Amyloid-like Aggregation Propensities of Metabolites - Homogentisic acid, N-Acetyl aspartic acid and Isovaleric acid.

The transformation of metabolites into amyloidogenic aggregates represent an intriguing dimension in the pathophysiology of metabolic disorders, including alkaptonuria, canavan disease, and isovaleric acidemia. Central to this phenomenon are the metabolites homogentisic acid (HA), N-acetyl aspartic acid (NAA), and isovaleric acid (IVA), which we found, weave an intricate network of self-assembled structures. Leveraging an array of microscopy techniques, we traced the morphological behavior of these assemblies that exhibit concentration and time-dependent morphological transitions from isolated globules to clustered aggregates. MD simulation studies suggest significant role of hydrogen bonding interactions in the aggregation process. While displaying strong amyloidogenic propensity in solution, these aged aggregates were significantly cytotoxic to mouse neural N2a cell lines.  In vivo effect in Caenorhabditis elegans (C. elegans) nematode further validated cytotoxicity of aggregates. Our findings provide fresh insights to amyloidogenic nature of HA, NAA, and IVA aggregates and their possible role in associated metabolic disorders such as alkaptonuria, canavan disease and isovaleric acidemia.

MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the seventh most common cause of mortality and one of the major causes of disability and vulnerability in the elderly. AD is characterized by gradual cognitive deterioration, the buildup of misfolded amyloid beta (Aß) peptide, and the generation of neurofibrillary tangles. Despite enormous scientific progress, there is no effective cure for AD. Thus, exploring new treatment options to stop AD or at least slow down its progress is important. In this study, we investigated the potential therapeutic effects of MCC950 on NLRP3-mediated inflammasome-driven inflammation and autophagy in AD. Rats treated with streptozotocin (STZ) exhibited simultaneous activation of the NLRP3 inflammasome and autophagy, as confirmed by Western blot, immunofluorescence, and co-immunoprecipitation analyses. MCC950, a specific NLRP3 inhibitor, was intraperitoneally administered (50 mg/kg body weight) to rats with AD-like symptoms induced by intracerebroventricular STZ injections (3 mg/kg body weight). MCC950 effectively suppressed STZ-induced cognitive impairment and anxiety by inhibiting NLRP3-dependent neuroinflammation. Moreover, our findings indicate that MCC950 exerts neuroprotective effects by attenuating autophagy in neuronal cells. The inhibiting effects of MCC950 on inflammasome activation and autophagy were reproduced in vitro, provding further mechansistic insights into MCC950 therapeutic action. Our findings suggest that MCC950 impedes the progression of AD and may also improve cognitive function through the mitigation of autophagy and NLRP3 inflammasome inhibition.

An unnatural amino acid modified human insulin derivative for visual monitoring of insulin aggregation.

Insulin often forms toxic fibrils during production and transportation, which are deposited as amyloids at repeated injection sites in diabetic patients. Distinguishing early fibrils from non-fibrillated insulin is difficult. Herein, we introduce a chemically modified human insulin derivative with a distinct visual colour transition upon aggregation, facilitating insulin quality assessment.

Bi2Te2Se and Sb2Te3 heterostructure based photodetectors with high responsivity and broadband photoresponse: experimental and theoretical analysis.

Topological insulators have emerged as one of the most promising candidates for the fabrication of novel electronic and optoelectronic devices due to the unique properties of nontrivial Dirac cones on the surface and a narrow bandgap in the bulk. In this work, the Sb2Te3 and Bi2Te2Se materials, and their heterostructure are fabricated by metal-organic chemical vapour deposition and evaporation techniques. Photodetection of these materials and their heterostructure shows that they detect light in a broadband range of 600 to 1100 nm with maximum photoresponse of Sb2Te3, Bi2Te2Se and Sb2Te3/Bi2Te2Se at 1100, 1000, and 1000 nm, respectively. The maximum responsivity values of Sb2Te3, Bi2Te2Se, and their heterostructure are 183, 341.8, and 245.9 A W-1 at 1000 nm, respectively. A computational study has also been done using density functional theory (DFT). Using the first-principles methods based on DFT, we have systematically investigated these topological insulators and their heterostructure's electronic and optical properties. The band structures of Sb2Te3 and Bi2Te2Se thin films (3 QL) and their heterostructure are calculated. The bandgaps of Sb2Te3 and Bi2Te2Se are 26.4 and 23 meV, respectively, while the Sb2Te3/Bi2Te2Se heterostructure shows metallic behaviour. For the optical properties, the dielectric function's real and imaginary parts are calculated using DFT and random phase approximation (RPA). It is observed that these topological materials and their heterostructure are light absorbers in a broadband range, with maximum absorption at 1.90, 2.40, and 3.21 eV.

