Ancestral ribonucleases back in motion for evolutionary-dynamics guided protein design.

The dynamics behavior of a protein is essential for its functionality. Here, Doucet et al. demonstrate how the evolutionary analysis of conformational pathways within a protein family serves to identify common core scaffolds that accommodate branch-specific functional regions controlled by flexibility switches, offering a model for evolutionary-dynamics based protein design.

Drug repositioning identifies histone deacetylase inhibitors that promote innate immunity in non-tuberculous mycobacterial infection.

Non-tuberculosis infections in immunocompromised patients represent a cause for concern, given the increased risks of infection, and limited treatments available. Herein, we report that molecules for binding to the catalytic site of histone deacetylase (HDAC) inhibit its activity, thus increasing the innate immune response against environmental mycobacteria. The action of HDAC inhibitors (iHDACs) was explored in a model of type II pneumocytes and macrophages infection by .

Murine Ribonuclease 6 Limits Bacterial Dissemination during Experimental Urinary Tract Infection.

Introduction: The ribonuclease (RNase) A superfamily encodes cationic antimicrobial proteins with potent microbicidal activity toward uropathogenic bacteria. Ribonuclease 6 (RNase6) is an evolutionarily conserved, leukocyte-derived antimicrobial peptide with potent microbicidal activity toward uropathogenic Escherichia coli (UPEC), the most common cause of bacterial urinary tract infections (UTIs). In this study, we generated Rnase6-deficient mice to investigate the hypothesis that endogenous RNase 6 limits host susceptibility to UTI.

Structural determinants for tRNA selective cleavage by RNase 2/EDN.

tRNA-derived fragments (tRFs) have emerged as key players of immunoregulation. Some RNase A superfamily members participate in the shaping of the tRFs population. By comparing wild-type and knockout macrophage cell lines, our previous work revealed that RNase 2 can selectively cleave tRNAs.

A Common Polymorphism in Impacts Its Antimicrobial Activity toward Uropathogenic .

Human Ribonuclease (RNase) 6 is a monocyte and macrophage-derived protein with potent antimicrobial activity toward uropathogenic bacteria. The gene is heterogeneous in humans due to the presence of single nucleotide polymorphisms (SNPs). rs1045922 is the most common non-synonymous SNP, resulting in a G to A substitution that determines an arginine (R) to glutamine (Q) transversion at position 66 in the protein sequence.

Human Ribonuclease 6 Has a Protective Role during Experimental Urinary Tract Infection.

Mounting evidence suggests that antimicrobial peptides and proteins (AMPs) belonging to the RNase A superfamily have a critical role in defending the bladder and kidney from bacterial infection. RNase 6 has been identified as a potent, leukocyte-derived AMP, but its impact on urinary tract infection (UTI) in vivo has not been demonstrated. To test the functional role of human RNase 6, we generated RNASE6 transgenic mice and studied their susceptibility to experimental UTI.

Exploring the RNase A scaffold to combine catalytic and antimicrobial activities. Structural characterization of RNase 3/1 chimeras.

Design of novel antibiotics to fight antimicrobial resistance is one of the first global health priorities. Novel protein-based strategies come out as alternative therapies. Based on the structure-function knowledge of the RNase A superfamily we have engineered a chimera that combines RNase 1 highest catalytic activity with RNase 3 unique antipathogen properties.

Negative schizophrenic symptoms as prefrontal cortex dysfunction: Examination using a task measuring goal neglect.

Background: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition.

Method: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'.

Essential Role of Enzymatic Activity in the Leishmanicidal Mechanism of the Eosinophil Cationic Protein (RNase 3).

The recruitment of eosinophils into lesions is frequently associated with a favorable evolution. A feasible effector for this process is eosinophil cationic protein (ECP, RNase 3), one of the main human eosinophil granule proteins, endowed with a broad spectrum of antimicrobial activity, including parasites. ECP was active on promastigotes and axenic amastigotes (LC's = 3 and 16 μM, respectively) but, in contrast to the irreversible membrane damage caused on bacteria and reproduced by its -terminal peptides, it only induced a mild and transient plasma membrane destabilization on promastigotes.

Neural correlates of referential/persecutory delusions in schizophrenia: examination using fMRI and a virtual reality underground travel paradigm.

Background: The brain functional correlates of delusions have been relatively little studied. However, a virtual reality paradigm simulating travel on the London Underground has been found to evoke referential ideation in both healthy subjects and patients with schizophrenia, making brain activations in response to such experiences potentially identifiable.

Method: Ninety patients with schizophrenia/schizoaffective disorder and 28 healthy controls underwent functional magnetic resonance imaging while they viewed virtual reality versions of full and empty Barcelona Metro carriages.

Synergistic interaction between pH and NaCl in the limits of germination and outgrowth of Clostridium sporogenes and Group I Clostridium botulinum vegetative cells and spores after heat treatment.

