Anti-viral defence by an mRNA ADP-ribosyltransferase that blocks translation.

Host-pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution of sophisticated immunity mechanisms throughout biology, including in bacterial defence against bacteriophages. Here we characterize the widely distributed anti-phage defence system CmdTAC, which provides robust defence against infection by the T-even family of phages.

A bacterial immunity protein directly senses two disparate phage proteins.

Eukaryotic innate immune systems use pattern recognition receptors to sense infection by detecting pathogen-associated molecular patterns, which then triggers an immune response. Bacteria have similarly evolved immunity proteins that sense certain components of their viral predators, known as bacteriophages. Although different immunity proteins can recognize different phage-encoded triggers, individual bacterial immunity proteins have been found to sense only a single trigger during infection, suggesting a one-to-one relationship between bacterial pattern recognition receptors and their ligands.

New onset diabetic ketoacidosis in a renal transplant recipient.

Post-transplant diabetes mellitus (PTDM) is a well-known solid organ transplant complication, which can be related to immunosuppressants, particularly tacrolimus. We report an unusual presentation of PTDM with diabetic ketoacidosis (DKA). This is unique as PTDM typically resembles Type 2 DM, whereas DKA is associated with Type 1 DM and has rarely been reported as a complication of tacrolimus.

Principles of bacterial innate immunity against viruses.

All organisms must defend themselves against viral predators. This includes bacteria, which harbor immunity factors such as restriction-modification systems and CRISPR-Cas systems. More recently, a plethora of additional defense systems have been identified, revealing a richer, more sophisticated immune system than previously appreciated.

Mechanism of phage sensing and restriction by toxin-antitoxin-chaperone systems.

Toxin-antitoxins (TAs) are prokaryotic two-gene systems composed of a toxin neutralized by an antitoxin. Toxin-antitoxin-chaperone (TAC) systems additionally include a SecB-like chaperone that stabilizes the antitoxin by recognizing its chaperone addiction (ChAD) element. TACs mediate antiphage defense, but the mechanisms of viral sensing and restriction are unexplored.

Protein design using structure-based residue preferences.

Recent developments in protein design rely on large neural networks with up to 100s of millions of parameters, yet it is unclear which residue dependencies are critical for determining protein function. Here, we show that amino acid preferences at individual residues-without accounting for mutation interactions-explain much and sometimes virtually all of the combinatorial mutation effects across 8 datasets (R ~ 78-98%). Hence, few observations (~100 times the number of mutated residues) enable accurate prediction of held-out variant effects (Pearson r > 0.

A phage-encoded RNA-binding protein inhibits the antiviral activity of a toxin-antitoxin system.

Bacteria harbor diverse mechanisms to defend themselves against their viral predators, bacteriophages. In response, phages can evolve counter-defense systems, most of which are poorly understood. In T4-like phages, the gene tifA prevents bacterial defense by the type III toxin-antitoxin (TA) system toxIN, but the mechanism by which TifA inhibits ToxIN remains unclear.

Selection of a de novo gene that can promote survival of Escherichia coli by modulating protein homeostasis pathways.

Cellular novelty can emerge when non-functional loci become functional genes in a process termed de novo gene birth. But how proteins with random amino acid sequences beneficially integrate into existing cellular pathways remains poorly understood. We screened ~10 genes, generated from random nucleotide sequences and devoid of homology to natural genes, for their ability to rescue growth arrest of Escherichia coli cells producing the ribonuclease toxin MazF.

Toxic antiphage defense proteins inhibited by intragenic antitoxin proteins.

Recombination-promoting nuclease (Rpn) proteins are broadly distributed across bacterial phyla, yet their functions remain unclear. Here, we report that these proteins are toxin-antitoxin systems, comprised of genes-within-genes, that combat phage infection. We show the small, highly variable Rpn -terminal domains (Rpn), which are translated separately from the full-length proteins (Rpn), directly block the activities of the toxic Rpn.

Toxic anti-phage defense proteins inhibited by intragenic antitoxin proteins.

Unlabelled: Recombination-promoting nuclease (Rpn) proteins are broadly distributed across bacterial phyla, yet their functions remain unclear. Here we report these proteins are new toxin-antitoxin systems, comprised of genes-within-genes, that combat phage infection. We show the small, highly variable Rpn -terminal domains (Rpn ), which are translated separately from the full-length proteins (Rpn ), directly block the activities of the toxic full-length proteins.

Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells.

During initiation of antiviral and antitumor T cell-mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on major histocompatibility complex (MHC) class I molecules. Cross-presentation relies on the unusual "leakiness" of endocytic compartments in DCs, whereby internalized proteins escape into the cytosol for proteasome-mediated generation of MHC I-binding peptides. Given that type 1 conventional DCs excel at cross-presentation, we searched for cell type-specific effectors of endocytic escape.

Marginal specificity in protein interactions constrains evolution of a paralogous family.

The evolution of novel functions in biology relies heavily on gene duplication and divergence, creating large paralogous protein families. Selective pressure to avoid detrimental cross-talk often results in paralogs that exhibit exquisite specificity for their interaction partners. But how robust or sensitive is this specificity to mutation? Here, using deep mutational scanning, we demonstrate that a paralogous family of bacterial signaling proteins exhibits marginal specificity, such that many individual substitutions give rise to substantial cross-talk between normally insulated pathways.