Inhibiting Erastin-Induced Ferroptotic Cell Death by Purine-Based Chelators.

Ferroptosis is a cell death event caused by increased lipid peroxidation leading to iron-dependent oxidative stress and is associated with a wide variety of diseases. In recent years, ferroptosis inhibition has emerged as a novel strategy to target different pathologies. Here, we report the synthesis of two purine derivatives, 1 and 2, for iron chelation strategy and evaluate their potency to inhibit erastin-induced ferroptosis. Both compounds showed efficient iron chelation in solution as well as in cellular environment. The crystal structure of the purine derivatives with iron demonstrated a 2 : 1 (ligand to metal center) stoichiometry for iron and purine derivative complexation. The synthesized compounds also decrease the reactive oxygen species concentration in cell cultures. Compound 2 showed better potency towards the prevention of ferroptotic cell death as compared to commercially available iron chelator in the erastin-induced ferroptosis cell culture model. Such purine analogues are potential functional scaffolds for the development of target molecules for ferroptosis inhibition.

Strategies for Interference of Insulin Fibrillogenesis: Challenges and Advances.

The discovery of insulin came with very high hopes for diabetic patients. In 2021, the world celebrated the 100th anniversary of the discovery of this vital hormone. However, external use of insulin is highly affected by its aggregating tendency that occurs during its manufacturing, transportation, and improper handling which ultimately leads to its pharmaceutically and biologically ineffective form. In this review, we aim to discuss the various approaches used for decelerating insulin aggregation which results in the enhancement of its overall structural stability and usage. The approaches that are discussed are broadly classified as either a measure through excipient additions or by intrinsic modifications in the insulin native structure.

Blended polar/nonpolar peptide conjugate interferes with human insulin amyloid-mediated cytotoxicity.

Insulin, a peptide hormone and a key regulator of blood glucose level, is routinely administered to type-I diabetic patients to achieve the required glycemic control. Insulin aggregation and ensuing amyloidosis has been observed at repeated insulin injection sites and in injectable formulations. The latter occurs due to insulin agglomeration during shipping and storage. Such insulin amyloid leads to enhanced immunogenicity and allow potential attachment to cell membranes leading to cell permeability and apoptosis. Small molecule inhibitors provide useful interruption of this process and inhibit protein misfolding as well as amyloid formation. In this context, we report the propensity of a palmitoylated peptide conjugate to inhibit insulin aggregation and amyloid-mediated cytotoxicity, via designed interference with polypeptide interfacial interactions.

Superiority of Higher-Volume Fresh Feces Compared to Lower-Volume Frozen Feces in Fecal Microbiota Transplantation for Recurrent Clostridioides Difficile Colitis.

GOALS: To compare the clinical outcomes of different protocols for fecal microbiota transplantation (FMT) in two community hospitals with similar patient demographics. BACKGROUND: FMT is commonly performed for recurrent or refractory Clostridioides difficile infection (rCDI). The clinical efficacy of FMT for this indication has been well established. However, there has been no standardization or optimization of the amount of fecal material, method of feces preparation, or route of delivery for FMT. STUDY: In this retrospective study, patients with rCDI received FMT using commercially available frozen fecal preparation (22.7 g) at Center A and locally prepared fresh fecal filtrate (30-50 g) at Center B. The primary outcome was defined as complete resolution of clinical symptoms related to rCDI after at least 8 weeks of follow-up. RESULTS: Fifty patients from each center were included in the study. Clinical success after initial FMT with lower-volume frozen fecal preparation at Center A was 32/50 (64.0%) compared to 49/50 (98.0%) with higher-volume fresh fecal filtrate at Center B (p < 0.0001). Seventeen patients in Center A and 1 patient in Center B underwent at least one repeat FMT. Overall clinical success was achieved in 43/50 (86%) of patients in Center A and 50/50 (100%) in Center B (p = 0.012). CONCLUSIONS: Our results suggest superior clinical efficacy of a larger amount of fresh fecal filtrate over a smaller amount of commercially available frozen fecal preparation. Further studies are needed to examine the effect of varying amounts of feces and the optimal protocol for FMT in patients with rCDI.

