Long non-coding RNA and RNA-binding protein interactions in cancer: Experimental and machine learning approaches.

Understanding the complex and specific roles played by non-coding RNAs (ncRNAs), which comprise the bulk of the genome, is important for understanding virtually every hallmark of cancer. This large group of molecules plays pivotal roles in key regulatory mechanisms in various cellular processes. Regulatory mechanisms, mediated by long non-coding RNA (lncRNA) and RNA-binding protein (RBP) interactions, are well documented in several types of cancer. Their effects are enabled through networks affecting lncRNA and RBP stability, RNA metabolism including N6-methyladenosine (m6A) and alternative splicing, subcellular localization, and numerous other mechanisms involved in cancer. In this review, we discuss the reciprocal interplay between lncRNAs and RBPs and their involvement in epigenetic regulation via histone modifications, as well as their key role in resistance to cancer therapy. Other aspects of RBPs including their structural domains, provide a deeper knowledge on how lncRNAs and RBPs interact and exert their biological functions. In addition, current state-of-the-art knowledge, facilitated by machine and deep learning approaches, unravels such interactions in better details to further enhance our understanding of the field, and the potential to harness RNA-based therapeutics as an alternative treatment modality for cancer are discussed.

A modeling framework for embedding-based predictions for compound-viral protein activity.

MOTIVATION: A global effort is underway to identify compounds for the treatment of COVID-19. Since de novo compound design is an extremely long, time-consuming and expensive process, efforts are underway to discover existing compounds that can be repurposed for COVID-19 and new viral diseases.We propose a machine learning representation framework that uses deep learning induced vector embeddings of compounds and viral proteins as features to predict compound-viral protein activity. The prediction model in-turn uses a consensus framework to rank approved compounds against viral proteins of interest. RESULTS: Our consensus framework achieves a high mean Pearson correlation of 0.916, mean R2 of 0.840 and a low mean squared error of 0.313 for the task of compound-viral protein activity prediction on an independent test set. As a use case, we identify a ranked list of 47 compounds common to three main proteins of SARS-COV-2 virus (PL-PRO, 3CL-PRO and Spike protein) as potential targets including 21 antivirals, 15 anticancer, 5 antibiotics and 6 other investigational human compounds. We perform additional molecular docking simulations to demonstrate that majority of these compounds have low binding energies and thus high binding affinity with the potential to be effective against the SARS-COV-2 virus. AVAILABILITY AND IMPLEMENTATION: All the source code and data is available at: https://github.com/raghvendra5688/Drug-Repurposing and https://dx.doi.org/10.17632/8rrwnbcgmx.3. We also implemented a web-server at: https://machinelearning-protein.qcri.org/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Flavin Adenine Dinucleotide (FAD) and Pyridoxal 5'-Phosphate (PLP) Bind to Sox9 and Alter the Expression of Key Pancreatic Progenitor Transcription Factors.

Cofactor flavin adenine dinucleotide (FAD), a compound with flavin moiety and a derivative of riboflavin (vitamin B2), is shown to bind to Sox9 (a key transcription factor in early pancreatic development) and, subsequently, induce a large increase in markers of pancreatic development, including Ngn3 and PTF1a. Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, also binds to Sox9 and results in a similar increase in pancreatic development markers. Sox9 is known to be specifically important for pancreatic progenitors. Previously, there was no known link between FAD, PLP, or other co-factors and Sox9 for function. Thus, our findings show the mechanism by which FAD and PLP interact with Sox9 and result in the altered expression of pancreatic progenitor transcription factors involved in the pancreas development.

Molecular Analysis and Conformational Dynamics of Human MC4R Disease-Causing Mutations.

Obesity is a chronic disease with increasing cases among children and adolescents. Melanocortin 4 receptor (MC4R) is a G protein-coupled transporter involved in solute transport, enabling it to maintain cellular homeostasis. MC4R mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. A number of mutations have been reported in MC4R that are responsible for causing obesity and related complications. Delineating these mutations and analyzing their effect on MC4R's structure will help in the clinical intervention of the disease condition as well as designing potential drugs against it. Sequence-based pathogenicity and structure-based protein stability analyses were conducted on naturally occurring variants. We used computational tools to analyze the conservation of these mutations on MC4R's structure to map the structural variations. Detailed structural analyses were carried out for the active site mutations (i.e., D122N, D126Y, and S188L) and their influence on the binding of calcium and the agonist or antagonist. We performed molecular dynamics (MD) simulations of the wild-type and selected mutations to delineate the conformational changes, which provided us with possible reasons for MC4R's instability in these mutations. This study provides insight into the potential direction toward understanding the molecular basis of MC4R dysfunction in disease progression and obesity.

