Ca2+ sensor-mediated ROS scavenging suppresses rice immunity and is exploited by a fungal effector.

Plant immunity is activated upon pathogen perception and often affects growth and yield when it is constitutively active. How plants fine-tune immune homeostasis in their natural habitats remains elusive. Here, we discover a conserved immune suppression network in cereals that orchestrates immune homeostasis, centering on a Ca2+-sensor, RESISTANCE OF RICE TO DISEASES1 (ROD1). ROD1 promotes reactive oxygen species (ROS) scavenging by stimulating catalase activity, and its protein stability is regulated by ubiquitination. ROD1 disruption confers resistance to multiple pathogens, whereas a natural ROD1 allele prevalent in indica rice with agroecology-specific distribution enhances resistance without yield penalty. The fungal effector AvrPiz-t structurally mimics ROD1 and activates the same ROS-scavenging cascade to suppress host immunity and promote virulence. We thus reveal a molecular framework adopted by both host and pathogen that integrates Ca2+ sensing and ROS homeostasis to suppress plant immunity, suggesting a principle for breeding disease-resistant, high-yield crops.

Tailor-Made Amino Acids in Pharmaceutical Industry: Synthetic Approaches to Aza-Tryptophan Derivatives.

Over the recent years there has been a noticeable upsurge of interest in aza-analogs of tryptophan which are isosteric to the latter and found numerous applications in medicinal, bioorganic chemistry, and peptide research. In the present review article, five aza-tryptophan derivatives are profiled, including aza-substitution in the positions 2, on the five-membered ring, as well as in positions 4, 5, 6, and 7 on the six-membered ring. A detailed and comprehensive literature overview of the synthetic methods for the preparation of these aza-tryptophans is presented and general facets of the biological properties and most promising applications are discussed.

Nanotechnology-based bone regeneration in orthopedics: a review of recent trends.

Nanotechnology has revolutionized the field of bone regeneration, offering innovative solutions to address the challenges associated with conventional therapies. This comprehensive review explores the diverse landscape of nanomaterials - including nanoparticles, nanocomposites and nanofibers - tailored for bone tissue engineering. We delve into the intricate design principles, structural mimicry of native bone and the crucial role of biomaterial selection, encompassing bioceramics, polymers, metals and their hybrids. Furthermore, we analyze the interface between cells and nanostructured materials and their pivotal role in engineering and regenerating bone tissue. In the concluding outlook, we highlight emerging frontiers and potential research directions in harnessing nanomaterials for bone regeneration.

Super-secondary structure peptidomimetics: design and synthesis of an α-α hairpin analogue.

The α-α helix motif presents key recognition domains in protein-protein and protein-oligonucleotide binding, and is one of the most common super-secondary structures. Herein we describe the design, synthesis and structural characterization of an α-α hairpin analogue based on a tetra-coordinated Pd(II) bis-(iminoisoquinoline) complex as a template for the display of two α-helix mimics. This approach is exemplified by the attachment of two biphenyl peptidomimetics to reproduce the side-chains of the i and i+4 residues of two helices.

An insight in Salmonella typhi associated autoimmunity candidates' prediction by molecular mimicry.

Autoimmune diseases develop when the immune system targets healthy cells and tissues of an individual. In developing countries, S. typhi (a gram-negative pathogenic bacteria) remains a major public health issue. This study aimed to employ bioinformatics analyses to determine the 3D structural-based molecular mimicry and sequence of S. typhi and human host proteins. In addition, to classify possible antigenic microbial peptides homologous to human peptides and comprehend the molecular basis of S. typhi-related autoimmune disorders. Protein sequences were obtained from the NCBI database, and redundancy was removed using the CD-HIT tool. The BLASTp comparative sequence analysis was followed for molecular mimicry identification of human and S. typhi protein sequences. The PathDIP database was utilized to simulate essential physical relationships between proteins and curated pathways for metabolic processes. Subsequently, the IEDB database was used to find cross-reactive MHC class-II binding epitopes that could trigger an autoimmune reaction. SPARKS-X computational biology resource was also used to determine the structural homology between human and S. typhi peptides. The BLASTp study showed that S. typhi and the human host have several proteins holding considerable sequence similarities based on a set threshold of e ≤ 10-6 and bit score ≥100. The PathDIP putatively identified that these proteins enriched in a total of 68 metabolic pathways by a significant P-value (P < 0.005). The PSORTb analysis predicted that 26 out of these proteins are cytosolic, 1 predicted to be periplasmic protein, and 1 predicted to be localized in the cytoplasmic membrane. IEDB data analysis predicted many S.typhi and human homologs epitopes as a good binder of human HLA, i.e. DRB1*01:01, DPA1*03:01/DPB1*04:02, and DQA1*01:02/DQB1*06:02 with IC50 < 50 nM. Finally, the docking data demonstrated that homolog lead epitopes promisingly interact with HLA and immune TLR4 receptors by exhibiting the best docking scores and molecular interactions. The analyses ultimately identified several potential candidate proteins and peptides that could cause S.typhi infection-mediated autoimmune diseases in humans.

Morbid Sequences Suggest Molecular Mimicry between Microbial Peptides and Self-Antigens: A Possibility of Inciting Autoimmunity.

Understanding etiology of autoimmune diseases has been a great challenge for designing drugs and vaccines. The pathophysiology of many autoimmune diseases may be attributed to molecular mimicry provoked by microbes. Molecular mimicry hypothesizes that a sequence homology between foreign and self-peptides leads to cross-activation of autoreactive T cells. Different microbial proteins are implicated in various autoimmune diseases, including multiple sclerosis, human type 1 diabetes, primary biliary cirrhosis and rheumatoid arthritis. It may be imperative to identify the microbial epitopes that initiate the activation of autoreactive T cells. Consequently, in the present study, we employed immunoinformatics tools to delineate homologous antigenic regions between microbes and human proteins at not only the sequence level but at the structural level too. Interestingly, many cross-reactive MHC class II binding epitopes were detected from an array of microbes. Further, these peptides possess a potential to skew immune response toward Th1-like patterns. The present study divulges many microbial target proteins, their putative MHC-binding epitopes, and predicted structures to establish the fact that both sequence and structure are two important aspects for understanding the relationship between molecular mimicry and autoimmune diseases. Such findings may enable us in designing potential immunotherapies to tolerize autoreactive T cells.

Structure of the Toll/interleukin 1 receptor (TIR) domain of the immunosuppressive Brucella effector BtpA/Btp1/TcpB.

BtpA/Btp1/TcpB is a virulence factor produced by Brucella species that possesses a Toll interleukin-1 receptor (TIR) domain. Once delivered into the host cell, BtpA interacts with MyD88 to interfere with TLR signalling and modulates microtubule dynamics. Here the crystal structure of the BtpA TIR domain at 3.15 Å is presented. The structure shows a dimeric arrangement of a canonical TIR domain, similar to the Paracoccus denitrificans Tir protein but secured by a unique long N-terminal α-tail that packs against the TIR:TIR dimer. Structure-based mutations and multi-angle light scattering experiments characterized the BtpA dimer conformation in solution. The structure of BtpA will help with studies to understand the mechanisms involved in its interactions with MyD88 and with microtubules.