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Large-scale computing technologies have enabled high-throughput virtual screening involving thousands to millions of drug candidates. It is not trivial, however, for biochemical scientists to evaluate the technical alternatives and their implications for running such large experiments. Besides experience with the molecular docking tool itself, the scientist needs to learn how to run it on high-performance computing (HPC) infrastructures, and understand the impact of the choices made. Here, we review such considerations for a specific tool, AutoDock Vina, and use experimental data to illustrate the following points: (1) an additional level of parallelization increases virtual screening throughput on a multi-core machine; (2) capturing of the random seed is not enough (though necessary) for reproducibility on heterogeneous distributed computing systems; (3) the overall time spent on the screening of a ligand library can be improved by analysis of factors affecting execution time per ligand, including number of active torsions, heavy atoms and exhaustiveness. We also illustrate differences among four common HPC infrastructures: grid, Hadoop, small cluster and multi-core (virtual machine on the cloud). Our analysis shows that these platforms are suitable for screening experiments of different sizes. These considerations can guide scientists when choosing the best computing platform and set-up for their future large virtual screening experiments.

Mammalian genomes harbor abundant transposable elements (TEs) and their remnants, with numerous epigenetic repression mechanisms enacted to silence TE transcription. However, TEs are upregulated during early development, neuronal lineage, and cancers, although the epigenetic factors contributing to the transcription of TEs have yet to be fully elucidated. Here, we demonstrate that the male-specific lethal (MSL)-complex-mediated histone H4 acetylation at lysine 16 (H4K16ac) is enriched at TEs in human embryonic stem cells (hESCs) and cancer cells. This in turn activates transcription of subsets of full-length long interspersed nuclear elements (LINE1s, L1s) and endogenous retrovirus (ERV) long terminal repeats (LTRs). Furthermore, we show that the H4K16ac-marked L1 and LTR subfamilies display enhancer-like functions and are enriched in genomic locations with chromatin features associated with active enhancers. Importantly, such regions often reside at boundaries of topologically associated domains and loop with genes. CRISPR-based epigenetic perturbation and genetic deletion of L1s reveal that H4K16ac-marked L1s and LTRs regulate the expression of genes in cis . Overall, TEs enriched with H4K16ac contribute to the cis -regulatory landscape at specific genomic locations by maintaining an active chromatin landscape at TEs. Here, the authors show that chromatin at certain transposable elements (TEs) is coated with acetylation at H4K16, which can lead to increased local chromatin accessibility and transcription activation. In turn, these acetylated TEs display enhancer-like capabilities to regulate gene expression in cis .

Background Asbestos, a group of naturally occurring fibrous silicate minerals, is known for its fire-resistant and insulating properties but is also recognized as a cause of several diseases, including mesothelioma and lung cancer. Lung content analysis using electron microscopy is considered the most reliable method for assessing past asbestos exposure, especially in medico-legal settings. However, there is no universally accepted reference value to distinguish between background and risk-associated exposure levels. This systematic review evaluates the quantification and time trends of asbestos lung burden in the general population over recent decades. Main body Twenty studies published between 1980 and 2023 were included, analysing asbestos lung content from autopsies performed between 1967 and 2023 on 890 individuals from diverse geographic regions. All studies detected asbestos in lung tissue, with concentrations ranging from 3187 to 7,310,000 fibres per gram of dry weight (ff/gdw). Most studies reported values above thresholds often cited for background exposure. No clear trend in asbestos concentration or fibre type was observed over time. Recent studies from Italy, conducted after the national asbestos ban, showed variable results: one reported concentrations above 100,000 ff/gdw in Milan, while another found much lower levels elsewhere in Northern Italy. Amphiboles such as tremolite may contaminate chrysotile, and their presence in lung tissue could reflect either industrial use or other environmental sources. Amphiboles have lower solubility in the respiratory tract, whereas chrysotile may dissolve more rapidly. Data comparability across studies and laboratories is limited due to methodological differences, as previously noted in the literature. This review summarizes studies conducted in US, Canada, Japan, Korea and Europe, based on autopsies from individuals without occupational asbestos exposure. Conclusion Asbestos is consistently found in lung tissue from the general population, with no evident decline in concentrations over the past five decades. The persistence of non-commercial amphiboles, even after regulatory bans, highlights ongoing environmental exposure and complicates disease attribution in medico-legal contexts. The current literature is limited and methodologically heterogeneous, underscoring the need for standardized laboratory methods and updated reference values. However, surveillance of asbestos-related diseases, especially mesothelioma, requires detailed exposure assessment, including patient interviews, as mineral particle levels alone may not capture individual susceptibility or exposure history.

Respiratory syncytial virus (RSV) is a major cause of diseases of the respiratory tract in young children and babies, being mainly associated with bronchiolitis. RSV infection occurs primarily in pulmonary epithelial cells and, once infection is established, an immune response is triggered and neutrophils are recruited. In this study, we investigated the mechanisms underlying NET production induced by RSV. We show that RSV induced the classical ROS-dependent NETosis in human neutrophils and that RSV was trapped in DNA lattices coated with NE and MPO. NETosis induction by RSV was dependent on signaling by PI3K/AKT, ERK and p38 MAPK and required histone citrullination by PAD-4. In addition, RIPK1, RIPK3 and MLKL were essential to RSV-induced NETosis. MLKL was also necessary to neutrophil necrosis triggered by the virus, likely promoting membrane-disrupting pores, leading to neutrophil lysis and NET extrusion. Finally, we found that RSV infection of alveolar epithelial cells or lung fibroblasts triggers NET-DNA release by neutrophils, indicating that neutrophils can identify RSV-infected cells and respond to them by releasing NETs. The identification of the mechanisms responsible to mediate RSV-induced NETosis may prove valuable to the design of new therapeutic approaches to treat the inflammatory consequences of RSV bronchiolitis in young children.