Direct activation of a bacterial innate immune system by a viral capsid protein.

Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns (PAMPs), many bacterial immune systems that respond to bacteriophage infection require phage-specific triggers to be activated. However, the identities of such triggers and the sensing mechanisms remain largely unknown.

Prophage-like gene transfer agents promote Caulobacter crescentus survival and DNA repair during stationary phase.

Gene transfer agents (GTAs) are prophage-like entities found in many bacterial genomes that cannot propagate themselves and instead package approximately 5 to 15 kbp fragments of the host genome that can then be transferred to related recipient cells. Although suggested to facilitate horizontal gene transfer (HGT) in the wild, no clear physiological role for GTAs has been elucidated. Here, we demonstrate that the α-proteobacterium Caulobacter crescentus produces bona fide GTAs.

A functional selection reveals previously undetected anti-phage defence systems in the E. coli pangenome.

The ancient, ongoing coevolutionary battle between bacteria and their viruses, bacteriophages, has given rise to sophisticated immune systems including restriction-modification and CRISPR-Cas. Many additional anti-phage systems have been identified using computational approaches based on genomic co-location within defence islands, but these screens may not be exhaustive. Here we developed an experimental selection scheme agnostic to genomic context to identify defence systems in 71 diverse E.

The evolution of a counter-defense mechanism in a virus constrains its host range.

Bacteria use diverse immunity mechanisms to defend themselves against their viral predators, bacteriophages. In turn, phages can acquire counter-defense systems, but it remains unclear how such mechanisms arise and what factors constrain viral evolution. Here, we experimentally evolved T4 phage to overcome a phage-defensive toxin-antitoxin system, , in .

Management of Transplant Renal Artery Pseudoaneurysm and Literature Review.

Renal transplantation is the ultimate treatment for end-stage renal disease patients. However, vascular complications can impact renal allograft outcomes. Extrarenal pseudoaneurysms (EPSA) are a rare complication occurring in 1% of transplant recipients.

The DarTG toxin-antitoxin system provides phage defence by ADP-ribosylating viral DNA.

Toxin-antitoxin (TA) systems are broadly distributed, yet poorly conserved, genetic elements whose biological functions are unclear and controversial. Some TA systems may provide bacteria with immunity to infection by their ubiquitous viral predators, bacteriophages. To identify such TA systems, we searched bioinformatically for those frequently encoded near known phage defence genes in bacterial genomes.

The use of non-transplant biologics in solid organ transplant recipients: A practical review for the frontline clinician.

Biologics have become the forefront of medicine for management of autoimmune conditions, leading to improved quality of life. Many autoimmune conditions occur in solid organ transplant (SOT) recipients and persist following transplant. However, the use of biologics in this patient population is not well studied, and questions arise related to risk of infection and adjustments to induction and maintenance immunosuppression.

Ancestral reconstruction of duplicated signaling proteins reveals the evolution of signaling specificity.

Gene duplication is crucial to generating novel signaling pathways during evolution. However, it remains unclear how the redundant proteins produced by gene duplication ultimately acquire new interaction specificities to establish insulated paralogous signaling pathways. Here, we used ancestral sequence reconstruction to resurrect and characterize a bacterial two-component signaling system that duplicated in α-proteobacteria.

Osseointegration of a New, Ultrahydrophilic and Nanostructured Dental Implant Surface: A Comparative In Vivo Study.

This study compared the osseointegration of acid-etched, ultrahydrophilic, micro- and nanostructured implant surfaces (ANU) with non-ultra-hydrophilic, microstructured (SA) and non-ultrahydrophilic, micro- and nanostructured implant surfaces (AN) in vivo. Fifty-four implants ( = 18 per group) were bilaterally inserted into the proximal tibia of New Zealand rabbits ( = 27). After 1, 2, and 4 weeks, bone-implant contact (BIC, %) in the cortical (cBIC) and spongious bone (sBIC), bone chamber ingrowth (BChI, %), and the supra-crestal, subperiosteal amount of newly formed bone, called percentage of linear bone fill (PLF, %), were analyzed.

ssDNA is an allosteric regulator of the SOS-independent DNA damage response transcription activator, DriD.

DNA damage repair systems are critical for genomic integrity. However, they must be coordinated with DNA replication and cell division to ensure accurate genomic transmission. In most bacteria, this coordination is mediated by the SOS response through LexA, which triggers a halt in cell division until repair is completed.

A Silent Operon of Photorhabdus luminescens Encodes a Prodrug Mimic of GTP.

With the overmining of actinomycetes for compounds acting against Gram-negative pathogens, recent efforts to discover novel antibiotics have been focused on other groups of bacteria. Teixobactin, the first antibiotic without detectable resistance that binds lipid II, comes from an uncultured , a betaproteobacterium; odilorhabdins, from , are broad-spectrum inhibitors of protein synthesis, and darobactins from target BamA, the essential chaperone of the outer membrane of Gram-negative bacteria. and are symbionts of the nematode gut microbiome and attractive producers of secondary metabolites.