Plasma Bead Entrapped Liposomes as a Potential Drug Delivery System to Combat Fungal Infections.

Fibrin-based systems offer promises in drug and gene delivery as well as tissue engineering. We established earlier a fibrin-based plasma beads (PB) system as an efficient carrier of drugs and antigens. In the present work, attempts were made to further improve its therapeutic efficacy exploiting innovative ideas, including the use of plasma alginate composite matrices, proteolytic inhibitors, cross linkers, and dual entrapment in various liposomal formulations. In vitro efficacy of the different formulations was examined. Pharmacokinetics of the formulations encapsulating Amphotericin B (AmpB), an antifungal compound, were investigated in Swiss albino mice. While administration of the free AmpB led to its rapid elimination (<72 h), PB/liposome-PB systems were significantly effective in sustaining AmpB release in the circulation (>144 h) and its gradual accumulation in the vital organs, also compared to the liposomal formulations alone. Interestingly, the slow release of AmpB from PB was unusual compared to other small molecules in our earlier findings, suggesting strong interaction with plasma proteins. Molecular interaction studies of bovine serum albumin constituting approximately 60% of plasma with AmpB using isothermal titration calorimetry and in silico docking verify these interactions, explaining the slow release of AmpB entrapped in PB alone. The above findings suggest that PB/liposome-PB could be used as safe and effective delivery systems to combat fungal infections in humans.

BCrystal: an interpretable sequence-based protein crystallization predictor.

MOTIVATION: X-ray crystallography has facilitated the majority of protein structures determined to date. Sequence-based predictors that can accurately estimate protein crystallization propensities would be highly beneficial to overcome the high expenditure, large attrition rate, and to reduce the trial-and-error settings required for crystallization. RESULTS: In this study, we present a novel model, BCrystal, which uses an optimized gradient boosting machine (XGBoost) on sequence, structural and physio-chemical features extracted from the proteins of interest. BCrystal also provides explanations, highlighting the most important features for the predicted crystallization propensity of an individual protein using the SHAP algorithm. On three independent test sets, BCrystal outperforms state-of-the-art sequence-based methods by more than 12.5% in accuracy, 18% in recall and 0.253 in Matthew's correlation coefficient, with an average accuracy of 93.7%, recall of 96.63% and Matthew's correlation coefficient of 0.868. For relative solvent accessibility of exposed residues, we observed higher values to associate positively with protein crystallizability and the number of disordered regions, fraction of coils and tripeptide stretches that contain multiple histidines associate negatively with crystallizability. The higher accuracy of BCrystal enables it to accurately screen for sequence variants with enhanced crystallizability. AVAILABILITY AND IMPLEMENTATION: Our BCrystal webserver is at https://machinelearning-protein.qcri.org/ and source code is available at https://github.com/raghvendra5688/BCrystal. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Glutaminase Affects the Transcriptional Activity of Peroxisome Proliferator-Activated Receptor γ (PPARγ) via Direct Interaction.

Phosphate-activated glutaminases catalyze the deamidation of glutamine to glutamate and play key roles in several physiological and pathological processes. In humans, GLS encodes two multidomain splicing isoforms: KGA and GAC. In both isoforms, the canonical glutaminase domain is flanked by an N-terminal region that is folded into an EF-hand-like four-helix bundle. However, the splicing event replaces a well-structured three-repeat ankyrin domain in KGA with a shorter, unordered C-terminal stretch in GAC. The multidomain architecture, which contains putative protein-protein binding motifs, has led to speculation that glutaminases are involved in cellular processes other than glutamine metabolism; in fact, some proteins have been identified as binding partners of KGA and the isoforms of its paralogue gene, GLS2. Here, a yeast two-hybrid assay identified nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) as a new binding partner of the glutaminase. We show that KGA and GAC directly bind PPARγ with a low-micromolar dissociation constant; the interaction involves the N-terminal and catalytic domains of glutaminases as well as the ligand-binding domain of the nuclear receptor. The interaction occurs within the nucleus, and by sequestering PPARγ from its responsive element DR1, the glutaminases decreased nuclear receptor activity as assessed by a luciferase reporter assay. Altogether, our findings reveal an unexpected glutaminase-binding partner and, for the first time, directly link mitochondrial glutaminases to an unanticipated role in gene regulation.

