Synthesis, biological activities, and structure-activity relationships of Morita-Baylis-Hillman adducts: An update.

The Morita-Baylis-Hillman (MBH) reaction is a unique C-C bond-forming technique for the generation of multifunctional allylic alcohols (MBH adducts) in a single operation. In recent years, these MBH adducts have emerged as a novel class of compounds with significant biological potential, including anticancer, anti-leishmanial, antibacterial, antifungal, anti-herbicidal effects and activity against Chagas disease, and so on. The aim of this review is to assimilate the literature findings from 2011 onwards related to the synthesis and biological potential of MBH adducts, with an emphasis on their structure-activity relationships (SAR). Although insight into the biological mechanisms of action for this recently identified pharmacophore is currently in its nascent stages, the mechanisms described so far are reviewed herein.

Amyloid fibril polymorphism in the heart of an ATTR amyloidosis patient with polyneuropathy attributed to the V122Δ variant.

ATTR amyloidosis is a phenotypically heterogeneous disease characterized by the pathological deposition of transthyretin in the form of amyloid fibrils into various organs. ATTR amyloidosis may stem from mutations in variant (ATTRv) amyloidosis, or aging in wild-type (ATTRwt) amyloidosis. ATTRwt generally manifests as a cardiomyopathy phenotype, whereas ATTRv may present as polyneuropathy, cardiomyopathy, or mixed, in combination with many other symptoms deriving from secondary organ involvement. Over 130 different mutational variants of transthyretin have been identified, many of them being linked to specific disease symptoms. Yet, the role of these mutations in the differential disease manifestation remains elusive. Using cryo-electron microscopy, here we structurally characterized fibrils from the heart of an ATTRv patient carrying the V122Δ mutation, predominantly associated with polyneuropathy. Our results show that these fibrils are polymorphic, presenting as both single and double filaments. Our study alludes to a structural connection contributing to phenotypic variation in ATTR amyloidosis, as polymorphism in ATTR fibrils may manifest in patients with predominantly polyneuropathic phenotypes.

ATTRv-V30M Type A amyloid fibrils from heart and nerves exhibit structural homogeneity.

ATTR amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin, a protein integral to transporting retinol and thyroid hormones. Transthyretin is primarily produced by the liver and circulates in blood as a tetramer. The retinal epithelium also secretes transthyretin, which is secreted to the vitreous humor of the eye. Because of mutations or aging, transthyretin can dissociate into amyloidogenic monomers triggering amyloid fibril formation. The deposition of transthyretin amyloid fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryo-electron microscopy, here we determined the structures of amyloid fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found that fibrils from both tissues share a consistent structural conformation, similar to the previously described structure of cardiac fibrils from an individual with the same genotype, but different from the fibril structure obtained from the vitreous humor. Our study hints to a uniform fibrillar architecture across different tissues within the same individual, only when the source of transthyretin is the liver. Moreover, this study provides the first description of ATTR fibrils from the nerves of a patient and enhances our understanding of the role of deposition site and protein production site in shaping the fibril structure in ATTRv-V30M amyloidosis.

Multi-organ structural homogeneity of amyloid fibrils in ATTRv-T60A amyloidosis patients, revealed by Cryo-EM.

ATTR amyloidosis is a degenerative disorder characterized by the systemic deposition of the protein transthyretin. These amyloid aggregates of transthyretin (ATTR) can deposit in different parts of the body causing diverse clinical manifestations. Our laboratory aims to investigate a potential relationship between the different genotypes, organ of deposition, clinical phenotypes, and the structure of ATTR fibrils. Using cryo-electron microscopy, we have recently described how the neuropathic related mutations ATTRv-I84S and ATTRv-V122∆ can drive structural polymorphism in ex vivo fibrils. Here we question whether the mutation ATTRv-T60A, that commonly triggers cardiac and neuropathic symptoms, has a similar effect. To address this question, we extracted and determined the structure of ATTR-T60A fibrils from multiple organs (heart, thyroid, kidney, and liver) from the same patient and from the heart of two additional patients. We have found a consistent conformation among all the fibril structures, acquiring the "closed-gate morphology" previously found in ATTRwt and others ATTRv related to cardiac or mixed manifestations. The closed-gate morphology is composed by two segments of the protein that interact together forming a polar channel, where the residues glycine 57 to isoleucine 68 act as a gate of the polar cavity. Our study indicates that ATTR-T60A fibrils present in peripheral organs adopt the same structural conformation in all patients, regardless of the organ of deposition.

APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a syndrome that is characterized by the rapid development of organ failures predisposing these patients to a high risk of short-term early death. The main causes of organ failure in these patients are bacterial infections and systemic inflammation, both of which can be severe. For the majority of these patients, a prompt liver transplant is still the only effective course of treatment. Kidneys are one of the most frequent extrahepatic organs that are affected in patients with ACLF, since acute kidney injury (AKI) is reported in 22.8-34% of patients with ACLF. Approach and management of kidney injury could improve overall outcomes in these patients. Importantly, patients with ACLF more frequently have stage 3 AKI with a low rate of response to the current treatment modalities. The objective of the present position paper is to critically review and analyze the published data on AKI in ACLF, evolve a consensus, and provide recommendations for early diagnosis, pathophysiology, prevention, and management of AKI in patients with ACLF. In the absence of direct evidence, we propose expert opinions for guidance in managing AKI in this very challenging group of patients and focus on areas of future research. This consensus will be of major importance to all hepatologists, liver transplant surgeons, and intensivists across the globe.

Cryo-EM confirms a common fibril fold in the heart of four patients with ATTRwt amyloidosis.

ATTR amyloidosis results from the conversion of transthyretin into amyloid fibrils that deposit in tissues causing organ failure and death. This conversion is facilitated by mutations in ATTRv amyloidosis, or aging in ATTRwt amyloidosis. ATTRv amyloidosis exhibits extreme phenotypic variability, whereas ATTRwt amyloidosis presentation is consistent and predictable. Previously, we found an unprecedented structural variability in cardiac amyloid fibrils from polyneuropathic ATTRv-I84S patients. In contrast, cardiac fibrils from five genotypically-different patients with cardiomyopathy or mixed phenotypes are structurally homogeneous. To understand fibril structure's impact on phenotype, it is necessary to study the fibrils from multiple patients sharing genotype and phenotype. Here we show the cryo-electron microscopy structures of fibrils extracted from four cardiomyopathic ATTRwt amyloidosis patients. Our study confirms that they share identical conformations with minimal structural variability, consistent with their homogenous clinical presentation. Our study contributes to the understanding of ATTR amyloidosis biopathology and calls for further studies.

O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology.

Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer's and Parkinson's disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.

Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy.

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

Qualitative assessment of Aloe vera as natural tissue fixative: An institutional study.

Objectives: The art of microscopy is only appreciable in well-fixed tissues. We conducted this study to determine the effectiveness of Aloe vera as a tissue fixative and compare its results with the natural fixatives already studied in the literature. Materials and Methods: A pilot study was tried out using commercially available fresh chicken and fish with Aloe vera, and then after getting the promising results similar study protocol was carried out using 10-autopsied human tissue. Four natural fixatives-30% jaggery solution, 20% honey solution, 20% sugar solution, 20% Aloe vera solution and 10% formalin were used for fixation in the study. Fixation of tissues was carried out at room temperature for 24 h. All pre- and postfixation measurements were recorded using stereomicroscope and its software. The difference between pre-and postfixation was calculated and later, all pieces were kept for routine tissue processing followed by routine staining. The tissue sections were assessed for quality, and the whole procedure was blinded among three oral pathologists who scored them. Results: The mean percentage of shrinkage in each bit with different reagents was calculated. The shrinkage seen with 10% formalin and 20% Aloe vera were more likely similar. Among all the natural fixatives, qualitatively also Aloe vera excelled and its results were comparable to that of formalin. Conclusion: The use of Aloe vera in the present study as fixative is the first of its kind, as exhaustive search of the literature shows only its use as transport media in dentistry.

O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology.

