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BackgroundThe purpose of this study was to evaluate the outcomes of alveoplasty and primary closure following dental extractions in patients with an elevated medication-related osteonecrosis of the jaw (MRONJ) risk.

Patients with existing or a history of medication-related osteonecrosis of the jaw (MRONJ) are considered to be at a higher risk of further developing MRONJ, particularly if dental extractions are necessary. It is assumed that their underlying risk factors predispose them to developing MRONJ and they are allocated into an ‘elevated risk group'. There is no evidence to quantify this risk level; however, it has led to an avoidance of dental extractions in this cohort. However, avoidance of dental extractions is not a realistic treatment option to prevent MRONJ and there is emerging evidence that inflammatory dental disease, such as peri-apical pathology or periodontal disease, can trigger the pathogenesis of MRONJ. The current case series retrospectively reviewed 28 patients with existing or a history of MRONJ who underwent dental extractions (n = 65) via our departmental protocol, which includes elective circumferential socket alveoplasty and primary closure. Our outcomes show that MRONJ did not develop at the new extraction site, with a post-operative review period of at least six months. These results provide promising evidence that dental extractions can be performed in this group of patients with <1% risk of developing MRONJ at the new surgical site, if appropriate measures are undertaken.

The continuation of bone-modifying agents (BMAs) in patients with established medication-related osteonecrosis of the jaw (MRONJ) is a common concern among dentists and oncologists. There is little evidence supporting or refuting the continued use of BMAs or drug holidays and their impact on established MRONJ. This paper evaluates the outcome of continued BMAs use on the patient's MRONJ status. A retrospective review of 29 oncology patients undergoing active cancer care for either metastatic disease or multiple myeloma was conducted. Data on demographics, oncological status, BMA history and MRONJ status were collected. In total, 90% of patients were judged to have healed or stable MRONJ while continuing BMAs. Most patients (69%) continued the same BMA regime (three- or four-weekly) that they were on before developing MRONJ. The average number of BMAs doses received after an MRONJ diagnosis was 12 (range 1-48). Three patients (10.3%) were found to have MRONJ progression, with two patients developing new sites of necrosis. This real-world dataset suggests that the majority of MRONJ cases remain stable and will not worsen with the continuation of BMAs.

Prokaryotes synthesize fatty acids using a type II synthesis pathway (FAS). In this process, the central player, i.e., the acyl carrier protein (ACP), sequesters the growing acyl chain in its internal hydrophobic cavity. As the acyl chain length increases, the cavity expands in size, which is reflected in the NMR chemical shift perturbations and crystal structures of the acyl-ACP intermediates. A few eukaryotic organelles, such as plastids and mitochondria, also harbor type II fatty acid synthesis machinery. Plastid FAS from spinach and Plasmodium falciparumhas been characterized at the molecular level, but the mitochondrial pathway remains unexplored. Here, we report NMR studies of the mitochondrial acyl–acyl carrier protein intermediates of Leishmania major(acyl-LmACP). Our studies show that LmACP experiences remarkably small conformational changes upon acylation, with perturbations confined to helices II and III only. CastP determined that the cavity size of apo-LmACP (PDB entry 5ZWT) is less than that of Escherichia coliACP (PDB 1T8K). Thus, the small chemical shift perturbations observed in the LmACP intermediates, coupled with CastP results, suggest an unusually small cavity when fully expanded. The faster rate of C8-LmACP chain hydrolysis compared to E. coliACP (EcACP) also supports these convictions. Structure comparison of LmACP with other type II ACP disclosed unique differences in the helix I and loop I conformations, as well as several residues present there. Numerous hydrophobic residues in helix I and loop I (conserved in all mitochondrial ACPs) are substituted with hydrophilic residues in the bacterial/plastid type II ACP. For instance, Phe and leucine at positions 14 and 34 in LmACP are substituted with a hydrophilic residue and Ala in bacterial/plastid type II ACP. Mutation of Leu 34 to Ala (corresponding residue in EcACP) resulted in a complete loss of structure, underscoring its importance in maintaining the ACP fold. Thus, our NMR studies, combined with insights from the crystal structure, highlight several unique features of LmACP, distinct from the prokaryote and plastid type II ACP. Given the high sequence identity, the features might be conserved in all mitochondrial ACPs.

