Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors.

The main protease (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like protease and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic cysteine and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19.

Regulation of Onecut2 by miR-9-5p in Japanese encephalitis virus infected neural stem/progenitor cells.

Japanese encephalitis virus (JEV) is one of the major neurotropic viral infections that is known to dysregulate the homeostasis of neural stem/progenitor cells (NSPCs) and depletes the stem cell pool. NSPCs are multipotent stem cell population of the central nervous system (CNS) which are known to play an important role in the repair of the CNS during insults/injury caused by several factors such as ischemia, neurological disorders, CNS infections, and so on. Viruses have evolved to utilize host factors for their own benefit and during JEV infection, host factors, including the non-coding RNAs such as miRNAs, are reported to be affected, thereby cellular processes regulated by the miRNAs exhibit perturbed functionality. Previous studies from our laboratory have demonstrated the role of JEV infection in dysregulating the function of neural stem cells (NSCs) by altering the cell fate and depleting the stem cell pool leading to a decline in stem cell function in CNS repair mechanism post-infection. JEV-induced alteration in miRNA expression in the NSCs is one of the major interest to us. In prior studies, we have observed an altered expression pattern of certain miRNAs following JEV infection. In this study, we have validated the role of JEV infection in NSCs in altering the expression of miR-9-5p, which is a known regulator of neurogenesis in NSCs. Furthermore, we have validated the interaction of this miRNA with its target, Onecut2 (OC2), in primary NSCs utilizing miRNA mimic and inhibitor transfection experiments. Our findings indicate a possible role of JEV mediated dysregulated interaction between miR-9-5p and its putative target OC2 in NSPCs. IMPORTANCE: MicroRNAs have emerged as key disease pathogenic markers and potential therapeutic targets. In this study, we solidify this concept by studying a key miRNA, miR-9-5p, in Japanese encephalitis virus infection of neural stem/progenitor cells. miRNA target Onecut2 has a possible role in stem cell pool biology. Here, we show a possible mechanistic axis worth investing in neurotropic viral biology.

Formulation of Functional Liquid Diets Under IDDSI Levels 0 to 2 for Dysphagia Patients: Physico-Chemical, Sensory, Antioxidant and Electromyographic Oral Processing Analyses.

Dysphagia is a significant health concern especially amongst the old age population. It is an ailment brought on by the weakening of the swallowing muscles. To reduce the risk of choking in dysphagia patients, the food is usually diluted to suit their swallowing ability. But dilution results in reducing the nutritional density of the foods thus causing undernutrition and malnutrition in patients. In this study, functional liquid diets were formulated under International Dysphagia Diet Standardization Initiative (IDDSI) levels 0-2. The developed diets were analysed for their proximate composition, colour, antioxidant and sensory properties. Antioxidant activities were determined using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and total phenolic content (TPC) methods. The highest ABTS+ value was observed in pumpkin puree (level-2) i.e. 98.59%. Black carrot juice (level-1) showed the highest DPPH free radical scavenging activity and FRAP value viz. 88.43% and 689.33 µM TE/g, respectively. Electromyography (EMG) is an upcoming technique of food texture evaluation which provides real-time information about food oral processing. In this study, an EMG was conducted to measure the myoelectrical activity of human suprahyoid and masseter muscles by placing electrodes on the skin's surface during the oral processing of liquid. The EMG parameters correlated significantly with viscosity, ease of swallowing and IDDSI levels of the formulated diets. Hence EMG can be used as a tool for design and development of textured-modified diets for dysphagia patients. The sensory scores of formulated diets in this study were high indicating that these liquid diets may be incorporated into the diet plans of dysphagia patients.

Heterocyclic-Based Analogues against Sarcine-Ricin Loop RNA from Escherichia coli: In Silico Molecular Docking Study and Machine Learning Classifiers.

