Human T-cell Leukemia Virus type HTLV- is an untreatable retrovirus that causes lethal malignancies and degenerative inflammatory conditions Effective treatments have been delayed by substantial gaps in our knowledge of the fundamental virology especially when compared to the closely related virus HIV A recently developed and highly effective anti-HIV strategy ...More |Related Solutions: NT8^®

Human T-cell Leukemia Virus type 1 (HTLV-1) is an untreatable retrovirus that causes lethal malignancies and degenerative inflammatory conditions. Effective treatments have been delayed by substantial gaps in our knowledge of the fundamental virology, especially when compared to the closely related virus, HIV. A recently developed and highly effective anti-HIV strategy is to target the virus with drugs that interfere with capsid integrity and interactions with the host. Importantly, the first in class anti-capsid drug approved, lenacapavir, can provide long-acting pre-exposure prophylaxis. Such a property would provide a means to prevent the transmission of HTLV-1, but its capsid has not previously been considered as a drug target. Here we describe the first high-resolution crystal structures of the HTLV-1 capsid protein, define essential lattice interfaces, and identify a previously unknown ligand-binding pocket. We show that this pocket is essential for virus infectivity, providing a potential target for future anti-capsid drug development. Less |Related Solutions: NT8^®

Prophages dormant bacteriophage genomes integrated within the bacterial chromosome play pivotal roles in shaping microbial communities when awakened Our current understanding of prophage activation is largely shaped by a narrow set of traditional DNA-damaging inducers such as mitomycin C and ciprofloxacin which trigger the bacterial SOS response This study employed ...More |Related Solutions: Tempest^®

Prophages, dormant bacteriophage genomes integrated within the bacterial chromosome, play pivotal roles in shaping microbial communities when awakened. Our current understanding of prophage activation is largely shaped by a narrow set of traditional DNA-damaging inducers, such as mitomycin C and ciprofloxacin, which trigger the bacterial SOS response. This study employed high-throughput screening of 3,921 compounds to identify novel prophage inducers using model lambdoid prophage HK97. We identified multiple new inducers across diverse pharmacological classes, including dietary supplements and therapeutics. Despite the variety in compounds, all acted through SOS-dependent pathways. However, bleomycin, an antineoplastic antibiotic, demonstrated broad-spectrum and potent prophage induction exceeding standard inducers, with activity validated across multiple phage-host pairings. These findings expand the repertoire of prophage inducers into commonly ingested xenobiotics and introduce bleomycin as a powerful, cost-effective tool for prophage research.
Around 75% of bacteria carry within them dormant viruses (prophages), which can awaken when the bacterium is stressed, killing the bacterium. Historically, this has been done using DNA-damaging antibiotics, but increasingly, more such signals have been discovered. Here, through a high-throughput screen, we identify phage-waking activity in several commonly consumed compounds, such as the SSRI Prozac, as well as a new DNA-damaging agent that is much more effective in waking phages than the previous gold standard. Less |Related Solutions: Tempest^®

The composition of the primordial genetic material remains uncertain Studies of duplex structure and stability and of nonenzymatic template copying chemistry provide insight into the viability of potentially primordial genetic polymers Recent work suggests that - deoxyribo-purine nucleotides may have been generated together with ribonucleotides on the early Earth Since ...More |Related Solutions: NT8^®

The composition of the primordial genetic material remains uncertain. Studies of duplex structure and stability, and of nonenzymatic template copying chemistry, provide insight into the viability of potentially primordial genetic polymers. Recent work suggests that 2′- deoxyribo-purine nucleotides may have been generated together with ribonucleotides on the early Earth. Since DNA/RNA duplexes are known to be less stable than RNA/RNA duplexes, we have examined the impact of dA, dI, and dG substitutions on RNA structure and nonenzymatic template copying. We find that single 2′-deoxyribo-purine substitutions reduce RNA duplex stability, as expected. Crystallographic studies show that such substitutions lead to minimal structural changes but point to diminished solvation as a likely reason for duplex destabilization. Kinetic studies show that dI and dG substrates exhibit slightly weaker template binding and slower rates of template-directed primer extension than the corresponding ribo-purine substrates. In contrast, dA substrates exhibit much slower reaction kinetics but higher template affinity than rA substrates. Our results suggest that a mixed RNA/DNA primordial genetic polymer would have suffered from moderately slower rates of template copying, but that this could have been offset by an advantage due to more facile strand separation or exchange. Less |Related Solutions: NT8^®

Plasma and cerebrospinal fluid are complementary sources of biomarkers for neurodegenerative diseases The wide dynamic range of protein abundances particularly in plasma hampers detection of low-abundance proteins Depletion of high-abundance proteins and efficient enzymatic digestion can improve proteome coverage but must be carefully optimized for reproducibility throughput and cost-efficiency for ...More |Related Solutions: Mantis^®

Plasma and cerebrospinal fluid are complementary sources of biomarkers for
neurodegenerative diseases. The wide dynamic range of protein abundances, particularly in
plasma, hampers detection of low-abundance proteins. Depletion of high-abundance proteins
and efficient enzymatic digestion can improve proteome coverage but must be carefully
optimized for reproducibility, throughput, and cost-efficiency for use in large-scale clinical
proteomic studies.
We developed a scalable sample preparation workflow for plasma and cerebrospinal fluid (CSF)
that integrates depletion of high-abundance proteins, optimized digestion using Lys-C and
trypsin, and compatibility with both label-free and tandem mass tag (TMTpro)-based
quantification. We systematically evaluated protein depletion and enzyme digestion conditions,
and the effect of deoxycholate on digestion, monitoring the number of detectable proteins and
the quantitation precision. Less |Related Solutions: Mantis^®

The increase in multidrug-resistant bacteria underscores an urgent need for additional antibiotics Here we integrate small-molecule high-throughput screening with a deep-learning-based virtual screening approach to uncover new antibacterial compounds We screen million small molecules against a sensitized Escherichia coli strain yielding thousands of hits We use these data to train ...More |Related Solutions: Tempest^®

The increase in multidrug-resistant bacteria underscores an urgent need for additional antibiotics. Here, we integrate small-molecule high-throughput screening with a deep-learning-based virtual screening approach to uncover new antibacterial compounds. We screen ~2 million small molecules against a sensitized Escherichia coli strain, yielding thousands of hits. We use these data to train a deep learning model, GNEprop, to predict antibacterial activity, retrospectively validating robustness with respect to out-of-distribution generalization and activity cliff prediction. Virtual screening of over 1.4 billion synthetically accessible compounds identifies potential candidates, of which 82 exhibit antibacterial activity on the same strain, illustrating a 90-fold improved hit rate over the high-throughput screening experiment used for training. Many newly identified compounds exhibit high dissimilarity to known antibiotics, potency beyond the training bacterial strain and selectivity. Biological characterization identifies specific, validated targets, indicating promising avenues for further exploration in antibiotic discovery. Less |Related Solutions: Tempest^®