Time to start taking time seriously: how to investigate unexpected biological rhythms within infectious disease research.

The discovery of rhythmicity in host and pathogen activities dates back to the Hippocratic era, but the causes and consequences of these biological rhythms have remained poorly understood. Rhythms in infection phenotypes or traits are observed across taxonomically diverse hosts and pathogens, suggesting general evolutionary principles. Understanding these principles may enable rhythms to be leveraged in manners that improve drug and vaccine efficacy or disrupt pathogen timekeeping to reduce virulence and transmission.

Development of compounds for targeted degradation of mammalian cryptochrome proteins.

The mammalian cryptochrome proteins (CRY1 and CRY2) are transcriptional repressors most notable for their role in circadian transcriptional feedback. Not all circadian rhythms depend on CRY proteins, however, and the CRY proteins are promiscuous interactors that also regulate many other processes. In cells with chronic CRY deficiency, protein homeostasis is highly perturbed, with a basal increase in cellular stress and activation of key inflammatory signalling pathways.

Chronic CRYPTOCHROME deficiency enhances cell-intrinsic antiviral defences.

The within-host environment changes over circadian time and influences the replication and severity of viruses. Genetic knockout of the circadian transcription factors CRYPTOCHROME 1 and CRYPTOCHROME 2 (/; CKO) leads to altered protein homeostasis and chronic activation of the integrated stress response (ISR). The adaptive ISR signalling pathways help restore cellular homeostasis by downregulating protein synthesis in response to endoplasmic reticulum overloading or viral infections.

Negative Pressure Ventilation Ex-Situ Lung Perfusion Preserves Porcine and Human Lungs for 36-Hours.

Introduction: Preclinically, 24-hour continuous Ex-Situ Lung Perfusion (ESLP) is the longest duration achieved in large animal models and rejected human lungs. Here, we present our 36-hour Negative Pressure Ventilation (NPV)-ESLP protocol applied to porcine and rejected human lungs.

Methods: Five sets of donor domestic pig lungs (45-55 kg) underwent 36-hour NPV-ESLP.

Mild Permissive Alkalosis Improves Outcomes in Porcine Negative Pressure Ventilation Ex-Situ Lung Perfusion.

Background: Ex-Situ Lung Perfusion (ESLP) employs a membrane deoxygenator and mixed (N/O/CO) or pure sweep gas (CO) to target venous blood gas composition with physiologic pCO and pH. Clinically, mild permissive alkalosis counteracts elevated pulmonary vascular resistance (PVR) to improve perfusion. Increased PVR and pulmonary artery pressure (PAP) during ESLP mirrors rising pro-inflammatory cytokines.

Protein structure alignment by Reseek improves sensitivity to remote homologs.

Motivation: Recent breakthroughs in protein fold prediction from amino acid sequences have unleashed a deluge of new structures, presenting new opportunities and challenges to bioinformatics.

Results: Reseek is a novel protein structure alignment algorithm based on sequence alignment where each residue in the protein backbone is represented by a letter in a "mega-alphabet" of 85 899 345 920 (∼1011) distinct states. Reseek achieves substantially improved sensitivity to remote homologs compared to state-of-the-art methods including DALI, TMalign, and Foldseek, with comparable speed to Foldseek, the fastest previous method.

Viroid-like colonists of human microbiomes.

Here, we describe "obelisks," a class of heritable RNA elements sharing several properties: (1) apparently circular RNA ∼1 kb genome assemblies, (2) predicted rod-like genome-wide secondary structures, and (3) open reading frames encoding a novel "Oblin" protein superfamily. A subset of obelisks includes a variant hammerhead self-cleaving ribozyme. Obelisks form their own phylogenetic group without detectable similarity to known biological agents.

Moderate-Flow Perfusion is Superior to Low-Flow Perfusion in Ex Situ Lung Perfusion.

Background: Full-flow perfusion during prolonged ex situ lung perfusion (ESLP) results in unacceptable pulmonary edema formation. Clinical ESLP at 30% to 50% predicted cardiac output (CO) supports acceptable physiologic outcomes; however, progressive pulmonary edema still develops. Lower flow rates may provide equivalent physiologic preservation with less edema formation due to reduced hydrostatic pressures.

Correction: Ribovirus classification by a polymerase barcode sequence.

[This corrects the article DOI: 10.7717/peerj.14055.