BACKGROUND: Heterocyclic-based drugs have strong bioactivities, are active pharmacophores, and are used to design several antibacterial drugs. Due to the diverse biodynamic properties of well-known heterocyclic cores, such as quinoline, indole, and its derivatives, they have a special place in the chemistry of nitrogen-containing heterocyclic molecules. OBJECTIVE: The objective of this study is to analyze the interaction of several heterocyclic molecules using molecular docking and machine learning approaches to find out the possible antibacterial drugs. METHODS: The molecular docking analysis of heterocyclic-based analogues against the sarcin-Ricin Loop RNA from E. coli with a C2667-2'-OCF3 modification (PDB ID: 6ZYB) is discussed. RESULTS: Many heterocyclic-based derivatives show several residual interaction, affinity, and hydrogen bonding with sarcin-Ricin Loop RNA from E. coli with a C2667-2'-OCF3 alteration which are identified by the investigation of in silico molecular docking analysis of such heterocyclic derivatives. CONCLUSION: The dataset from the molecular docking study was used for additional optimum analysis, and the molecular descriptors were classified using a variety of machine learning classifiers, including the GB Classifier, CB Classifier, RF Classifier, SV Classifier, KNN Classifier, and Voting Classifier. The research presented here showed that heterocyclic derivatives may operate as potent antibacterial agents when combined with other compounds to produce highly efficient antibacterial agents.

Delineating the mechanism of fragility at BCL6 breakpoint region associated with translocations in diffuse large B cell lymphoma.

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into non-B DNA. Results revealed that the Cluster II sequence folded into overlapping hairpin structures and identified sequences that undergo base pairing at the stem region. Further, the formation of cruciform DNA blocked DNA replication. The sodium bisulfite modification assay revealed the single-strandedness of the region corresponding to hairpin DNA in both strands of the genome. Further, we report the formation of intramolecular parallel G4 and triplex DNA, at Cluster II. Taken together, our studies reveal that multiple non-canonical DNA structures exist at the BCL6 cluster II breakpoint region and contribute to the fragility leading to BCL6 translocation in DLBCL patients.

Block Copolymer Encapsulation of Disarib, an Inhibitor of BCL2 for Improved Chemotherapeutic Potential.

A chemical inhibitor of antiapoptotic protein, BCL2, known as Disarib, suffers poor solubility in aqueous environments; thereby limiting its potential as a chemotherapeutic agent. To overcome this limitation and enhance the therapeutic efficacy of Disarib, we have employed the encapsulation of this small molecule inhibitor within P123 copolymer matrix. Micelles were synthesized using a thin-film hydration technique, and a comprehensive analysis was undertaken to evaluate the resulting micelle properties, including morphology, particle size, intermolecular interactions, encapsulation efficiency, and in vitro release characteristics. This assessment utilized various physicochemical techniques including UV spectroscopy, FTIR spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), and small-angle X-ray scattering (SAXS). Disarib-loaded P123 micelle formulation denoted as P123D exhibited a well-defined particle size of approximately 29.2 nm spherical core-shell morphology. Our investigations revealed a notable encapsulation efficiency of 75%, and we observed a biphasic release pattern for the encapsulated Disarib. Furthermore, our cytotoxicity assessment of P123D micelles against mouse breast adenocarcinoma, mouse lymphoma, and human leukemic cell lines showed 40-45% increase in cytotoxicity compared with the administration of Disarib alone in the breast adenocarcinoma cell line. Enhancement in the cytotoxicity of P123D was found to be higher or limited; however, it is important to observe that the encapsulation method significantly enhanced the aqueous solubility of Disarib as it has the best solubility in dimethyl sulfoxide (DMSO) in the unencapsulated state.

Evaluation of potential role of R-loop and G-quadruplex DNA in the fragility of c-MYC during chromosomal translocation associated with Burkitt's lymphoma.

t(8;14) translocation is the hallmark of Burkitt's lymphoma and results in c-MYC deregulation. During the translocation, c-MYC gene on chromosome 8 gets juxtaposed to the Ig switch regions on chromosome 14. Although the promoter of c-MYC has been investigated for its mechanism of fragility, little is known about other c-MYC breakpoint regions. We have analyzed the translocation break points at the exon 1/intron 1 of c-MYC locus from patients with Burkitt's lymphoma. Results showed that the breakpoint region, when present on a plasmid, could fold into an R-loop confirmation in a transcription-dependent manner. Sodium bisulfite modification assay revealed significant single-strandedness on chromosomal DNA of Burkitt's lymphoma cell line, Raji, and normal lymphocytes, revealing distinct R-loops covering up to 100 bp region. Besides, ChIP-DRIP analysis reveals that the R-loop antibody can bind to the breakpoint region. Further, we show the formation of stable parallel intramolecular G-quadruplex on non-template strand of the genome. Finally, incubation of purified AID in vitro or overexpression of AID within the cells led to enhanced mutation frequency at the c-MYC breakpoint region. Interestingly, anti-γH2AX can bind to DSBs generated at the c-MYC breakpoint region within the cells. The formation of R-loop and G-quadruplex was found to be mutually exclusive. Therefore, our results suggest that AID can bind to the single-stranded region of the R-loop and G4 DNA, leading to the deamination of cytosines to uracil and induction of DNA breaks in one of the DNA strands, leading to double-strand break, which could culminate in t(8;14) chromosomal translocation.

