Tumor-targeting bacteria as immune stimulants - the future of cancer immunotherapy?

Cancer immunotherapies have been widely hailed as a breakthrough for cancer treatment in the last decade, epitomized by the unprecedented results observed with checkpoint blockade. Even so, only a minority of patients currently achieve durable remissions. In general, responsive patients appear to have either a high number of tumor neoantigens, a preexisting immune cell infiltrate in the tumor microenvironment, or an 'immune-active' transcriptional profile, determined in part by the presence of a type I interferon gene signature.

Clostridium Bacteria: Harnessing Tumour Necrosis for Targeted Gene Delivery.

Necrosis is a common feature of solid tumours that offers a unique opportunity for targeted cancer therapy as it is absent from normal healthy tissues. Tumour necrosis provides an ideal environment for germination of the anaerobic bacterium Clostridium from endospores, resulting in tumour-specific colonisation. Two main species, Clostridium novyi-NT and Clostridium sporogenes, are at the forefront of this therapy, showing promise in preclinical models.

Inhibitors of bacterial immune systems: discovery, mechanisms and applications.

To contend with the diversity and ubiquity of bacteriophages and other mobile genetic elements, bacteria have developed an arsenal of immune defence mechanisms. Bacterial defences include CRISPR-Cas, restriction-modification and a growing list of mechanistically diverse systems, which constitute the bacterial 'immune system'. As a response, bacteriophages and mobile genetic elements have evolved direct and indirect mechanisms to circumvent or block bacterial defence pathways and ensure successful infection.

A Portable and Disposable Electrochemical Sensor Utilizing Laser-Scribed Graphene for Rapid SARS-CoV-2 Detection.

The COVID-19 pandemic caused by the virus SARS-CoV-2 was the greatest global threat to human health in the last three years. The most widely used methodologies for the diagnosis of COVID-19 are quantitative reverse transcription polymerase chain reaction (RT-qPCR) and rapid antigen tests (RATs). PCR is time-consuming and requires specialized instrumentation operated by skilled personnel.

Insights into the role of JAK2-I724T variant in myeloproliferative neoplasms from a unique cohort of New Zealand patients.

Objectives: This study aimed to compile bioinformatic and experimental information for missense variants previously reported in myeloproliferative neoplasms (MPN) and determine if germline -I724T, recently found to be common in New Zealand Polynesians, associates with MPN.

Methods: For all variants found in the literature, gnomAD_exome allele frequencies were extracted and REVEL scores were calculated using the dbNSFP database. We investigated the prevalence of -I724T in a cohort of 111 New Zealand MPN patients using a TaqMan assay, examined its allelic co-occurrence with -V617F using Oxford Nanopore sequencing, and modelled the impact of I724T on JAK2 using I-Mutant and ChimeraX software.

Polymyxin B and ethylenediaminetetraacetic acid act synergistically against and .

Polymyxin B and ethylenediaminetetraacetic acid are antimicrobials possessing antibiofilm activity. They act by displacement and chelation, respectively, of divalent cations in bacterial membranes and may therefore act synergistically when applied in combination. If so, this combination of agents may be useful for the treatment of diseases like cystic fibrosis (CF), in which biofilms are present on the respiratory epithelium.

A dual-targeting succinate dehydrogenase and FF-ATP synthase inhibitor rapidly sterilizes replicating and non-replicating Mycobacterium tuberculosis.

Mycobacterial bioenergetics is a validated target space for antitubercular drug development. Here, we identify BB2-50F, a 6-substituted 5-(N,N-hexamethylene)amiloride derivative as a potent, multi-targeting bioenergetic inhibitor of Mycobacterium tuberculosis. We show that BB2-50F rapidly sterilizes both replicating and non-replicating cultures of M.

He Rourou Whai Painga, an Aotearoa New Zealand dietary pattern for metabolic health and whānau wellbeing: protocol for a randomized controlled trial.