Normothermic Perfusion is Superior to Cold Perfusion in Porcine Ex Situ Lung Perfusion.

Background: Cold ex situ lung perfusion (ESLP) has demonstrated improved preservation in small animal ESLP compared to normothermic ESLP and cold static preservation. We hypothesized that cold negative pressure ventilation (NPV)-ESLP would improve graft function in a porcine transplantation model.

Methods: Four perfusate temperatures were examined with 12 hours NPV-ESLP in a large animal transplantation model.

Chemoproteomics validates selective targeting of M1 alanyl aminopeptidase as an antimalarial strategy.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant (A-M1) and (A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent in vitro antimalarial activity with no significant host cytotoxicity.

Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn's Disease.

Objective: Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn's disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis.

Author Correction: Propylene glycol inactivates respiratory viruses and prevents airborne transmission.

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Photoplethysmography and intracardiac pressures: early insights from a pilot study.

Aims: Invasive haemodynamic monitoring of heart failure (HF) is used to detect deterioration in an early phase thereby preventing hospitalizations. However, this invasive approach is costly and presently lacks widespread accessibility. Hence, there is a pressing need to identify an alternative non-invasive method that is reliable and more readily available.

Chemoproteomics validates selective targeting of Plasmodium M1 alanyl aminopeptidase as an antimalarial strategy.

New antimalarial drug candidates that act via novel mechanisms are urgently needed to combat malaria drug resistance. Here, we describe the multi-omic chemical validation of M1 alanyl metalloaminopeptidase as an attractive drug target using the selective inhibitor, MIPS2673. MIPS2673 demonstrated potent inhibition of recombinant ( A-M1) and ( A-M1) M1 metalloaminopeptidases, with selectivity over other and human aminopeptidases, and displayed excellent antimalarial activity with no significant host cytotoxicity.

On-target, dual aminopeptidase inhibition provides cross-species antimalarial activity.

To combat the global burden of malaria, development of new drugs to replace or complement current therapies is urgently required. Here, we show that the compound is a selective, nanomolar inhibitor of both and aminopeptidases M1 and M17, leading to inhibition of end-stage hemoglobin digestion in asexual parasites. can kill sexual-stage , is active against murine malaria, and does not show any shift in activity against a panel of parasites resistant to other antimalarials.

Cardiovascular disease in Alpha 1 antitrypsin deficiency: an observational study assessing the role of neutrophil proteinase activity and the suitability of validated screening tools.

Background: Alpha 1 Antitrypsin Deficiency (AATD) is a rare, inherited lung disease which shares features with Chronic Obstructive Pulmonary Disease (COPD) but has a greater burden of proteinase related tissue damage. These proteinases are associated with cardiovascular disease (CVD) in the general population. It is unclear whether patients with AATD have a greater risk of CVD compared to usual COPD, how best to screen for this, and whether neutrophil proteinases are implicated in AATD-associated CVD.

Automated cardiac arrest detection using a photoplethysmography wristband: algorithm development and validation in patients with induced circulatory arrest in the DETECT-1 study.

Background: Unwitnessed out-of-hospital cardiac arrest is associated with low survival chances because of the delayed activation of the emergency medical system in most cases. Automated cardiac arrest detection and alarming using biosensor technology would offer a potential solution to provide early help. We developed and validated an algorithm for automated circulatory arrest detection using wrist-derived photoplethysmography from patients with induced circulatory arrests.

Viroid-like colonists of human microbiomes.

Here, we describe the "Obelisks," a previously unrecognised class of viroid-like elements that we first identified in human gut metatranscriptomic data. "Obelisks" share several properties: (i) apparently circular RNA ~1kb genome assemblies, (ii) predicted rod-like secondary structures encompassing the entire genome, and (iii) open reading frames coding for a novel protein superfamily, which we call the "Oblins". We find that Obelisks form their own distinct phylogenetic group with no detectable sequence or structural similarity to known biological agents.

Cluster randomised controlled trial of specialist-led integrated COPD care (INTEGR COPD).

Objective: Studies in hospital settings demonstrate that there is greater guideline adherence when care is delivered by a respiratory specialist, however, this has not been explored in primary care. The aim of this study is to determine the impact integrating respiratory specialists into primary care has on the delivery of guideline adherent chronic obstructive pulmonary disease (COPD) care.

Methods: 18 general practitioner (GP) practices were randomised to provide either usual or specialist-led COPD care.