Relationship between attachment style of 4-7-year-old children and their behavior during dental visit.

Background: The general health and quality of life are directly correlated with oral health. Oral health is one of the unique health concerns that apply to all children. Pediatric dentistry is built on effective communication with children, which is also a requirement for providing pediatric dental care. Many pediatric dentists find it difficult to anticipate children's behavior and how they will respond to therapeutic procedures. The purpose of this study was to evaluate children's attachment types in order to forecast their behavior during a dentist appointment. Materials and Methods: The participants were 120 children between the ages of 4 and 7 who were reported to the Department of Pediatric and Preventive Dentistry, Institute of Dental Sciences, Bareilly. The youngsters were evaluated by a dental graduate student. While they waited in the waiting area, the parents were asked to complete the Kinship Center Attachment Questionnaire regarding their kids. In the second visit, dental work was scheduled for the kids who had met the requirements for inclusion in the first visit. Another pediatric dentistry postgraduate student evaluated the children's conduct during the dental procedure using a predefined questionnaire and the Frankl scale. The Chi-squared test, t-test, Pearson's correlation coefficient, and linear regression were used to examine the data. Results: According to the findings, 55.8% of the total children were cooperative, among which 59.1% were female and 52.0% were males. The average age of the kids was 6.2 ± 0.95. Moreover, 21.3% of kids had insecure attachment styles and 78.7% of kids had secure attachment types. The child-dentist communication and the insecure ambivalent attachment pattern were significantly correlated. As a result, our study demonstrated that children's safe attachment styles varied with age. Our results showed that there is an inverse relationship between children's collaboration and age, with cooperation rising as age increases. Conclusions: According to the findings of this study and considering its limitations, in young ages, the attachment style of the mother plays an important role in behavior of children. The significant correlations existed between the insecure ambivalent attachment style and child-dentist communication, as well as the secure attachment type and mother-child separation.

Sodium Butyrate Induced Neural Stem/Progenitor Cell Death in an Experimental Model of Japanese Encephalitis.

The anti-inflammatory and neuroprotective effects of short chain fatty acid (SCFA) butyrate have been explored in a wide array of neurological pathologies. It is a 4-carbon SCFA produced from the fermentation of dietary fibers by the gut-microbiota. As evident from previous literature, butyrate plays a wide array of functions in CNS and interestingly enhances the differentiation potential of Neural stem/Progenitor Cells (NSPCs). Japanese encephalitis virus (JEV) is a well-known member of the Flaviviridae family and has been shown to alter neural stem cell pool of the brain, causing devastating consequences. In this study, we administered sodium butyrate (NaB) post JEV infection in BALB/c mouse model to examine any possible amelioration of the viral infection in NSPCs. In addition, ex vivo neurospheres and in vitro model of NSPCs were also used to study the effect of sodium butyrate in JEV infection. As an unprecedented finding, butyrate treated infected animals presented early onset of symptoms, as compared to their respective JEV infected groups. Alongside, we observed an increased viral load in NSPCs isolated from these animals as well as in cell culture models upon sodium butyrate treatment. Cytometric bead array analysis also revealed an increase in inflammatory cytokines, particularly, MCP-1 and IL-6. Further, increased expression of the key members of the canonical NF-κB pathway, viz-a-viz p-NF-κB, p-Iκ-Bα and p-IKK was observed. Overall, the increased inflammation and cell death caused early symptom progression in NaB-treated JEV infected animal model, which is contradictory to the well documented protective nature of NaB and therefore a better understanding of SCFA-based modulation of the gut-brain axis in viral infections is required.

Investigating the Interplay between Tomato Leaf Curl New Delhi Virus Infection, Starch Metabolism and Antioxidant Defence System in Potato (Solanum tuberosum L.).