The origin and evolution of human glutaminases and their atypical C-terminal ankyrin repeats.

On the basis of tissue-specific enzyme activity and inhibition by catalytic products, Hans Krebs first demonstrated the existence of multiple glutaminases in mammals. Currently, two human genes are known to encode at least four glutaminase isoforms. However, the phylogeny of these medically relevant enzymes remains unclear, prompting us to investigate their origin and evolution. Using prokaryotic and eukaryotic glutaminase sequences, we built a phylogenetic tree whose topology suggested that the multidomain architecture was inherited from bacterial ancestors, probably simultaneously with the hosting of the proto-mitochondrion endosymbiont. We propose an evolutionary model wherein the appearance of the most active enzyme isoform, glutaminase C (GAC), which is expressed in many cancers, was a late retrotransposition event that occurred in fishes from the Chondrichthyes class. The ankyrin (ANK) repeats in the glutaminases were acquired early in their evolution. To obtain information on ANK folding, we solved two high-resolution structures of the ANK repeat-containing C termini of both kidney-type glutaminase (KGA) and GLS2 isoforms (glutaminase B and liver-type glutaminase). We found that the glutaminase ANK repeats form unique intramolecular contacts through two highly conserved motifs; curiously, this arrangement occludes a region usually involved in ANK-mediated protein-protein interactions. We also solved the crystal structure of full-length KGA and present a small-angle X-ray scattering model for full-length GLS2. These structures explain these proteins' compromised ability to assemble into catalytically active supra-tetrameric filaments, as previously shown for GAC. Collectively, these results provide information about glutaminases that may aid in the design of isoform-specific glutaminase inhibitors.

Structural basis for competitive inhibition of 3,4-dihydroxy-2-butanone-4-phosphate synthase from Vibrio cholerae.

The riboflavin biosynthesis pathway has been shown to be essential in many pathogens and is absent in humans. Therefore, enzymes involved in riboflavin synthesis are considered as potential antibacterial drug targets. The enzyme 3,4-dihydroxy-2-butanone-4-phosphate synthase (DHBPS) catalyzes one of the two committed steps in the riboflavin pathway and converts d-ribulose 5-phosphate (Ru5P) to l-3,4-dihydroxy-2-butanone 4-phosphate and formate. Moreover, DHBPS is shown to be indispensable for Mycobacterium, Salmonella, and Helicobacter species. Despite the essentiality of this enzyme in bacteria, no inhibitor has been identified hitherto. Here, we describe kinetic and crystal structure characterization of DHBPS from Vibrio cholerae (vDHBPS) with a competitive inhibitor 4-phospho-d-erythronohydroxamic acid (4PEH) at 1.86-Å resolution. In addition, we also report the structural characterization of vDHBPS in its apo form and in complex with its substrate and substrate plus metal ions at 1.96-, 1.59-, and 2.04-Å resolution, respectively. Comparison of these crystal structures suggests that 4PEH inhibits the catalytic activity of DHBPS as it is unable to form a proposed intermediate that is crucial for DHBPS activity. Furthermore, vDHBPS structures complexed with substrate and metal ions reveal that, unlike Candida albicans, binding of substrate to vDHBPS induces a conformational change from an open to closed conformation. Interestingly, the position of second metal ion, which is different from that of Methanococcus jannaschii, strongly supports an active role in the catalytic mechanism. Thus, the kinetic and structural characterization of vDHBPS reveals the molecular mechanism of inhibition shown by 4PEH and that it can be explored further for designing novel antibiotics.

Structural basis for the role of C-terminus acidic tail of Saccharomyces cerevisiae ubiquitin-conjugating enzyme (Rad6) in E3 ligase (Bre1) mediated recognition of histones.