The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such α-Synuclein and Tau, which are implicated in the pathogenesis of Alzheimer's and Parkinson's disease, can form different types of fibril structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, and pathology spreading patterns in the brain. Therefore, understanding the molecular and structural determinants contributing to the formation of different amyloid strains or their distinct features could open new avenues for developing disease-specific diagnostics and therapies. In this work, we report that O-GlcNAc modification of α-Synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by Cryo-EM, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson's disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-Synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that post-translational modifications, such as O-GlcNAc modification, of α-Synuclein are key determinants of α-Synuclein amyloid strains and pathogenicity. These findings have significant implications for how we investigate and target amyloids in the brain and could possibly explain the lack of correlation between amyloid burden and neurodegeneration or cognitive decline in some subtypes of NDDs.

An efficient metal-free and catalyst-free C-S/C-O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides.

An operationally simple and metal-free approach is described for the synthesis of pyrazole-tethered thioamide and amide conjugates. The thioamides were generated by employing a three-component reaction of diverse pyrazole C-3/4/5 carbaldehydes, secondary amines, and elemental sulfur in a single synthetic operation. The advantages of this developed protocol refer to the broad substrate scope, metal-free and easy to perform reaction conditions. Moreover, the pyrazole C-3/5-linked amide conjugates were also synthesized via an oxidative amination of pyrazole carbaldehydes and 2-aminopyridines using hydrogen peroxide as an oxidant.

Identifying the early predictors of non-response to steroids in patients with flare of autoimmune hepatitis causing acute-on-chronic liver failure.

BACKGROUND AND AIMS: Early identification of non-response to steroids is critical in patients with autoimmune hepatitis (AIH) causing acute-on-chronic liver failure (ACLF). We assessed if this non-response can be accurately identified within first few days of treatment. METHODS: Patients with AIH-ACLF without baseline infection/hepatic encephalopathy were identified from APASL ACLF research consortium (AARC) database. Diagnosis of AIH-ACLF was based mainly on histology. Those treated with steroids were assessed for non-response (defined as death or liver transplant at 90 days for present study). Laboratory parameters, AARC, and model for end-stage liver disease (MELD) scores were assessed at baseline and day 3 to identify early non-response. Utility of dynamic SURFASA score [- 6.80 + 1.92*(D0-INR) + 1.94*(∆%3-INR) + 1.64*(∆%3-bilirubin)] was also evaluated. The performance of early predictors was compared with changes in MELD score at 2 weeks. RESULTS: Fifty-five out of one hundred and sixty-five patients (age-38.2 ± 15.0 years, 67.2% females) with AIH-ACLF [median MELD 24 (IQR: 22-27); median AARC score 7 (6-9)] given oral prednisolone 40 (20-40) mg per day were analyzed. The 90 day transplant-free survival in this cohort was 45.7% with worse outcomes in those with incident infections (56% vs 28.0%, p = 0.03). The AUROC of pre-therapy AARC score [0.842 (95% CI 0.754-0.93)], MELD [0.837 (95% CI 0.733-0.94)] score and SURFASA score [0.795 (95% CI 0.678-0.911)] were as accurate as ∆MELD at 2 weeks [0.770 (95% CI 0.687-0.845), p = 0.526] and better than ∆MELD at 3 days [0.541 (95% CI 0.395, 0.687), p < 0.001] to predict non-response. Combination of AARC score > 6, MELD score > 24 with SURFASA score ≥ - 1.2, could identify non-responders at day 3 (concomitant- 75% vs either - 42%, p < 0.001). CONCLUSION: Baseline AARC score, MELD score, and the dynamic SURFASA score on day 3 can accurately identify early non-response to steroids in AIH-ACLF.

Inferred networks, machine learning, and health data.