The potato apical leaf curl disease is caused by tomato leaf curl New Delhi virus-potato (ToLCNDV-potato), which severely alters a plant's starch metabolism, starch hydrolysing enzymes, and antioxidant mechanism. In this study, the result suggested that ToLCNDV-potato significantly (p < 0.01) affected the morphological parameters and photosynthetic pigment system in both the cultivars of potato, viz., Kufri Pukhraj (susceptible) and Kufri Bahar (tolerant). However, the impact of ToLCNDV-potato was lower in Kufri Bahar. Moreover, the viral infection in potato showed significant (p < 0.01) enhancement in the leakage of plant oxidative metabolites such as proline and malondialdehyde (MDA) which was further confirmed with higher electrolyte leakage. The viral infection imbalance of starch metabolism in the leaves ultimately affects the carbohydrate profile. ToLCNDV-potato significantly lowered starch synthesis, enhanced the accumulation of sucrose, glucose, fructose and-which was further validated by enzymatic estimation of ß-amylase-α-amylase and phosphorylase activity in the leaves of both cultivars. The antioxidant enzymes, viz., catalase, ascorbate peroxidase, and superoxide dismutase, were reported to be enhanced in both the cultivars due to ToLCNDV-potato infection. The higher enhancement of antioxidant enzyme activity was observed in Kufri Bahar, which signifies its resistant attributes. These findings in the potato plant broaden our understanding of the regulatory mechanisms of starch metabolism and antioxidant activity and provide proof of concept for breeding potato for ToLCNDV-potato tolerance.

A Coumarin-Imidazothiadiazole Derivative, SP11 Abrogates Tumor Growth by Targeting HSP90 and Its Client Proteins.

Despite several treatment options for blood cancer, mortality remains high due to relapse and the disease's aggressive nature. Elevated levels of HSP90, a molecular chaperone essential for protein folding, are associated with poor prognosis in leukemia and lymphoma. HSP90 as a target for chemotherapy has been met with limited success due to toxicity and induction of heat shock. This study tested the activity of an HSP90 inhibitor, SP11, against leukemic cells, mouse lymphoma allograft, and xenograft models. SP11 induced cytotoxicity in vitro in leukemic cell lines and induced cell death via apoptosis, with minimal effect on normal cells. SP11 induced cell death by altering the status of HSP90 client proteins both in vitro and in vivo. SP11 reduced the tumor burden in allograft and xenograft mouse models without apparent toxicity. The half-life of SP11 in the plasma was approximately 2 h. SP11 binding was observed at both the N-terminal and C-terminal domains of HSP90. C-terminal binding was more potent than N-terminal binding of HSP90 in silico and in vitro using isothermal calorimetry. SP11 bioavailability and minimal toxicity in vivo make it a potential candidate to be developed as a novel anticancer agent.

2-Oxindole and related heterocycles: synthetic methodologies for their natural products and related derivatives.

Natural goods, medications, and pharmaceutically active substances all contain substituted oxindoles. Generally, the C-3 stereocenter of the substituents of oxindoles and their absolute arrangement have a substantial impact on the bioactivity of these substances. In this case, the desire for contemporary probe and drug-discovery programs for the synthesis of chiral compounds using desirable scaffolds with high structural diversity further drives research in this field. Also, the new synthetic techniques are generally simple to apply for the synthesis of other similar scaffolds. Herein, we review the distinct approaches for the synthesis of diverse useful oxindole scaffolds. Specifically, the research findings on the naturally existing 2-oxindole core and a variety of synthetic compounds having a 2-oxindole core are discussed. We present an overview of the construction of oxindole-based synthetic and natural products. In addition, the chemical reactivity of 2-oxindole and its related derivatives in the presence of chiral and achiral catalysts are thoroughly discussed. The data compiled herein provides broad information related to the bioactive product design, development, and applications of 2-oxindoles and the reported techniques will be helpful for the investigation of novel reactions in the future.

Comparative evaluation of Hand, Rotary and Reciprocation motion on Dentin thickness and instrumentation time in Primary anterior teeth using CBCT: An observational study.

