High-throughput quantitative assessments of the chemical complementarity of celiac disease-related IGH CDR3s and a gliadin epitope.

The long-term value of efficient antigen discovery includes gaining insights into the variety of potential cancer neoantigens, effective vaccines lacking adverse effects, and adaptive immune receptor (IR) targets for blocking adaptive IR-antigen interactions in autoimmunity. While the preceding goals have been partially addressed via big data approaches to HLA (human leukocyte antigen)-epitope binding, there has been little such progress in the big data setting for adaptive IR-epitope binding. This delay in progress for the latter is likely due to, among other things, the much more complicated adaptive IR repertoire in an individual compared to individual HLA alleles. Thus, results described here represent the application of an algorithm for efficient assessment of immunoglobulin heavy chain complementarity determining region-3 (IGH CDR3)-gliadin epitope interactions, with a focus on epitopes known to be associated with an immune response in celiac disease. The hydrophobic, chemical complementarity between celiac case IGH CDR3s and known celiac epitopes was found to be greater in comparison to the hydrophobic, chemical complementarity between the same celiac case IGH CDR3s and a series of control epitopes. Thus, the approaches indicated here likely offer guidance for the development of conveniently applied algorithms for antigen verification and discovery.

Peptide hydrogen-bonded organic frameworks.

Hydrogen-bonded porous frameworks (HPFs) are versatile porous crystalline frameworks with diverse applications. However, designing chiral assemblies or biocompatible materials poses significant challenges. Peptide-based hydrogen-bonded porous frameworks (P-HPFs) are an exciting alternative to conventional HPFs due to their intrinsic chirality, tunability, biocompatibility, and structural diversity. Flexible, ultra-short peptide-based P-HPFs (composed of 3 or fewer amino acids) exhibit adaptable porous topologies that can accommodate a variety of guest molecules and capture hazardous greenhouse gases. Longer, folded peptides present challenges and opportunities in designing P-HPFs. This review highlights recent developments in P-HPFs using ultra-short peptides, folded peptides, and foldamers, showcasing their utility for gas storage, chiral recognition, chiral separation, and medical applications. It also addresses design challenges and future directions in the field.

Conformation Controlled Hydrogelation of Minimalistic α, γ Hybrid Peptide.

A majority of short peptide (≤7 amino acids) hydrogels are primarily assembled via cross ß-structure formation. In contrast to the natural trend, herein, we report the formation of supramolecular hydrogel from the ultrashort hybrid folded peptide composed of canonical α-amino acid and noncanonical γ-amino acid, Fmoc-γPhe-Phe-OH. The designed hybrid peptide hydrogel is composed of entangled fibers, has viscoelastic properties, exhibits proteolytic stability, and exhibits cytocompatibility with L929 fibroblast cells. Mutating the peptide sequence by altering the position of γPhe from the N-termini to C-termini transforms the self-assembly into crystalline aggregates. Combining FTIR, 2D NMR, and DFT calculations revealed that the hydrogel-forming peptide adopts a C9 H-bonded conformation, resembling the well-known γ-turn. However, the isomeric hybrid peptide adopts an extended structure. The present study highlights the importance of secondary structure in the higher order assembly of minimalist hybrid peptides and broadens the range of secondary structures to design short peptide-based hydrogels.

Synthesis and mechanistic study of Aß42 C-terminus domain derived tetrapeptides that inhibit Alzheimer's Aß-aggregation-induced neurotoxicity.

Amyloid plaque formation in the brain is mainly responsible for the onset of Alzheimer's disease (AD). Structure-based peptides have gained importance in recent years, and rational design of the peptide sequences for the prevention of Aß-aggregation and related toxicity is imperative. In this study, we investigate the structural modification of tetrapeptides derived from the hydrophobic C-terminal region of Aß42 "VVIA-NH2" and its retro-sequence "AIVV-NH2." A preliminary screening of synthesized peptides through an MTT cell viability assay followed by a ThT fluorescence assay revealed a peptide 13 (Ala-Ile-Aib-Val-NH2) that showed protection against Aß-aggregation and associated neurotoxicity. The presence of the α-helix inducer "Aib" in peptide 13 manifested the conformational transition from cross-ß-sheets to α-helical content in Aß42. The absence of fibrils in electron microscopic analysis suggested the inhibitory potential of peptide 13. The HRMS, DLS, and ANS studies further confirmed the inhibitory activity of 13, and no cytotoxicity was observed. The structure-based peptide described herein is a promising amyloid-ß inhibitor and provides a new lead for the development of AD therapeutics.