Ubiquitination of histone H2B on chromatin is key to gene regulation. E3 ligase Bre1 and E2 Rad6 in Saccharomyces cerevisiae associate together to catalyze mono-ubiquitination at histone H2BK123. Prior studies identified the role of a highly dynamic C-terminal acidic tail of Rad6 indispensable for H2BK123 mono-ubiquitination. However, the mechanistic basis for the Rad6-acidic tail role remained elusive. Using different structural and biophysical approaches, this study for the first time uncovers the direct role of Rad6-acidic tail in interaction with the Bre1 Rad6-Binding Domain (RBD) and recognition of histones surface to facilitate histone H2B mono-ubiquitination. A combination of NMR, SAXS, ITC, site-directed mutagenesis and molecular dynamics studies reveal that RBD domain of Bre1 interacts with Rad6 to stabilize the dynamics of acidic tail. This Bre1-RBD mediated stability in acidic tail of Rad6 could be one of the key factors for facilitating correct recognition of histone surface and ubiquitin-transfer at H2BK123. We provide biophysical evidence that Rad6-acidic tail and a positivity charged surface on histone H2B are involved in recognition of E2:Histones. Taken together, this study uncovers the mechanistic basis for the role of Rad6-acidic in Bre1-RBD mediated recognition of histone surface that ensure the histone H2B mono-ubiquitination.

Structural insights into the unique recognition module between α-synuclein peptide and nanobody.

Nanobodies are single-domain fragments of antibodies with comparable specificity and affinity to antibodies. They are emerging as versatile tools in biology due to their relatively small size. Here, we report the crystal structure of a specific nanobody Nbα-syn01, bound to a 14 amino acid long peptide of α-synuclein (αSyn), a 140-residue protein whose aggregation is associated with Parkinson's disease. The complex structure exhibits a unique binding pattern where the αSyn peptide replaces the N-terminal region of nanobody. Recognition is mediated principally by extended main chain interaction of the αSyn peptide and specificity of the interaction lies in the central 48-52 region of αSyn peptide. Structure-guided truncation of Nbα-syn01 shows tighter binding to αSyn peptide and improved inhibition of α-synuclein aggregation. The structure of the truncated complex was subsequently determined and was indistinguishable to full length complex as the full-length form had no visible electron density for the N-terminal end. These findings reveal the molecular basis for a previously unobserved binding mode for nanobody recognition of α-synuclein, providing an explanation for the enhanced binding, and potential for an alternate framework for structure-based protein engineering of nanobodies to develop better diagnostic and therapeutic tools.

BRET-based biosensors for SARS-CoV-2 oligonucleotide detection.

The need for the early detection of emerging pathogenic viruses and their newer variants has driven the urgent demand for developing point-of-care diagnostic tools. Although nucleic acid-based methods such as reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and loop-mediated isothermal amplification (LAMP) have been developed, a more facile and robust platform is still required. To address this need, as a proof-of-principle study, we engineered a prototype-the versatile, sensitive, rapid, and cost-effective bioluminescence resonance energy transfer (BRET)-based biosensor for oligonucleotide detection (BioOD). Specifically, we designed BioODs against the SARS-CoV-2 parental (Wuhan strain) and B.1.617.2 Delta variant through the conjugation of specific, fluorescently modified molecular beacons (sensor module) through a complementary oligonucleotide handle DNA functionalized with the NanoLuc (NLuc) luciferase protein such that the dissolution of the molecular beacon loop upon the binding of the viral oligonucleotide will result in a decrease in BRET efficiency and, thus, a change in the bioluminescence spectra. Following the assembly of the BioODs, we determined their kinetics response, affinity for variant-specific oligonucleotides, and specificity, and found them to be rapid and highly specific. Furthermore, the decrease in BRET efficiency of the BioODs in the presence of viral oligonucleotides can be detected as a change in color in cell phone camera images. We envisage that the BioODs developed here will find application in detecting viral infections with variant specificity in a point-of-care-testing format, thus aiding in large-scale viral infection surveillance.

Inhibitors of riboflavin biosynthetic pathway enzymes as potential antibacterial drugs.

Multiple drug resistance is the main obstacle in the treatment of bacterial diseases. Resistance against antibiotics demands the exploration of new antimicrobial drug targets. A variety of in silico and genetic approaches show that the enzymes of the riboflavin biosynthetic pathway are crucial for the survival of bacteria. This pathway is absent in humans thus enzymes of the riboflavin biosynthetic pathway are emerging drug targets for resistant pathogenic bacterial strains. Exploring the structural details, their mechanism of action, intermediate elucidation, and interaction analysis would help in designing suitable inhibitors of these enzymes. The riboflavin biosynthetic pathway consists of seven distinct enzymes, namely, 3,4-dihydroxy-2-butanone 4-phosphate synthase, GTP cyclohydrolase II, pyrimidine deaminase/reductase, phosphatase, lumazine synthase, and riboflavin synthase. The present review summarizes the research work that has been carried out on these enzymes in terms of their structures, active site architectures, and molecular mechanism of catalysis. This review also walks through small molecule inhibitors that have been developed against several of these enzymes.