Background: Ultimate goal of BMP is to extirpate the pulp tissue completely, microorganisms, debris & shaping the canal which preserves the original course of the canal to receive an obturating material. Due to various morphological challenges present in deciduous root canal, there is high demand of an improved quality & design of file system with less working length to prevent undesirable complication & reduce treatment time. Aim: To evaluate & inter-compare the dentin thickness and instrumentation time in root dentin of deciduous teeth after BMP in Hand, Rotary & Reciprocation motion with single-file systems. Material and Methods: 60 extracted primary single rooted teeth with un-resorbed roots were included in the study. Teeth were divided into three groups consisting of 20 teeth in each group. In Group-1 Root canal preparation was done with pediatric Hand files, In Group-2 with pediatric Single-file system in rotary motion and in Group-3 with pediatric Single-file system in reciprocating motion. Teeth were scanned before & after preparation with CBCT. Segments were analyzed for dentin thickness at 3mm,5mm and 7mm respectively. Instrumentation time was recorded by an assistant. Results: Mean instrumentation time of Rotary was least as compared to Reciprocation & Hand respectively, instrumentation time taken by hand filing was significantly higher. Reciprocating filing helps in better dentin debridement at apical and the middle third and no difference was found at the coronal third among all three groups. Conclusions: Reciprocating filing helps in better dentin debridement and rotary instrumentation requires least time for canal preparation. Key words:Hand Files, Rotary Files, Reciprocating motion, CBCT.

Quinoline-based Anti-oncogenic Molecules: Synthesis and Biological Evaluation.

Quinoline and its analogues are found in various natural products, many of which are active pharmacophores with significant bioactivities. This article discussed the plethora of quinoline derivatives and their analogues that have anti-cancer properties. The review will be helpful for the scientific community since several possible anticancer drugs based on quinolines are discussed here. In addition to this, the synthetic aspect of many such quinoline derivatives showing anti-cancer activities is also revealed in this article. These quinoline-based anti-oncogenic molecules can be synthesized using several acids, bases, and azides or with the help of reagents like Jone's reagent and Lawesson's reagent.

Molecular Docking Study for Binding Affinity of 2H-thiopyrano[2,3-b]quinoline Derivatives against CB1a.

Quinoline-based molecules are major constituents in natural products, active pharmacophores, and have excellent biological activities. Using 2H-thiopyrano[2,3-b]quinoline derivatives and CB1a protein (PDB ID: 2IGR), the molecular docking study has been revealed in this article. The study of in silico molecular docking analysis of such derivatives to determine the binding affinity, residual interaction, and hydrogen bonding of several 2H-thiopyrano[2,3-b]quinolines against CB1a is reported here. The current work demonstrated that 2H-thiopyrano[2,3-b]quinoline derivatives could be effective antitumor agents to produce potent anticancer medicines in the near future.

Identification and characterization of mercaptopyrimidine-based small molecules as inhibitors of nonhomologous DNA end joining.

Mercaptopyrimidine derivatives are heterocyclic compounds with potent biological activities including antiproliferative, antibacterial, and anti-inflammatory properties. The present study describes the synthesis and characterization of several mercaptopyrimidine derivatives through condensation of 5,6-diamino-2-mercaptopyrimidin-4-ol with various heterocyclic and aromatic aldehydes. Previous studies have shown that SCR7, synthesized from 5,6-diamino-2-mercaptopyrimidin-4-ol, induced cytotoxicity by targeting cancer cells by primarily inhibiting DNA Ligase IV involved in nonhomologous end joining, one of the major DNA double-strand break repair pathways. Inhibition of DNA repair pathways is considered as an important strategy for cancer therapy. Due to limitations of SCR7 in terms of IC50 in cancer cells, here we have designed, synthesized, and characterized potent derivatives of SCR7 using 5,6-diamino-2-mercaptopyrimidin-4-ol as the starting material. Several synthesized imine compounds exhibited significant improvement in inhibition of end joining and cytotoxicity up to 27-fold lower concentrations than SCR7. Among these, two compounds, SCR116 and SCR132, showed increased cancer cell death in a Ligase IV-dependent manner. Treatment with the compounds also led to reduction in V(D)J recombination efficiency, cell cycle arrest at G2/M phase, accumulation of double-strand breaks inside cells, and improved anti-cancer potential when combined with γ-radiation and radiomimetic drugs. Thus, we describe novel inhibitors of NHEJ with higher efficacy and potential, which can be developed as cancer therapeutics.

