs in ADS, 11 of them being quantified in this matrix for the first time.

The role of systemic immune-inflammation index in predicting pathological complete response of breast cancer after neoadjuvant therapy and the establishment of related predictive model.

Objective: To investigate the role of systemic immune-inflammation index (SII) in complete pathological response (pCR) of breast cancer patients after neoadjuvant chemotherapy, and to establish and validate a nomogram for predicting pCR.

Methods: Breast cancer patients were selected from the First Affiliated Hospital of Xi'an Jiaotong University from January 2020 to December 2023. The optimal cut-off value of SII was calculated via ROC curve.

Activating p53 with a Mutant-Specific Small Molecule.

is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 () due to its ability to engage mutant p53 and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription.

Sensing, feeling and sentience in unicellular organisms and living cells.

Cells represent the basic units of life, not only as structural building blocks, but also as cognitive agents endowed with subjective cellular feelings, sentience (consciousness), and cognitive infocomputatioal competence. Living cells act as 'Kantian Wholes': All of its parts exist for and by means of the whole system, allowing cells to use sentient agency for solving existential problems and evolve as living self-organizing units. Cell sentience is based on its excitable plasma membrane generating bioelectromagnetic fields that link to a whole-cell sensory architecture.

Starvation-induced metabolic rewiring affects mTORC1 composition in vivo.

Lysosomes play a crucial role in metabolic adaptation to starvation, but detailed in vivo studies are scarce. Therefore, we investigated the changes of the proteome of liver lysosomes in mice starved short-term for 6h or long-term for 24h. We verified starvation-induced catabolism by weight loss, ketone body production, drop in blood glucose and an increase of 3-methylhistidine.

Multicomponent syntheses enable the discovery of novel quisinostat-derived chemotypes as histone deacetylase inhibitors.

In this study, we synthesized and evaluated novel histone deacetylase (HDAC) inhibitors derived from the clinical candidate quisinostat. A library of 16 compounds categorized in three novel chemotypes was rapidly generated using multicomponent reactions (MCRs), enabling efficient structure-activity relationship studies. First, the compounds were evaluated for their activity against the Plasmodium falciparum strains 3D7 and Dd2, the main malaria-causing parasite, identifying compound 18b of the type C series as the most potent.

Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a de facto innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli.

Simulation of soil phosphorus dynamics and crop yield for organic and mineral fertilization treatments at two long-term field sites.

The efficacy of phosphorus (P) based fertilizers is frequently compromised by soil dynamics that render much of the applied P unavailable for crops. This study aimed to: (i) validate a new P model's prediction of plant-available P; (ii) analyze the effects of organic versus mineral fertilization on P availability and crop yield; and (iii) examine temporal changes in P pools under various fertilization regimes. Data were collected from two long-term field trials, Dikopshof and Bad Lauchstädt, in Germany, using organic (FYM), mineral (MIN), a combination of organic and mineral (MIX) fertilizers, and unfertilized treatments.

Fine-tuning stress responses by auxiliary feedback loops that sense damage repair.

Mogk and den Brave discuss exciting results from a comprehensive screen of heat shock response components in yeast, published in this issue by Pincus and colleagues (https://doi.org/10.1083/jcb.

Functional connectivity changes in two cortico-hippocampal networks of Alzheimer's disease continuum and their correlations with cognition: A SILCODE study.

Background: The anterior-temporal (AT) and posterior-medial (PM) networks have been proposed to play pivotal roles in the memory processing associated with Alzheimer's disease (AD). Nevertheless, these two networks' intrinsic functional coupling characteristics are still vague in different AD stages.

Objective: To explore the functional connectivity (FC) alterations within and across the AT&PM networks in patients with dementia of the Alzheimer's type (DAT), mild cognitive impairment (MCI), subjective cognitive decline (SCD), and normal controls (NC).