ObjectiveBirmingham City Council commenced electric scooter (e-scooter) trials in September 2020 as part of the wider UK effort to introduce e-scooters as an alternative method of transport. We aimed to review and evaluate maxillofacial injuries in the initial trial period of one year and comment on the safety implications.

As primary care dental services continue to offer conscious sedation in practice, this article presents the findings from a record-keeping audit carried out at a dental teaching hospital in the UK. National guidance was used to set out the gold standards for record-keeping. Various shortcomings in terms of documentation were identified. This article enables dental practitioners involved in dental sedation to review their own sedation record-keeping to meet current national standards and ultimately improve clinical practice and the quality of patient care.

Dental practitioners are well versed in informing patients of the risks and benefits associated with dental extractions. The purpose of this service evaluation was to determine whether patients understood and recalled information relevant to their planned oral surgery procedure, prior to second stage consent.A questionnaire was distributed to patients who were attending for their elective treatment appointment. This explored their ability to recall the planned intervention, the modality of treatment (local anaesthetic, intravenous sedation, or general anaesthetic), understanding of alternative treatment options and the risks associated with the procedure. Completed responses were received from 29 of the distributed questionnaires (response rate=58%). The majority of patients were not aware of the following risks with their procedure: pain, bleeding, bruising, swelling, infection, damage to adjacent structures.Despite a well-documented consent form and comprehensive discussion, we identified that patients may not comprehend or recollect the risks associated with their dental extraction. As dental professionals we have a duty to seek ways to facilitate patient understanding and maximise their autonomy.

ERAP1 and ERAP2 are endoplasmic reticulum zinc-binding aminopeptidases that play crucial roles in processing peptides for loading onto class I major histocompatibility complex proteins. These enzymes are therapeutic targets in cancer and autoimmune disorders. The discovery of inhibitors specific to ERAP1 or ERAP2 has been challenging due to the similarity in their active site residues and domain architectures. Here, we identify 4-methoxy-3-{[2-piperidin-1-yl-4-(trifluoromethyl) phenyl] sulfamoyl} benzoic acid (compound 61) as a novel inhibitor of ERAP2 and determine the crystal structure of ERAP2 bound to compound 61. Compound 61binds near the catalytic center of ERAP2, at a distinct site from previously known peptidomimetic inhibitors, and inhibits by an uncompetitive mechanism. Surprisingly, for ERAP1, compound 61was found to activate model substrate hydrolysis, similarly to the previously characterized 5-trifluoromethyl regioisomer of compound 61, known as compound 3.We characterized the specificity determinants of ERAP1 and ERAP2 that control the binding of compounds 3and 61. At the active site of ERAP1, Lys380 in the S1′ pocket is a key determinant for the binding of both compounds 3and 61. At the allosteric site, ERAP1 binds either compound, leading to the activation of model substrate hydrolysis. Although ERAP2 substrate hydrolysis is not activated by either compound, the mutation of His904 to alanine reveals a cryptic allosteric site that allows for the activation by compound 3. Thus, we have identified selectivity determinants in the active and allosteric sites of ERAP2 that govern the binding of two similar compounds, which potentially could be exploited to develop more potent and specific inhibitors.

Background: Alzheimer’s disease is a neurological condition causing cognitive inability and dementia. The pathological lesions and neuronal damage in the brain are caused by self-aggregated fragments of mutated Amyloidal precursor protein (APP). Objective: The controlled APP processing by inhibition of secretase is the strategy to reduce Aβ load to treat Alzheimer’s disease. Methods: A QSAR study was performed on 55 Pyrrolidine based ligands as BACE-1 inhibitors with an activity magnitude greater than 4 of compounds. Results: In the advent of designing new BACE-1 inhibitors, the pharmacophore model with correlation (r = 0.90) and root mean square deviation (RMSD) of 0.87 was developed and validated. Further, the hits retrieved by the in-silico approach were evaluated by docking interactions. Conclusion: Two structurally diverse compounds exhibited Asp32 and Thr232 binding with the BACE-1 receptor. The aryl-substituted carbamate compound exhibited the highest fit value and docking score. The biological activity evaluation by in-vitro assay was found to be >0.1μM.