Synthetic Strategies for Quinoline Based Derivatives as Potential Bioactive Heterocycles.

Quinoline derivatives are an important class of heterocyclic compounds and possess various applications in synthetic organic chemistry, medicinal chemistry, material chemistry and natural product chemistry. This review article describes the different quinoline derivatives having antimalarial, analgesic, anti-inflammatory, antineoplastic, antibacterial, antifungal, antiviral, anthelmintic, antiprotozoal, cardiovascular, CNS and other useful bioactivities. We have delineated the general synthetic routes for the synthesis of many bioactive quinoline based heterocycles. In addition to this, we have also discussed the crucial synthetic routes as well as their mechanistic paths for the formation of bioactive quinoline derivatives. The study shows that substitution at the 4 and 8- position of quinoline is more crucial for bioactivity as compared to other positions.

Antimicrobial effect of herbal and conventional root canal endodontic irrigants against persistent pathogens.

Evaluation and comparison of natural products like triphala, eucalyptus and carvacol with conventional root canal irrigant such as sodium hypochlorite (NaOCL) and Chlorhexidine against persistent root canal pathogens like E. faecalis is of interest. Samples were taken both before irrigation as well as after irrigation. CFU was counted after the plates had been incubated overnight at temperature of 37°C overnight. The herbal products showed antibacterial effectiveness against persistent root canal pathogens like E. faecalis. The antibacterial effectiveness was high in NaOCL, chlorhexidine and eucalyptus extract.

Unleashing a novel function of Endonuclease G in mitochondrial genome instability.

Having its genome makes the mitochondrion a unique and semiautonomous organelle within cells. Mammalian mitochondrial DNA (mtDNA) is a double-stranded closed circular molecule of about 16 kb coding for 37 genes. Mutations, including deletions in the mitochondrial genome, can culminate in different human diseases. Mapping the deletion junctions suggests that the breakpoints are generally seen at hotspots. '9 bp deletion' (8271-8281), seen in the intergenic region of cytochrome c oxidase II/tRNALys, is the most common mitochondrial deletion. While it is associated with several diseases like myopathy, dystonia, and hepatocellular carcinoma, it has also been used as an evolutionary marker. However, the mechanism responsible for its fragility is unclear. In the current study, we show that Endonuclease G, a mitochondrial nuclease responsible for nonspecific cleavage of nuclear DNA during apoptosis, can induce breaks at sequences associated with '9 bp deletion' when it is present on a plasmid or in the mitochondrial genome. Through a series of in vitro and intracellular studies, we show that Endonuclease G binds to G-quadruplex structures formed at the hotspot and induces DNA breaks. Therefore, we uncover a new role for Endonuclease G in generating mtDNA deletions, which depends on the formation of G4 DNA within the mitochondrial genome. In summary, we identify a novel property of Endonuclease G, besides its role in apoptosis and the recently described 'elimination of paternal mitochondria during fertilisation.

Infection Resistant Surface Coatings by Polymer Brushes: Strategies to Construct and Applications.

Bacteria-assisted infections on biomaterials used inside a body as an implant/device are one of the major threats to human health. Microbial-resistant coatings on biomaterials can potentially be considered to mitigate the biomaterial-associated infections. Usually biomaterials with leachable antimicrobial coatings, though economically attractive, provide only short-term protection of the surface against bacteria. Therefore, a stable, nonfouling or bactericidal, and biocompatible polymeric coating is highly desirable. In this regard, polymer brushes, defined as polymer chains tethered to a surface by one end, with suitable anti-infective functionality, represent a useful class of stable coatings which are covalently connected to the underlying surface, thus prolonging the infection resistance of the coated surface. Surface-initiated atom transfer radical polymerization (SI-ATRP) is a versatile technique for the generation of polymeric brushes via "grafting from" way. In this review, we have attempted to give a brief overview about the recent developments of surface coatings by infection-resistant polymer brushes synthesized via SI-ATRP and their applications in the biomedical field. On the basis of their charges, these anti-infective brushes can be classified into five different categories such as neutral, cationic, anionic, zwitterionic, and mixed brushes. The working mechanism of each type of brush in repelling (nonfouling/bacteriostatic) and/or killing (bactericidal) the bacteria has also been discussed. A brief summary of their future scope is also highlighted.