This paper presents a network science approach to investigate a health information dataset, the Sexual Acquisition and Transmission of HIV Cooperative Agreement Program (SATHCAP), to uncover hidden relationships that can be used to suggest targeted health interventions. From the data, four key target variables are chosen: HIV status, injecting drug use, homelessness, and insurance status. These target variables are converted to a graph format using four separate graph inference techniques: graphical lasso, Meinshausen Bühlmann (MB), k-Nearest Neighbors (kNN), and correlation thresholding (CT). The graphs are then clustered using four clustering methods: Louvain, Leiden, and NBR-Clust with VAT and integrity. Promising clusters are chosen using internal evaluation measures and are visualized and analyzed to identify marker attributes and key relationships. The kNN and CT inference methods are shown to give useful results when combined with NBR-Clust clustering. Examples of cluster analysis indicate that the methodology produces results that will be relevant to the public health community.

Improving photocatalytic efficiency of MnFe2O4 ferrites via doping with Zn2+/La3+ ions: photocatalytic dye degradation for water remediation.

The interference of industrial effluents such as dyes, surfactants, metals, polycyclic aromatic hydrocarbons, and pharmaceutical waste has become a severe global problem for human health due to their carcinogenic, mutagenic, and toxic properties. Ferrites were considered promising photocatalysts for the degradation of organic and inorganic dyes. This study mainly focused on improving the photocatalytic performance of MnFe2O4 nanoferrites via doping of Zn2+ and La3+ ions. The zinc and lanthanum substituted Mn1-xZnxLayFe2-yO4 nanoferrites were prepared by the sol-gel auto-combustion technique for the degradation of organic textile malachite green dye (MGD) under the natural solar irradiation. The synthesized nanoferrites were investigated for their structural properties, surface morphology and elemental analysis, optical studies, magnetic properties, and photocatalytic performance by XRD, FESEM/EDX, FTIR/Raman spectrum, vibrating sample magnetometer, and UV-visible spectrophotometer, respectively. The substitution of zinc and lanthanum improved the photocatalytic efficiency of nanoferrites, and about 96% of MGD was degraded by Mn0.97Zn0.03La0.04Fe1.96O4 after 60 min of irradiation. The results showed the pseudo-first-order kinetics for dye degradation using undoped and Zn/La-doped MnFe2O4 photocatalysts.

Anaerobic-aerobic treatment of wastewater and leachate: A review of process integration, system design, performance and associated energy revenue.

Hybrid anaerobic-aerobic biological systems are an environmentally sustainable way of recovering bioenergy during the treatment of high-strength wastewaters and landfill leachate. This study provides a critical review of three major categories of anaerobic-aerobic processes such as conventional wetland, high-rate and integrated bioreactor systems applied for treatment of wastewaters and leachate. A comparative assessment of treatment mechanisms, critical operating parameters, bioreactor configurations, process control strategies, efficacies, and microbial dynamics of anaerobic-aerobic systems is provided. The review also explores the influence of wastewater composition on treatment performance, ammonium nitrogen removal efficacy, impact of mixing leachate, energy consumption, coupled bioenergy production and economic aspects of anaerobic-aerobic systems. Furthermore, the operational challenges, prospective modifications, and key future research directions are discussed. This review will provide in-depth understanding to develop sustainable engineering applications of anaerobic-aerobic processes for effective co-treatment of wastewaters and leachate.

Morita-Baylis-Hillman reaction of 3-formyl-9H-pyrido[3,4-b]indoles and fluorescence studies of the products.

ß-Carboline is a privileged class of the alkaloid family and is associated with a broad spectrum of biological properties. 3-Formyl-9H-pyrido[3,4-b]indole is a such potent precursor belonging to this family which can be tailored for installing diversity at various positions of ß-carboline to generate unique molecular hybrids of biological importance. The present work is a step towards this and assimilates the results related to the exploration of 3-formyl-9H-ß-carbolines for the synthesis of ß-carboline C-3 substituted MBH adducts followed by evaluation of their fluorescent characteristic. The effect of contact time, solvent system, concentration and substituents was also studied during investigation of fluorescence properties of these derivatives.

Biosynthesized δ-Bi2O3 Nanoparticles from Crinum viviparum Flower Extract for Photocatalytic Dye Degradation and Molecular Docking.