Bioactive dietary agents have been shown to regulate multiple cancer hallmark pathways. Epidemiologic studies have linked consumption of Allium vegetables, such as garlic and onions, to decreased incidence of cancer. Diallyl trisulfide (DATS), a bioactive compound derived from Allium vegetables, has been investigated as an anti-cancer and chemopreventive agent. Preclinical studies provide ample evidence that DATS regulates multiple cancer hallmark pathways including cell cycle, apoptosis, angiogenesis, invasion, and metastasis. DATS has been shown to arrest cancer cells at multiple stages of the cell cycle with the G2/M arrest being the most widely reported. Additionally, increased pro-apoptotic capacity as a result of regulating intrinsic and extrinsic apoptotic pathway components has been widely reported following DATS treatment. Invasion, migration, and angiogenesis represent emerging targets of DATS and support its anti-cancer properties. This review summarizes DATS mechanisms of action as an anti-cancer and chemopreventive agent. These studies provide rationale for future investigation into its use as a cancer chemopreventive agent.

The mitogen-activated protein kinase (MAPK) network is a conserved signalling module that regulates cell fate by transducing a myriad of growth-factor signals 1 . The ability of this network to coordinate and process a variety of inputs from different growth-factor receptors into specific biological responses is, however, still not understood. We investigated how the MAPK network brings about signal specificity in PC-12 cells, a model for neuronal differentiation 2 . Reverse engineering by modular-response analysis 3 uncovered topological differences in the MAPK core network dependent on whether cells were activated with epidermal or neuronal growth factor (EGF or NGF). On EGF stimulation, the network exhibited negative feedback only, whereas a positive feedback was apparent on NGF stimulation. The latter allows for bi-stable Erk activation dynamics, which were indeed observed. By rewiring these regulatory feedbacks, we were able to reverse the specific cell responses to EGF and NGF. These results show that growth factor context determines the topology of the MAPK signalling network and that the resulting dynamics govern cell fate.

Notch signaling is often aberrantly activated in solid and hematological cancers and regulates cell fate decisions and the maintenance of cancer stem cells. In addition, increased expression of Notch pathway components is clinically associated with poorer prognosis in several types of cancer. Targeting Notch may have chemopreventive and anti-cancer effects, leading to reduced disease incidence and improved survival. While therapeutic agents are currently in development to achieve this goal, several researchers have turned their attention to dietary and natural agents for targeting Notch signaling. Given their natural abundance from food sources, the use of diet-derived agents to target Notch signaling offers the potential advantage of low toxicity to normal tissue. In this review, we discuss several dietary agents including curcumin, EGCG, resveratrol, and isothiocyanates, which modulate Notch pathway components in a context-dependent manner. Dietary agents modulate Notch signaling in several types of cancer and concurrently decrease in vitro cell viability and in vivo tumor growth, suggesting a potential role for their clinical use to target Notch pathway components, either alone or in combination with current therapeutic agents.

The recent commercialisation of the first disease-modifying drugs for Alzheimer's disease emphasises the need for consensus recommendations on the rational use of biomarkers to diagnose people with suspected neurocognitive disorders in memory clinics. Most available recommendations and guidelines are either disease-centred or biomarker-centred. A European multidisciplinary taskforce consisting of 22 experts from 11 European scientific societies set out to define the first patient-centred diagnostic workflow that aims to prioritise testing for available biomarkers in individuals attending memory clinics. After an extensive literature review, we used a Delphi consensus procedure to identify 11 clinical syndromes, based on clinical history and examination, neuropsychology, blood tests, structural imaging, and, in some cases, EEG. We recommend first-line and, if needed, second-line testing for biomarkers according to the patient's clinical profile and the results of previous biomarker findings. This diagnostic workflow will promote consistency in the diagnosis of neurocognitive disorders across European countries.

Thanatotranscriptome studies involve the examination of mRNA transcript abundance and gene expression patterns in the internal organs of deceased humans. Postmortem gene expression is indicative of the cellular status of a corpse at the time of death, a portion of which may represent a cascade of molecular events occasioned by death. Specific gene biomarkers identify perceptible transcriptional changes induced by stochastic responses to the cessation of biological functions. Transcriptome analyses of postmortem mRNA from a tissue fragment may determine unique molecular identifiers for specific organs and demonstrate unique patterns of gene expression that can provide essential contextual anatomical information. We evaluated the impact of targeted transcriptome analysis using RNA sequencing to reveal global changes in postmortem gene expression in liver tissues from 27 Italian and United States corpses: 3.5-hour-old to 37-day-old. We found that our single blind study using eight liver tissue-specific gene biomarkers (e.g. AMBP and AHSG ) is highly specific, with autopsy-derived organ samples correctly identified as tissues originating from postmortem livers. The results demonstrate that 98–100% of sequencing reads were mapped to these liver biomarkers. Our findings indicate that gene expression signatures of mRNA exposed up to 37 days of autolysis, can be used to validate the putative identity of tissue fragments.

The radiologist’s report is crucial for guiding care post-imaging, with ongoing advancements in report construction. Recent studies across various modalities and organ systems demonstrate enhanced clarity and communication through structured reports. This article will explain the benefits of disease-state specific reporting templates using prostate MRI as the model system. We identify key reporting components for prostate cancer detection and staging as well as imaging in active surveillance and following therapy. We discuss relevant reporting systems including PI-QUAL, PI-RADS, PRECISE, PI-RR and PI-FAB systems. Additionally, we examine optimal reporting structure including disruptive technologies such as graphical reporting and using artificial intelligence to improve report clarity and applicability.