Background: Cardiometabolic diseases are highly prevalent in Aotearoa New Zealand. Dietary intake is a modifiable risk factor for such diseases and certain dietary patterns, specifically the Mediterranean diet (MedDiet), are associated with improved metabolic health. This study aims to test whether an intervention including a Mediterranean dietary pattern incorporating high quality New Zealand foods (NZMedDiet pattern) and behavior change science can improve the metabolic health of participants and their household/whānau.

CRISPR-Cas immunity is repressed by the LysR-type transcriptional regulator PigU.

Bacteria protect themselves from infection by bacteriophages (phages) using different defence systems, such as CRISPR-Cas. Although CRISPR-Cas provides phage resistance, fitness costs are incurred, such as through autoimmunity. CRISPR-Cas regulation can optimise defence and minimise these costs.

Structome: a tool for the rapid assembly of datasets for structural phylogenetics.

Summary: Protein structures carry signal of common ancestry and can therefore aid in reconstructing their evolutionary histories. To expedite the structure-informed inference process, a web server, Structome, has been developed that allows users to rapidly identify protein structures similar to a query protein and to assemble datasets useful for structure-based phylogenetics. Structome was created by clustering of the structures in RCSB PDB using 90% sequence identity and representing each cluster by a centroid structure.

Genome sequences of Mx1, the first phage isolated, and Mx4, a generalized transducing myxophage.

is the best-studied member of the phylum Myxococcota, but the bacteriophages infecting it and their characterization remain limited. Here, we present complete genomes of Mx1, the first phage isolated, and of an Mx4 derivative widely used for generalized transduction, both unclassified Caudoviricetes with long, contractile tails.

The (Mānuka)-Specific Nectar and Honey Compound 3,6,7-Trimethyllumazine (Lepteridine) That Inhibits Matrix Metalloproteinase 9 (MMP-9) Activity.

3,6,7-trimethyllumazine (Lepteridine™) is a newly discovered natural pteridine derivative unique to Mānuka () nectar and honey, with no previously reported biological activity. Pteridine derivative-based medicines, such as methotrexate, are used to treat auto-immune and inflammatory diseases, and Mānuka honey reportedly possesses anti-inflammatory properties and is used topically as a wound dressing. MMP-9 is a potential candidate protein target as it is upregulated in recalcitrant wounds and intestinal inflammation.

Metagenomic domain substitution for the high-throughput modification of nonribosomal peptides.

The modular nature of nonribosomal peptide biosynthesis has driven efforts to generate peptide analogs by substituting amino acid-specifying domains within nonribosomal peptide synthetase (NRPS) enzymes. Rational NRPS engineering has increasingly focused on finding evolutionarily favored recombination sites for domain substitution. Here we present an alternative evolution-inspired approach that involves large-scale diversification and screening.

Design and Biological Evaluation of Piperazine-Bearing Nitrobenzamide Hypoxia/GDEPT Prodrugs: The Discovery of CP-506.

Off-target aerobic activation of PR-104A by human aldo-keto reductase 1C3 (AKR1C3) has confounded the development of this dual hypoxia/gene therapy prodrug. Previous attempts to design prodrugs resistant to AKR1C3 activation have resulted in candidates that require further optimization. Herein we report the evaluation of a lipophilic series of PR-104A analogues in which a piperazine moiety has been introduced to improve drug-like properties.

High fat diet-induced maternal obesity in mice impairs peripartum maternal behaviour.

Obesity during pregnancy represents a significant health issue and can lead to increased complications during pregnancy and impairments with breastfeeding, along with long-term negative health consequences for both mother and offspring. In rodent models, diet-induced obesity (DIO) during pregnancy leads to poor outcomes for offspring. Using a DIO mouse model, consisting of feeding mice a high fat diet for 8 weeks before mating, we recapitulate the effect of high pup mortality within the first 3 days postpartum.