Environmentally Benign, Intrinsically Coordinated, Lithium-Based Solid Electrolyte with a Modified Purine as Supporting Ligand.

Bioinspired materials have become increasingly competitive for electronic applications in recent years owing to the environment-friendly alternatives they offer. The notion of biocompatible solid organic electrolytes addresses the issues concerning potential leakage of corrosive liquids, volatility and flammability of electrolyte solvents. This study presents a new intrinsically coordinated LiI adenine complex that exhibits electrical conductivity as a solid electrolyte capable of self-sustained supply of LiI ions. It exhibits conductivity through moisture-assisted LiI ion motion up to 373 K, and possibly by an ion-hopping mechanism beyond 373 K. This purine-derived solid electrolyte shows enhanced conductivity and transference number demonstrating the potential of purine-based ligands and their coordination complexes in interesting materials applications.

Potential clinical application of an automated fluorescent microbial cell counter in the detection of urinary tract infection.

BACKGROUND: Urinary tract infections (UTI) account for millions of office visits and approximately 400 000 hospital admissions every year in the United States; as a result, the cost burden of UTI in the USA is estimated at approximately $2.8 billion. There is a great deal of interest in finding newer, faster, and more reliable methods for diagnosing UTI as compared to the standard urine culture. METHODS: An automated fluorescent microbial cell counter was used to compare urine samples found to be positive for Escherichia coli UTI via cell culturing (n = 11) with UTI-negative samples (n = 10). RESULTS: Patients with a positive urine culture had significantly higher cell count results using the microbial cell counter (1.01 × 108 cells/mL) as compared to the negative samples (2.35 × 106 cells/mL; P = .0022). CONCLUSIONS: These observations suggest that automated microbial cell counters may serve as a rapid, objective method for the detection of bacteriuria in urine samples submitted for evaluation of suspected UTI.

Exfoliating a CdII -Purine Framework: Conversion of Nanosheets-to-Nanofibers and Studies of Elastic and Capacitive Properties.

Layered bulk crystals are amenable to exfoliation to yield 2D nanosheets through isolation and intercalation processes, which could be further converted to 1D nanoscale structures. The latter inherit gross morphological and physical properties associated with the precursor structures. Herein, we report three purine-based crystal structures 1, 2, and 3, where 3 is obtained by a single-crystal-to-single-crystal transformation from 2 and is a conformational polymorph of 1. Next, we describe the sonication-assisted liquid exfoliation of 1, a CdII -purine coordination framework, into nanosheets and nanofibers in a solvent-dependent process. The exfoliation was carefully studied at low temperatures to ascertain this unique conversion. This work also features the determination of the Young's modulus and surface potential of the bioinspired CdII -based nanostructures by using amplitude modulation-frequency modulation atomic force microscopy and Kelvin probe force microscopy, respectively, revealing their interesting elastic and capacitive properties for their possible use in electronics and energy devices. Electron impedance spectroscopy measurements further established a higher value of capacitance for the exfoliated CdII framework as compared to the ligand alone.

Caspase-3 mediated programmed cell death by a gold-stabilised peptide carbene.

The synthesis of novel N-heterocyclic carbene complexes derived from a tripeptide ligand (L), containing non-natural amino acid, thiazolylalanine is described here. The peptide ligand was reacted with suitable precursors to generate gold and mercury carbene complexes. The plausible structures of both complexes were predicted by spectroscopic data and DFT calculations. The binding energy data was also analyzed to predict their stability. The gold carbene complex (1A), showed activity against MCF7 breast cancer cell line due to mitochondrial triggered caspase-3 mediated programmed cell death. Its internalization inside cells could be observed due to autofluorescence. This study affords a methodology for successful generation of peptide carbene complexes for their therapeutic potential.

Editorial: The National Organic Symposium Trust-Shaping Organic Chemistry in India for Over 30 Years.

Reasons to celebrate! The National Organic Symposium Trust (NOST) celebrated its 30th anniversary in 2018. This organization has been instrumental in shaping and influencing organic chemistry research in India.