Synthesis and mechanistic study of ultrashort peptides that inhibits Alzheimer's Aß-aggregation-induced neurotoxicity.

Misfolding/aggregation of ß-amyloid peptide lead to the formation of toxic oligomers or accumulation of amyloid plaques, which is a seminal step in the progression of Alzheimer's disease (AD). Despite continuous efforts in the development of therapeutic agents, the cure for AD remains a major challenge. Owing to specific binding affinity of structure-based peptides, we report the synthesis of new peptide-based inhibitors derived from the C-terminal sequences, Aß38-40 and Aß40-42. Preliminary screening using MTT cell viability assay and corroborative results from ThT fluorescence assay revealed a tripeptide showing significantly effective inhibition towards Aß1-42 aggregation and induced toxicity. Peptide 3 exhibited excellent cell viability of 94.3 % at 2 µM and of 100 % at 4 µM and 10 µM. CD study showed that peptide 3 restrict the conformation transition of Aß1-42 peptide towards cross-ß-sheet structure and electron microscopy validated the absence of Aß aggregates as indicated by the altered morphology of Aß1-42 in the presence of peptide 3. The HRMS-ESI, DLS and ANS studies were performed to gain mechanistic insights into the effect of inhibitor against Aß aggregation. This Aß-derived ultrashort motif provides impetus for the development of peptide-based anti-AD agents.

Chemical Complementarity of Blood-Sourced, Breast Cancer-Related TCR CDR3s and the CMV UL29 and IE1 Antigens is Associated with Worse Overall Survival.

Cytomegalovirus (CMV) infection is common and becomes a particular concern in immunocompromised patients. Understanding the potential role CMV plays in breast cancer patients' disease progression is important for providing more patient-specific treatments. In this study, we analyzed whether a breast cancer patient's blood-sourced T-cell receptor (TCR) complementarity determining-3 (CDR3) amino acid (AA) sequences could provide an indication of the impact of a systemic CMV infection. Specifically, we assessed the chemical complementarity of patient TCR CDR3 AAs and CMV antigens to determine whether patients with greater complementarity also represented different survival probabilities. Initially, we examined five distinct CMV antigens, of which two, IE1 and UL29, represented TCR (TRA+ RB)-CDR3-CMV antigen complementarity scores (CSs) whereby cases representing the upper 50th percentile of CSs had a worse overall survival (log-rank p = 5.034E-3, for IE1). Then, an analysis of CSs representing previously identified, TCR IE1 epitopes indicated that greater TRB CDR3-IE1 epitope complementarities represented a worse OS (log-rank p = 0.0111). These results raise the question of whether a systemic, anti-CMV response leads to increased systemic inflammation, which is either directly or indirectly supportive of tumor growth; or are patients succumbing to a direct impact of CMV functions on tumor growth or metastasis?

Design, synthesis, and applications of ring-functionalized histidines in peptide-based medicinal chemistry and drug discovery.

Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.

Direct Access to α,ß-Alkynylamides via Pd-Catalyzed Carbonylation of Terminal Alkynes with Amines Using Chloroform as the CO Surrogate.

We describe the first-time use of a palladium-di(1-adamantyl)-n-butylphosphine catalytic system for the synthesis of alk-2-ynamides from terminal alkynes via aminocarbonylation reaction. This method avoids the direct use of toxic CO gas by utilizing chloroform as an in situ CO source. The aminocarbonylation of both aromatic and aliphatic electron-rich alkyne nucleophiles is reported for the first time. The mild condition provides alk-2-ynamides within 50 min under microwave irradiation at 80 °C.