A metagenomic library cloning strategy that promotes high-level expression of captured genes to enable efficient functional screening.

Functional screening of environmental DNA (eDNA) libraries is a potentially powerful approach to discover enzymatic "unknown unknowns", but is usually heavily biased toward the tiny subset of genes preferentially transcribed and translated by the screening strain. We have overcome this by preparing an eDNA library via partial digest with restriction enzyme FatI (cuts CATG), causing a substantial proportion of ATG start codons to be precisely aligned with strong plasmid-encoded promoter and ribosome-binding sequences. Whereas we were unable to select nitroreductases from standard metagenome libraries, our FatI strategy yielded 21 nitroreductases spanning eight different enzyme families, each conferring resistance to the nitro-antibiotic niclosamide and sensitivity to the nitro-prodrug metronidazole.

CasPEDIA Database: a functional classification system for class 2 CRISPR-Cas enzymes.

CRISPR-Cas enzymes enable RNA-guided bacterial immunity and are widely used for biotechnological applications including genome editing. In particular, the Class 2 CRISPR-associated enzymes (Cas9, Cas12 and Cas13 families), have been deployed for numerous research, clinical and agricultural applications. However, the immense genetic and biochemical diversity of these proteins in the public domain poses a barrier for researchers seeking to leverage their activities.

Development and characterisation of a novel inhibitory anti-GH monoclonal antibody.

Excess growth hormone (GH) has been implicated in multiple cancer types and there is increasing interest in the development of therapeutic inhibitors targeting GH-GH receptor (GHR) signalling. Here we describe a panel of anti-GH monoclonal antibodies (mAbs) generated using a hybridoma approach and identify two novel inhibitory mAbs (1-8-2 and 1-46-3) that neutralised GH signalling. mAbs 1-8-2 and 1-46-3 exhibited strong inhibitory activity against GH-dependent cell growth in a Ba/F3-GHR cell viability assay, with EC50 values of 1.

Bacteriophages suppress CRISPR-Cas immunity using RNA-based anti-CRISPRs.

Many bacteria use CRISPR-Cas systems to combat mobile genetic elements, such as bacteriophages and plasmids. In turn, these invasive elements have evolved anti-CRISPR proteins to block host immunity. Here we unveil a distinct type of CRISPR-Cas Inhibition strategy that is based on small non-coding RNA anti-CRISPRs (Racrs).

Amino acid 17 in QRDR of Gyrase A plays a key role in fluoroquinolones susceptibility in mycobacteria.

Fluoroquinolones (FQs) play a key role in the treatment regimens against tuberculosis and non-tuberculous mycobacterial infections. However, there are significant differences in the sensitivities of different mycobacteria to FQs. In this study, we proved that this is associated with the polymorphism at amino acid 17 of quinolone resistance-determining region of Gyrase A by gene editing.

Eluding the immune system's frontline defense: Secreted complement evasion factors of pathogenic Gram-positive cocci.

The human complement system is an important part of the innate immune response in the fight against invasive bacteria. Complement responses can be activated independently by the classical pathway, the lectin pathway, or the alternative pathway, each resulting in the formation of a C3 convertase that produces the anaphylatoxin C3a and the opsonin C3b by specifically cutting C3. Other important features of complement are the production of the chemotactic C5a peptide and the generation of the membrane attack complex to lyse intruding pathogens.

Harnessing the power of a photoinitiated thiol-ene "click" reaction for the efficient synthesis of -lipidated collagen model peptide amphiphiles.

A photoinitiated thiol-ene "click" reaction was used to synthesize -lipidated collagen model peptide amphiphiles. Use of 2-iminothiolane provided an epimerization-free thiol handle required for thiol-ene based incorporation of lipid moieties onto collagen-based peptide sequences. This approach not only led to improvements in the triple helical characteristics of the resulting collagen model peptides but also increased the aqueous solubility of the peptide amphiphiles.