Peptide-Based Scaffold for Nitric Oxide Induced Differentiation of Neuroblastoma Cells.

Nitric oxide is a gaseous messenger involved in neuronal differentiation, development and synaptogenesis, in addition to many other physiological functions. Therefore, it is imperative to maintain an optimal nitric oxide concentration to ensure its biochemical function. A sustained nitric oxide releasing scaffold, which supports neuronal cell differentiation, as determined by morphometric analysis of neurite outgrowth, is described. Moreover, the effect of nitric oxide on the neuroblastoma cell line was also confirmed by immunofluorescent analysis of neuronal nuclear protein (NeuN), specific neuronal marker and neurofilament (NF) protein, which revealed a significant increase in their expression levels, in comparison with undifferentiated cells.

The retrospect and prospect of the applications of biotechnology in Phoenix dactylifera L.

Date palm (Phoenix dactylifera L.) is one of the most important fruit trees that contribute a major part to the economy of Middle East and North African countries. It is quintessentially called "tree of life" owing to its resilience to adverse climatic conditions, along with manifold nutritional-cum-medicinal attributes that comes from its fruits and other plant parts. Being a tree with such immense utility, it has gained substantial attention of tree breeders for its genetic advancement via in vitro biotechnological interventions. Herein, an extensive review of biotechnological research advances in date palm has been consolidated as one of the major research achievements during the past two decades. This article compares the different biotechnological techniques used in this species such as: tissue and organ culture, bioreactor-mediated large-scale propagation, cell suspension culture, embryogenic culture, protoplast culture, conservation (for short- and long-term) of germplasms, in vitro mutagenesis, in vitro selection against biotic and abiotic stresses, secondary metabolite production in vitro, and genetic transformation. This review provides an insight on crop improvement and breeding programs for improved yield and quality fruits; besides, it would undeniably facilitate the tissue culture-based research on date palm for accelerated propagation and enhanced production of quality planting materials, along with conservation and exchange of germplasms, and genetic engineering. In addition, the unexplored research methodologies and major bottlenecks identified in this review should be contemplated on in near future.

Supramolecular Photoactivatable Anticancer Hydrogels.

A photoactivatable dopamine-conjugated platinum(IV) anticancer complex (Pt-DA) has been incorporated into G-quadruplex G4K+ borate hydrogels by using borate ester linkages (Pt-G4K+B hydrogel). These were characterized by 11B NMR, attenuated total reflection Fourier transform infrared spectroscopy, circular dichroism, scanning electron microscopy and transmission electron microscopy. Microscopy investigations revealed the transformation of an extended fiber assembly into discrete flakes after incorporation of Pt-DA. Pt-DA showed photocytotoxicity against cisplatin-resistant A2780Cis human ovarian cancer cells (IC50 74 µM, blue light) with a photocytotoxic index <2, whereas Pt-G4K+B hydrogels exhibited more potent photocytotoxicity (IC50 3 µM, blue light) with a photocytotoxic index >5. Most notably, Pt-DA and Pt-G4K+B hydrogels show selective phototoxicity for cancer cells versus normal fibroblast cells (MRC5).

Coordination-Controlled One-Dimensional Molecular Chains in Hexapodal Adenine-Silver Ultrathin Films.

Growth of a silver coordination polymer of a C3-symmetric hexaadenine ligand is studied on highly oriented pyrolytic graphite (HOPG), using high-resolution atomic force microscopy (AFM). This unusual ligand offers 6-fold multidentate coordination sites, and consequently, a multidimensional growth of coordination polymer is expected. Notably, each discrete hexapodal unit is bridged by two silver ions along one of the crystallographic directions, resulting in high interaction energy along this direction. When the polymer was deposited on an HOPG surface from a dilute solution, we observed abundant one-dimensional (1D) coordination polymer chains, with a minimum width of approximately 4.5 nm. The single-crystal structure using X-ray analysis is compared with the surface patterns to reconcile and understand the structure of the 1D polymer on an HOPG surface. The energy levels of Ag-L1 within the proposed model were calculated, on the basis of the X-ray crystal structure, and compared to the ligand states to gain information about the electronic structure of ligand upon Ag coordination. On the basis of the wave functions of a few molecular orbitals (MOs) near the Fermi energy, it is surmised that unfilled MOs may play a crucial role in the transport properties of the Ag-L1 adlayer.