Bioinspired delta-bismuth oxide nanoparticles (δ-Bi2O3 NPs) have been synthesized using a greener reducing agent and surfactant via co-precipitation method. The originality of this work is the use of Crinum viviparum flower extract for the first time for the fabrication of NPs, which were further calcined at 800 °C to obtain δ-Bi2O3 NPs. Physicochemical studies such as FTIR spectroscopy and XPS confirmed the formation of Bi2O3 NPs, whereas XRD and Raman verified the formation of the cubic delta (δ) phase of Bi2O3 NPs. However, HRTEM revealed the spherical shape with diameter 10-20 nm, while BET studies expose mesoporous nature with a surface area of 71 m2/gm. The band gap for δ-Bi2O3 NPs was estimated to be 3.45 eV, which ensured δ-Bi2O3 to be a promising photocatalyst under visible-light irradiation. Therefore, based on the results of physicochemical studies, the bioinspired δ-Bi2O3 NPs were explored as active photocatalysts for the degradation of toxic dyes, viz., Thymol blue (TB) and Congo red (CR) under visible-light irradiation. The study showed 98.26% degradation of TB in 40 min and 69.67% degradation of CR in 80 min by δ-Bi2O3 NPs. The photogenerated holes and electrons were found responsible for this enhancement. Furthermore, molecular docking investigations were also performed for δ-Bi2O3 NPs to understand its biological function as New Delhi metallo-ß-lactamase 1 (NDM-1) [PDB ID 5XP9] enzyme inhibitor, and studies revealed good interaction with various amino acid residues and found good hydrogen bonding with a fine pose energy of -3.851 kcal/mole.

Robust and sustainable Mg1-xCexNiyFe2-yO4 magnetic nanophotocatalysts with improved photocatalytic performance towards photodegradation of crystal violet and rhodamine B pollutants.

This study aims at manufacturing Ce3+/Ni2+ ions doped Mg nanoferrites by the sol-gel method for the photocatalytic degradation of rhodamine B and crystal violet pollutants under visible natural sunlight. The particle size of synthesized nanoferrites was calculated through XRD, Hall-William plots, and TEM analysis, which perfectly agree with each other. FTIR study investigated the existence of stretching vibrations in M - O (metal-oxygen) complexes at the tetrahedral (A-site) and octahedral sites (B-site). The Raman spectra of synthesized nanophotocatalysts show the presence of four vibrational modes (Eg + 2T2g + A1g), providing suitable information of occupancy of Mg2+, Ce3+, Ni2+, and Fe3+ ions at the interstitial sites of undoped and Ce3+/Ni2+ doped MgFe2O4 crystal structure. The synthesized MGF3 nanophotocatalyst performs well with degradation of 97.674% crystal violet (CV) and 90.05% rhodamine B (RhB) under natural sunlight in 60 min. The experimental results showed that doped MgFe2O4 nanoferrites have a high tendency to photodegrade the RhB and CV dyes in an aqueous form. The pseudo-first-order equation reflects the best photocatalytic process kinetics and studied the feasibility of RhB and CV dyes adsorption on the doped and undoped MgFe2O4 nanoferrites. The results show good support for adsorption by the spontaneous photodegradation process. The excellent photocatalytic activity of synthesized nanoferrites under natural sunlight verifies them as a potential candidate for the photodegradation of organic dyes. Finally, the antibacterial activity of magnetic nanoferrites was examined against S. aureus and E. Coli. The studies demonstrated that synthesized magnetic nanoferrites were more effective against S. aureus.

Challenges and Recent Advances of Novel Chemical Inhibitors in Medulloblastoma Therapy.

Medulloblastoma is a common term used for the juvenile malignant brain tumor, and its treatment is exciting due to different genetic origins, improper transportation of drug across the blood-brain barrier, and chemo-resistance with various side effects. Currently, medulloblastoma divided into four significant subsections (Wnt, Shh, Group 3, and Group 4) is based on their hereditary modulation and histopathological advancement. In this chapter, we tried to combine several novel chemical therapeutic agents active toward medulloblastoma therapy. All these compounds have potent activity to inhibit the medulloblastoma.