Synthetic amino acids-derived peptides target Cryptococcus neoformans by inducing cell membrane disruption.

We investigated synthetic amino acid-based approach to design short peptide-based antibiotics. Tautomerically restricted, amphiphilic 1-aryl-l-histidines along with hydrophobic tryptophan were utilized to synthesize the designed peptides. l-Trp-l-His(1-biphenyl)-NHBzl (12e, IC50 = 1.91 µg/mL; MIC = 3.46 µg/mL) and l-His[1-(4-n-butylphenyl)]-l-Trp-l-His[1-(4-n-butylphenyl)]-NHBzl (16d, IC50 = 1.36 µg/mL; MIC = 2.46 µg/mL) produced potency against Cryptococcus neoformans. Peptides with moderate antibacterial activities (IC50s = 4.40-8.80 µg/mL) were also identified. The mechanism of action and cellular changes revealed that membrane disruption due to interactions of the positively charged peptides with the negatively charged membrane of the cryptococcal cells result in permeabilization, leading to pore formation. The internal localization of the peptides instigated the interactions with DNA causing fragmentation of the genetic material, which together with membrane disruption led to cell death. Flow cytometric analysis points to cells death by apoptotic pathway. Time kill kinetics and synergistic study confirmed the fungicidal nature and synergism with amphotericin B.

Synthesis, biological evaluation and mechanistic studies of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as a new structural class of antimicrobials.

In spite of several attempts to develop newer pharmacophores as potential antimicrobial agents, the benzimidazole scaffold is still considered as one of the most sought after structural component towards the design of compounds that act against a wide spectrum of microbes. Herein, we report the design and synthesis of a new structural class of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as antimicrobial agents. The most potent analog, 6g shows IC50 of 1.3 µM, 2.7 µM, 10.8 µM, 5.4 µM and 10.8 µM against Cryptococcus neoformans, Candida albicans, Candida parapsilosis, Escherichia coli and Staphylococcus aureus, respectively. Interestingly 6g exhibits selectivity towards the cryptococcal cells with fungicidal behavior. Propidium iodide uptake study shows permeabilization of pathogenic cells in the presence of 6g. Flow cytometric analysis confirms that cell death is predominantly due to apoptosis. Moreover, electron microscopic analysis specifies that it shrinks, disrupts and initiate pore(s) formation in the cell membrane leading to cell lysis.

Developing and testing the usability, acceptability, and future implementation of the Whole Day Matters Tool and User Guide for primary care providers using think-aloud, near-live, and interview procedures.

BACKGROUND: Canada's 24-Hour Movement Guidelines for Adults have shifted the focus from considering movement behaviours (i.e., physical activity, sedentary behaviour, and sleep) separately to a 24-h paradigm, which considers how they are integrated. Accordingly, primary care providers (PCPs) have the opportunity to improve their practice to promote all movement behaviours cohesively. However, PCPs have faced barriers to discussing physical activity alone (e.g., time, competing priorities, inadequate training), leading to low frequency of physical activity discussions. Consequently, discussing three movement behaviours may seem challenging. Tools to facilitate primary care discussions about physical activity have been developed and used; however, few have undergone usability testing and none have integrated all movement behaviours. Following a synthesis of physical activity, sedentary behaviour, and sleep tools for PCPs, we developed the Whole Day Matters Tool and User Guide that incorporate all movement behaviours. The present study aimed to explore PCPs' perceptions on the usability, acceptability, and future implementation of the Whole Day Matters Tool and User Guide to improve their relevancy among PCPs. METHODS: Twenty-six PCPs were observed and audio-video recorded while using the Tool and User Guide in a think-aloud procedure, then in a near-live encounter with a mock service-user. A debriefing interview using a guide informed by Normalization Process Theory followed. Recordings were transcribed verbatim and analysed using content analysis and a critical friend to enhance rigour. RESULTS: PCPs valued aspects of the Tool and User Guide including their structure, user-friendliness, visual appeal, and multi-behaviour focus and suggested modifications to improve usability and acceptability. Findings are further discussed in the context of Normalization Process Theory and previous literature. CONCLUSIONS: The Tool and User Guide were revised, including adding plain language, reordering and renaming sections, reducing text, and clarifying instructions. Results also informed the addition of a Preamble and a Handout for adults accessing care (i.e., patients/clients/service-users) to explain the evidence underpinning the 24-Hour Movement Guidelines for Adults and support a person-centered approach. These four resources (i.e., Tool, User Guide, Preamble, Handout) have since undergone a consensus building process to arrive at their final versions before being disseminated into primary care practice.