ERAP1 is an endoplasmic reticulum-resident zinc aminopeptidase that plays an important role in the immune system by trimming peptides for loading onto major histocompatibility complex proteins. Here, we report discovery of the first inhibitors selective for ERAP1 over its paralogues ERAP2 and IRAP. Compound 1(N-(N-(2-(1H-indol-3-yl)ethyl)carbamimidoyl)-2,5-difluorobenzenesulfonamide) and compound 2(1-(1-(4-acetylpiperazine-1-carbonyl)cyclohexyl)-3-(p-tolyl)urea) are competitive inhibitors of ERAP1 aminopeptidase activity. Compound 3(4-methoxy-3-(N-(2-(piperidin-1-yl)-5-(trifluoromethyl)phenyl)sulfamoyl)benzoic acid) allosterically activates ERAP1’s hydrolysis of fluorogenic and chromogenic amino acid substrates but competitively inhibits its activity toward a nonamer peptide representative of physiological substrates. Compounds 2and 3inhibit antigen presentation in a cellular assay. Compound 3displays higher potency for an ERAP1 variant associated with increased risk of autoimmune disease. These inhibitors provide mechanistic insights into the determinants of specificity for ERAP1, ERAP2, and IRAP and offer a new therapeutic approach of specifically inhibiting ERAP1 activity in vivo.

Cortex glia in Drosophilacentral nervous system form a niche around neural cells for necessary signals to establish cross talk with their surroundings. These cells grow and expand their thin processes around neural cell bodies. Although essential for the development and function of the nervous system, how these cells make extensive and intricate connected networks remains largely unknown. In this study, we show that Cut, a homeodomain transcription factor, directly regulates the fate of the cortex glia, impacting neural stem cell (NSC) homeostasis. Focusing on the thoracic ventral nerve cord, we found that Cut is required for the normal growth and development of cortex glia and timely increase in DNA content through endocycle to later divide via acytokinetic mitosis. Knockdown of Cut in cortex glia significantly reduces the growth of cellular processes, the network around NSCs, and their progeny's cell bodies. Conversely, overexpression of Cut induces overall growth of the main processes at the expense of side ones. Whereas the Cut knockdown slows down the timely increase of DNA, the Cut overexpression results in a significant increase in nuclear size and volume and a 3-fold increase in DNA content of cortex glia. Further, we note that constitutively high Cut also interfered with nuclei separation during acytokinetic mitosis. Since the cortex glia form syncytial networks around neural cells, the finding identifies Cut as a novel regulator of glial growth and variant cell cycles to support a functional nervous system.

Background: Rho-kinase is an essential downstream target of GTP-binding protein RhoA, and plays a crucial role in the calcium-sensitization pathway. Rho-kinase pathway is critically involved in phosphorylation state of myosin light chain, leading to increased contraction of smooth muscles. Inhibition of this pathway has turned out to be a promising target for several indications such as cardiovascular diseases, glaucoma and inflammatory diseases. Methods: The present work focuses on a division-based 2D quantitative structure-activity relationship (QSAR) analysis along with a docking study to predict structural features that may be essential for the enhancement of selectivity and potency of the target compounds. Furthermore, a set of indoles and azaindoles were also projected based on the regression equation as novel developments. Molecular docking was applied for exploring the binding sites of the newly predicted set of compounds with the receptor. Results: Results of the docked conformations suggested that introduction of non-bulky and substituted groups in the hinge region of ROCK-II ATP binding pocket would improve the activity by decreasing the bulkiness or length of the compounds. Conclusion: ADME studies were performed to ascertain the novelty and drug-like properties of the designed molecules, respectively.

Interaction interfaces comprise a finite number of sequence/structural motifs, which are often repeated in nature. Here we show how a helical motif present in the acyl carrier protein (ACP), involved in multiprotein interactions, displays a binding interface similar to that of the “ubiquitin interacting motif (UIM)”. Analysis of the crystal structures of the ACP–enzyme complexes gave the first hint that helix II of the ACP (“universal recognition helix”) utilizes UIM-like noncovalent interactions to associate with the type II fatty acid biosynthesis (FAS) pathway enzymes. The ACP interacting functional surface of the FAS enzymes comprises positively charged residues, flanking a central hydrophobic patch, akin to ubiquitin. Our nuclear magnetic resonance chemical shift perturbation studies, relaxation studies, and surface plasmon resonance measurements unequivocally show that helix II of ACP behaves like a UIM motif in its interactions with ubiquitin, by binding the Ile 44 functional surface of the latter. A synthetic peptide with the ACP helix II sequence showed equivalent binding to ubiquitin. The evolution of similar interaction motifs in the two systems has probably been driven by functional constraints, as both ACP and UIM participate in multiprotein interactions.