DNAJB3 attenuates ER stress through direct interaction with AKT.

Metabolic stress involved in several dysregulation disorders such as type 2 diabetes mellitus (T2DM) results in down regulation of several heat shock proteins (HSPs) including DNAJB3. This down regulation of HSPs is associated with insulin resistance (IR) and interventions which induce the heat shock response (HSR) help to increase the insulin sensitivity. Metabolic stress leads to changes in signaling pathways through increased activation of both c-jun N-terminal kinase-1 (JNK1) and the inhibitor of κB inflammatory kinase (IKKß) which in turn leads to inactivation of insulin receptor substrates 1 and 2 (IRS-1 and IRS-2). DNAJB3 interacts with both JNK1 and IKKß kinases to mitigate metabolic stress. In addition DNAJB3 also activates the PI3K-PKB/AKT pathway through increased phosphorylation of AKT1 and its substrate AS160, a Rab GTPase-activating protein, which results in mobilization of GLUT4 transporter protein and improved glucose uptake. We show through pull down that AK T1 is an interacting partner of DNAJB3, further confirmed by isothermal titration calorimetry (ITC) which quantified the avidity of AKT1 for DNAJB3. The binding interface was identified by combining protein modelling with docking of the AKT1-DNAJB3 complex. DNAJB3 is localized in the cytoplasm and ER, where it interacts directly with AKT1 and mobilizes AS160 for glucose transport. Inhibition of AKT1 resulted in loss of GLUT4 translocation activity mediated by DNAJB3 and also abolished the protective effect of DNAJB3 on tunicamycin-induced ER stress. Taken together, our findings provide evidence for a direct protein-protein interaction between DNAJB3 and AKT1 upon which DNAJB3 alleviates ER stress and promotes GLUT4 translocation.

Control of TGFß signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12.

Transforming growth factor ß (TGFß) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFß signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFß signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFß signalling in multiple models. Interestingly, TRIP12 control of TGFß signalling is completely independent of its E3 ubiquitin ligase activity. Instead, TRIP12 recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in TRIP12-/- cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFß signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFß signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila SMAD4 orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFß mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of TRIP12 in MDA-MB-231 breast cancer cells enhances the TGFß induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype TRIP12. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFß signalling in health and disease.

Molecular mechanism of glutaminase activation through filamentation and the role of filaments in mitophagy protection.

Glutaminase (GLS), which deaminates glutamine to form glutamate, is a mitochondrial tetrameric protein complex. Although inorganic phosphate (Pi) is known to promote GLS filamentation and activation, the molecular basis of this mechanism is unknown. Here we aimed to determine the molecular mechanism of Pi-induced mouse GLS filamentation and its impact on mitochondrial physiology. Single-particle cryogenic electron microscopy revealed an allosteric mechanism in which Pi binding at the tetramer interface and the activation loop is coupled to direct nucleophile activation at the active site. The active conformation is prone to enzyme filamentation. Notably, human GLS filaments form inside tubulated mitochondria following glutamine withdrawal, as shown by in situ cryo-electron tomography of cells thinned by cryo-focused ion beam milling. Mitochondria with GLS filaments exhibit increased protection from mitophagy. We reveal roles of filamentous GLS in mitochondrial morphology and recycling.

Novel engineered nanobodies specific for N-terminal region of alpha-synuclein recognize Lewy-body pathology and inhibit in-vitro seeded aggregation and toxicity.