Anticryptococcal activity and mechanistic studies of short amphipathic peptides.

Cryptococcus neoformans, an opportunistic fungal pathogen, causes cryptococcosis in immunocompromised persons. A series of modified L-histidines-containing peptides are synthesized that exhibit promising activity against C. neoformans. Analog 11d [L-His(2-adamantyl)-L-Trp-L-His(2-phenyl)-OMe] produced potency with an IC50 of 3.02 µg/ml (MIC = 5.49 µg/ml). This peptide is noncytotoxic and nonhaemolytic at the MIC and displays synergistic effects with amphotericin B at subinhibitory concentration. Mechanistic investigation of 11d using microscopic tools indicates cell wall and membrane disruption of C. neoformans, while flow cytometric analysis confirms cell death by apoptosis. This study indicates that 11d exhibits antifungal potential and acts via the rapid onset of action.

A Novel Technique for the Correction of Unilateral Craniofacial Fibrous Dysplasia Using Multiplanar Sequential Cutting Guides.

In this unique case report, the authors have described a new method for the correction of unilateral craniofacial fibrous dysplasia by using sequential cutting guides. Due to the complex 3-dimensional anatomy of zygoma, it needs to be chiseled in multiple planes to mimic the normal contralateral side. To achieve this, 3 different guides were used one after the other to perform osteotomies in different planes and remove the excess fibrous bone.

Synthetic amino acids-based short amphipathic peptides exhibit antifungal activity by targeting cell membrane disruption.

Availability of a limited number of antifungal drugs created a necessity to develop new antifungals with distinct mode of action. Investigation on a new series of peptides led us to identify Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor exhibiting IC50 value of 4.4 µg/mL against Cryptococcus neoformans. Analog 10g exhibit high selectivity to fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. 10g produced fungicidal effect on growing cryptococcal cells and displayed synergistic effect with amphotericin B. Overall cationic character of 10g resulted in interaction with negatively charged fungal membrane while hydrophobicity enhanced penetration inside the cryptococcal cells causing hole(s) formation and disruption to the membrane as evident by the scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy analyses. Flow cytometric investigation revealed rapid death of fungal cells by apopotic pathway.

Non-COVID-19 Cutaneous Mucormycosis from a Plastic Surgical Perspective.

Background Cutaneous mucormycosis is a rare and fulminant infection associated with high mortality. Plastic surgeons come across this infection in the settings of road traffic accidents, surgical site infections, and as a secondary infection with underlying bacterial soft tissue infections. Due to this infection's rarity and aggressive course, it is essential to initiate prompt multidisciplinary management at the first presentation. With this study, we aim to present a protocol for managing the condition. Methods This is a retrospective observational study of patients with cutaneous mucormycosis managed at a tertiary care hospital from January 1, 2016 to November 30, 2022 excluding patients with mucormycosis who tested positive for coronavirus disease 2019. Results Of 24 patients, 22 were males, and most were in the age group of 41 to 60 years. Sixteen patients survived and five out of eight deceased had comorbidities, six presented primarily without prior debridement, and six had trunk involvement. Conclusion A high index of clinical suspicion is necessary for early diagnosis and management of patients with invasive cutaneous mucormycosis. A multidisciplinary approach with appropriate medical and surgical management can improve outcomes in cases that otherwise carry a high mortality rate.

The yesterday, today and tomorrow of liver transplant.