Development of a rapid loop-mediated isothermal amplification assay for diagnosis and assessment of cure of Leishmania infection.

BACKGROUND: Leishmaniasis is a spectrum of diseases with great relevance to public health. Conventional diagnostic methods are time consuming, needing trained personnel. A robust, rapid and cost effective diagnostic test is warranted for on-time diagnosis and field application. METHODS: We have developed a loop mediated isothermal amplification (LAMP) assay with primers (n = 6) based on Leishmania donovani kDNA for detection of Leishmania infection, using a closed tube to prevent cross-contamination. The assay was used to detect Leishmania infection in biological samples obtained from patients of visceral leishmaniasis (VL), post kala-azar dermal leishmaniasis (PKDL) and cutaneous leishmaniasis (CL). RESULTS: The assay was positive for L. donovani, L. tropica and L. major parasites, with the highest sensitivity towards L. donovani (1 fg DNA). The high sensitivity of the assay for detection of L. donovani was reflected in its ability to detect parasite DNA within 30 min of amplification time with a threshold detection limit of ≥25 copies per reaction. The assay detected parasite in 64 of 66 VL blood samples (sensitivity, 96.9%; 95% CI: 89.6-99.2%), 15 of 15 VL bone marrow aspirate samples (sensitivity, 100%; 95% CI:79.6-100%), 65 of 67 PKDL tissue biopsy samples (sensitivity, 97%; 95% CI:89.7-99.2%). The assay was evaluated in a few cases of CL wherein it was found positive in 8 of 10 tissue biopsies (sensitivity, 80%; 95% CI: 49-94.3%). The assay was negative in all control blood (n = 76) and tissue biopsy (n = 24) samples (specificity, 100%; 95% CI: 96.3-100%). Further, the assay was evaluated for its utility in assessment of cure in treated VL and PKDL patients. The assay detected parasite DNA in 2 of 20VL blood samples and 2 of 21 PKDL tissue samples. Out of 4 cases that were positive for parasite DNA at post treatment stage, 2 patients (1VL and 1 PKDL) returned with relapse. CONCLUSIONS: The study demonstrated a Leishmania genus specific closed tube LAMP assay for reliable and rapid molecular diagnosis of VL and PKDL with potential for application in assessment of cure.

Carrier relaxation dynamics in type-II ZnO/CdSe quantum dot heterostructures.

Semiconductor heterostructures with type-II band alignment are well known for their engineering property of efficient charge separation in photogenerated carriers. Herein, type-II CdSe/ZnO core/shell quantum dot heterostructures with CdSe shells of different thicknesses have been synthesized and a study of carrier dynamics is carried out using femtosecond transient absorption and picosecond emission spectroscopy. Carrier lifetime measurements by transient emission spectroscopy have revealed reduced electron-hole overlap in the type-II localization regime of ZnO/CdSe heterostructures. Femtosecond transient absorption studies have revealed hot electron transfer from CdSe shell to ZnO core prior to electron cooling in the CdSe shell. In addition, a surface channel for the hole cooling process has been identified in the transient absorption measurements. Effects of carrier trapping at interfacial defect states and type-II localization on carrier recombination have been recognized in our transient absorption and emission studies of ZnO/CdSe QDs heterostructure.

Self-Exfoliated Guanidinium-Based Ionic Covalent Organic Nanosheets (iCONs).

Covalent organic nanosheets (CONs) have emerged as functional two-dimensional materials for versatile applications. Although π-π stacking between layers, hydrolytic instability, possible restacking prevents their exfoliation on to few thin layered CONs from crystalline porous polymers. We anticipated rational designing of a structure by intrinsic ionic linker could be the solution to produce self-exfoliated CONs without external stimuli. In an attempt to address this issue, we have synthesized three self-exfoliated guanidinium halide based ionic covalent organic nanosheets (iCONs) with antimicrobial property. Self-exfoliation phenomenon has been supported by molecular dynamics (MD) simulation as well. Intrinsic ionic guanidinium unit plays the pivotal role for both self-exfoliation and antibacterial property against both Gram-positive and Gram-negative bacteria. Using such iCONs, we have devised a mixed matrix membrane which could be useful for antimicrobial coatings with plausible medical benefits.