Nanobodies (Nbs), the single-domain antigen-binding fragments of dromedary heavy-chain antibodies (HCAb), are excellent candidates as therapeutic and diagnostic tools in synucleinopathies because of their small size, solubility and stability. Here, we constructed an immune nanobody library specific to the monomeric form of alpha-synuclein (α-syn). Phage display screening of the library allowed the identification of a nanobody, Nbα-syn01, specific for α-syn. Unlike previously developed nanobodies, Nbα-syn01 recognized the N-terminal region which is critical for in vitro and in vivo aggregation and contains many point mutations involved in early PD cases. The affinity of the monovalent Nbα-syn01 and the engineered bivalent format BivNbα-syn01 measured by isothermal titration calorimetry revealed unexpected results where Nbα-syn01 and its bivalent format recognized preferentially α-syn fibrils compared to the monomeric form. Nbα-syn01 and BivNbα-syn01 were also able to inhibit α-syn-seeded aggregation in vitro and reduced α-syn-seeded aggregation and toxicity in cells showing their potential to reduce α-syn pathology. Moreover, both nanobody formats were able to recognize Lewy-body pathology in human post-mortem brain tissue from PD and DLB cases. Additionally, we present evidence through structural docking that Nbα-syn01 binds the N-terminal region of the α-syn aggregated form. Overall, these results highlight the potential of Nbα-syn01 and BivNbα-syn01 in developing into a diagnostic or a therapeutic tool for PD and related disorders.

Mechanisms of amyloid proteins aggregation and their inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies.

Protein misfolding and aggregation can be induced by a wide variety of factors, such as dominant disease-associated mutations, changes in the environmental conditions (pH, temperature, ionic strength, protein concentration, exposure to transition metal ions, exposure to toxins, posttranslational modifications including glycation, phosphorylation, and sulfation). Misfolded intermediates interact with similar intermediates and progressively form dimers, oligomers, protofibrils, and fibrils. In amyloidoses, fibrillar aggregates are deposited in the tissues either as intracellular inclusion or extracellular plaques (amyloid). When such proteinaceous deposit occurs in the neuronal cells, it initiates degeneration of neurons and consequently resulting in the manifestation of various neurodegenerative diseases. Several different types of molecules have been designed and tested both in vitro and in vivo to evaluate their anti-amyloidogenic efficacies. For instance, the native structure of a protein associated with amyloidosis could be stabilized by ligands, antibodies could be used to remove plaques, oligomer-specific antibody A11 could be used to remove oligomers, or prefibrillar aggregates could be removed by affibodies. Keeping the above views in mind, in this review we have discussed protein misfolding and aggregation, mechanisms of protein aggregation, factors responsible for aggregations, and strategies for aggregation inhibition.

The role of amyloids in Alzheimer's and Parkinson's diseases.

With varying clinical symptoms, most neurodegenerative diseases are associated with abnormal loss of neurons. They share the same common pathogenic mechanisms involving misfolding and aggregation, and these visible aggregates of proteins are deposited in the central nervous system. Amyloid formation is thought to arise from partial unfolding of misfolded proteins leading to the exposure of hydrophobic surfaces, which interact with other similar structures and give rise to form dimers, oligomers, protofibrils, and eventually mature fibril aggregates. Accumulating evidence indicates that amyloid oligomers, not amyloid fibrils, are the most toxic species that causes Alzheimer's disease (AD) and Parkinson's disease (PD). AD has recently been recognized as the 'twenty-first century plague', with an incident rate of 1% at 60 years of age, which then doubles every fifth year. Currently, 5.3 million people in the US are afflicted with this disease, and the number of cases is expected to rise to 13.5 million by 2050. PD, a disorder of the brain, is the second most common form of dementia, characterized by difficulty in walking and movement. Keeping the above views in mind, in this review we have focused on the roles of amyloid in neurodegenerative diseases including AD and PD, the involvement of amyloid in mitochondrial dysfunction leading to neurodegeneration, are also considered in the review.

Transcription Factors: The Fulcrum Between Cell Development and Carcinogenesis.

Higher eukaryotic development is a complex and tightly regulated process, whereby transcription factors (TFs) play a key role in controlling the gene regulatory networks. Dysregulation of these regulatory networks has also been associated with carcinogenesis. Transcription factors are key enablers of cancer stemness, which support the maintenance and function of cancer stem cells that are believed to act as seeds for cancer initiation, progression and metastasis, and treatment resistance. One key area of research is to understand how these factors interact and collaborate to define cellular fate during embryogenesis as well as during tumor development. This review focuses on understanding the role of TFs in cell development and cancer. The molecular mechanisms of cell fate decision are of key importance in efforts towards developing better protocols for directed differentiation of cells in research and medicine. We also discuss the dysregulation of TFs and their role in cancer progression and metastasis, exploring TF networks as direct or indirect targets for therapeutic intervention, as well as specific TFs' potential as biomarkers for predicting and monitoring treatment responses.