With a very long history of setbacks and successes, organ transplantation is one of the greatest medical achievements of the twentieth century. Liver transplantation is currently the most effective method for treating end-stage liver disease. From humble beginnings, improvements in surgical technique, perioperative management, and immunosuppressive therapy have yielded excellent graft and patient outcomes. Most established 'liver transplant' (LT) centres have a 1-year survival rate exceeding 90%, and a 3-year survival rate of over 80%. With immense success, the need for hepatic grafts substantially exceeds their availability. This problem has been partially addressed by using split grafts, living donor liver transplantation (LDLT), and extended criteria grafts (ECG). This article reviews the immense progress made in various aspects of LT including evaluation, increasing donor pool, surgical advances, immunosuppression and anaesthesia related aspects and the way forward. With ongoing cutting edge research in technologies like artificial liver devices, tissue bioengineering and hepatocyte 'farms', the future of LT is more exciting than ever before.

Exploring Helical Peptides and Foldamers for the Design of Metal Helix Frameworks: Current Trends and Future Perspectives.

Flexible and biocompatible metal peptide frameworks (MPFs) derived from short and ultra-short peptides have been explored for the storage of greenhouse gases, molecular recognition, and chiral transformations. In addition to short flexible peptides, peptides with specifically folded conformations have recently been utilized to fabricate a variety of metal helix frameworks (MHFs). The secondary structures of the peptides govern the structure-assembly relationship and thereby control the formation of three-dimensional (3D)-MHFs. Particularly, the hierarchical structural organization of peptide-based MHFs has not yet been discussed in detail. Here, we describe the recent progress of metal-driven folded peptide assembly to construct 3D porous structures for use in future energy storage, chiral recognition, and biomedical applications, which could be envisioned as an alternative to the conventional metal-organic frameworks (MOFs).

Energy drink consumption: a rising public health issue.

Energy drink (ED) consumption has become a growing public health issue over the past few decades. Despite claims of being safe and beneficial, EDs have been linked to particularly fatal outcomes associated with the cardiovascular system which include atrial and ventricular arrhythmias, myocardial infarctions, cardiomyopathies, and sudden cardiac death. Large quantities of caffeine, taurine, sugars, and B-vitamins may be contributing to these outcomes by increasing the heart rate, blood pressure (BP), and contractility of the heart in addition to prolonging the QTc. There is still a substantial amount of unknown information on EDs that warrants more research and a dire need for age regulations, transparency of ingredients, clear labeling of adverse effects, and most importantly, education of consumers.

Palladium-Catalyzed Aminocarbonylation of (Hetero)aryl Iodides with α-Amino Acid Esters as Nucleophiles.

We report palladium-catalyzed aminocarbonylation of (hetero)aryl iodides with α-amino acid esters as nucleophiles. The synthesized N-capped α-amino acids are biologically important building blocks. The mild conditions provide products with high enantioselectivity at 80 °C in 35 min. The reactions are performed under air in a sealed vessel using chloroform as an in situ CO source. For the first time, regioselective carbonylation of histidine is also presented.

Harnessing rhizobacteria to fulfil inter-linked nutrient dependency on soil and alleviate stresses in plants.

Plant rhizo-microbiome comprises complex microbial communities that colonize at the interphase of plant roots and soil. Plant growth-promoting rhizobacteria (PGPR) in the rhizosphere provide important ecosystem services ranging from the release of essential nutrients for enhancing soil quality and improving plant health to imparting protection to plants against rising biotic and abiotic stresses. Hence, PGPR serve as restoring agents to rejuvenate soil health and mediate plant fitness in the facet of changing climate. Though it is evident that nutrient availability in soil is managed through inter-linked mechanisms, how PGPR expedite these processes remain less recognized. Promising results of PGPR inoculation on plant growth are continually reported in controlled environmental conditions, however, their field application often fails due to competition with native microbiota and low colonization efficiency in roots. The development of highly efficient and smart bacterial synthetic communities by integrating bacterial ecological and genetic features provides better opportunities for successful inoculant formulations. This review provides an overview of the interplay between nutrient availability and disease suppression governed by rhizobacteria in soil followed by the role of synthetic bacterial communities in developing efficient microbial inoculants. Moreover, an outlook on the beneficial activities of rhizobacteria in modifying soil characteristics to sustainably boost agroecosystem functioning is also provided.