Since its discovery, neuroglobin (Ngb), a neuron-specific oxygen binding hemoglobin, distinct from the classical myoglobin and blood hemoglobin, has attracted attention as an endogenous neuroprotectant. Recent reports suggest that Ngb protects neurons from brain stroke, ischemic stress-induced degeneration, and other brain disorders. Proteins with a specific role in neuroprotection are often associated with neurodegeneration, as well, depending on the cellular environment or specific cellular triggers that tilt the balance one way or the other. This investigation explored the potential role of Ngb in amyloid fibril-related neuronal disorder. Ngb was capable of amyloid formation in vitroat neutral pH and ambient temperature, in both apo and holo forms, albeit at a slower rate in the holo form, unlike other hemoglobins that exhibit such behavior exclusively in the apo states. Elevated temperature enhanced the rate of fibril formation significantly. The B-helix, which is known to play a major role in Ngb ligand binding kinetics, was found to be amyloidogenic with the Phe28B10amino acid side chain as the key inducer of fibrillation. The Ngb amyloid fibril was also significantly cytotoxic to neuroblastoma cell lines, compared to those obtained from reference hemoglobins. The Ngb fibril probably promoted toxicity by inducing channel formation in the cell membrane, as investigated here using synthetic lipid bilayer membranes and the propidium iodide uptake assay. These findings imply that Ngb plays a role in neurodegenerative disorders in vivo, for which there seems to be indirect evidence by association. Ngb thus presents a novel prospect for understanding amyloid-related brain disorders beyond the limited set of proteins currently investigated for such diseases.

•All pathogens survived during storage at 4°C, 10°C, and 22°C.•Higher pathogen survival at ambient temperature than refrigerated temperature storage was observed.•STEC population decreased least under ambient temperature storage.•Salmonellaspp. population decreased least under refrigerated temperature storage.

Medicines developed from traditional systems are well known for their various important pharmaceutical uses. Cancer has been known since ancient times and has been mentioned in the ancient Ayurvedic books. Thus natural based products play a significant role in cancer chemotherapeutics. Further, approximately 70% of anticancer compounds are based on natural products or have been derived from their structural scaffolds. Hence, there is a growing interest for developing medicines from these natural resources. Amongst the methods of treating cancer, therapies targeting cancer stem cell are found to control metastatic tumor which is a newly identified factor associated with relapse. This patent review aims to highlight the use of natural products to treat cancer by targeting the cancer stem cells. The review will also provide insights into the reported mechanisms by which the natural products act in order to suppress or kill cancer stem cells. The analysis has been done using various criteria such as the patenting trend over the years, comparison of active assignee and a comparison of the technical aspects as disclosed in the different patent documents. The analysis further highlights different bioactives, the scaffolds of which could thus be a promising candidate in the development of anti-cancer drugs by targeting the cancer stem cells. The technical aspects covered in this review include: Bioactives and formulations comprising the extracts or bioactives, their mode of action and the type of assay considered to study the efficacy of the natural products. Further the mapping has helped us to identify potential therapeutic areas to evaluate herbs/bioactives and their uses for developing new formulations.

Temporal changes in tumor necrosis factor-α (TNF-α) and nitric oxide synthase 2 (NOS 2) were evaluated in segments of duodenum, jejunum, and ileum removed from male Sprague-Dawley rats 30, 60, 120, 180, and 240 min after lipopolysaccharide (LPS), 5 mg/kg, intreperitoneally. Plasma was assayed for TNF-α and for nitrate/nitrite (NOx). Intestinal and plasma TNF-α were elevated by 60 min after LPS and were back to control levels by 180 min. For control rats, NOS 2 was detected in the ileum, but not in the duodenum or the jejunum. In rats treated with LPS, NOS 2 was detected in all areas of the intestine at 120 min and was greatest at 240 min. Plasma NOxwas elevated at 120 min and continued to increase to 240 min. The time course of changes in intestinal TNF-α and NOS 2 were similar to those reported for other tissues and suggest that the early and late actions of the LPS on the intestine may involve both mediators.