Group I Clostridium botulinum and Clostridium sporogenes are physiologically and genetically closely related. Both are widely distributed in the environment and can cause foodborne botulism. In this work, a physiological study was conducted with 37 isolates from spoiled canned food and five referenced strains of C.

Selective cleavage of ncRNA and antiviral activity by RNase2/EDN in THP1-induced macrophages.

RNase2 is the member of the RNaseA family most abundant in macrophages. Here, we knocked out RNase2 in THP-1 cells and analysed the response to Respiratory Syncytial Virus (RSV). RSV induced RNase2 expression, which significantly enhanced cell survival.

In Vivo Evaluation of ECP Peptide Analogues for the Treatment of Infection.

Antimicrobial peptides (AMPs) are alternative therapeutics to traditional antibiotics against bacterial resistance. Our previous work identified an antimicrobial region at the N-terminus of the eosinophil cationic protein (ECP). Following structure-based analysis, a 30mer peptide (ECPep-L) was designed that combines antimicrobial action against Gram-negative species with lipopolysaccharides (LPS) binding and endotoxin-neutralization activities.

Structure-Based Design of an RNase Chimera for Antimicrobial Therapy.

Bacterial resistance to antibiotics urges the development of alternative therapies. Based on the structure-function of antimicrobial members of the RNase A superfamily, we have developed a hybrid enzyme. Within this family, RNase 1 exhibits the highest catalytic activity and the lowest cytotoxicity; in contrast, RNase 3 shows the highest bactericidal action, alas with a reduced catalytic activity.

The synergic interaction between environmental factors (pH and NaCl) and the physiological state (vegetative cells and spores) provides new possibilities for optimizing processes to manage risk of C. sporogenes spoilage.

Clostridium sporogenes has been widely used as a surrogate for proteolytic C. botulinum for validating thermal processes in low-acid cans. To limit the intensity of heat treatments, industrials must use other ways of control as an association of acidic and saline environment after a low heat treatment.

Rationally Modified Antimicrobial Peptides from the N-Terminal Domain of Human RNase 3 Show Exceptional Serum Stability.

Multidrug resistance against conventional antibiotics poses an important threat to human health. In this context, antimicrobial peptides (AMPs) have been extensively studied for their antibacterial activity and promising results have been shown so far. However, AMPs tend to be rather vulnerable to protease degradation, which offsets their therapeutic appeal.

Correction: Lu et al. Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Hub Genes Associated with Mycobacterial Infection of Human Macrophages. 2021, , 97.

The authors wish to make the following corrections to this paper [...

Host Defence RNases as Antiviral Agents against Enveloped Single Stranded RNA Viruses.

Owing to the recent outbreak of Coronavirus Disease of 2019 (COVID-19), it is urgent to develop effective and safe drugs to treat the present pandemic and prevent other viral infections that might come in the future. Proteins from our own innate immune system can serve as ideal sources of novel drug candidates thanks to their safety and immune regulation versatility. Some host defense RNases equipped with antiviral activity have been reported over time.

Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Hub Genes Associated with Mycobacterial Infection of Human Macrophages.

Tuberculosis (TB) is still a leading cause of death worldwide. Treatments remain unsatisfactory due to an incomplete understanding of the underlying host-pathogen interactions during infection. In the present study, weighted gene co-expression network analysis (WGCNA) was conducted to identify key macrophage modules and hub genes associated with mycobacterial infection.

Human RNase3 immune modulation by catalytic-dependent and independent modes in a macrophage-cell line infection model.

The human RNase3 is a member of the RNaseA superfamily involved in host immunity. RNase3 is expressed by leukocytes and shows broad-spectrum antimicrobial activity. Together with a direct antimicrobial action, RNase3 exhibits immunomodulatory properties.

Magnetite Nanoparticles Functionalized with RNases against Intracellular Infection of .

Current treatments against bacterial infections have severe limitations, mainly due to the emergence of resistance to conventional antibiotics. In the specific case of strains, they have shown a number of resistance mechanisms to counter most antibiotics. Human secretory RNases from the RNase A superfamily are proteins involved in a wide variety of biological functions, including antimicrobial activity.

Synergism between Host Defence Peptides and Antibiotics Against Bacterial Infections.

Background: Antimicrobial resistance (AMR) to conventional antibiotics is becoming one of the main global health threats and novel alternative strategies are urging. Antimicrobial peptides (AMPs), once forgotten, are coming back into the scene as promising tools to overcome bacterial resistance. Recent findings have attracted attention to the potentiality of AMPs to work as antibiotic adjuvants.

Serial prolactin sampling as a confirmatory test for true hyperprolactinemia.

Introduction: Hyperprolactinemia may be due to physiological or pathological causes, and may be asymptomatic or induce hypogonadism, infertility, and/or galactorrhea. It is important to take prolactin samples while avoiding stress, as this may increase prolactin levels. Therefore, our aim was to assess the value of prolactin serial sampling after brachial vein cannulation.