Structural insights into the cross-exon to cross-intron spliceosome switch.

Early spliceosome assembly can occur through an intron-defined pathway, whereby U1 and U2 small nuclear ribonucleoprotein particles (snRNPs) assemble across the intron1. Alternatively, it can occur through an exon-defined pathway2-5, whereby U2 binds the branch site located upstream of the defined exon and U1 snRNP interacts with the 5' splice site located directly downstream of it. The U4/U6.U5 tri-snRNP subsequently binds to produce a cross-intron (CI) or cross-exon (CE) pre-B complex, which is then converted to the spliceosomal B complex6,7. Exon definition promotes the splicing of upstream introns2,8,9 and plays a key part in alternative splicing regulation10-16. However, the three-dimensional structure of exon-defined spliceosomal complexes and the molecular mechanism of the conversion from a CE-organized to a CI-organized spliceosome, a pre-requisite for splicing catalysis, remain poorly understood. Here cryo-electron microscopy analyses of human CE pre-B complex and B-like complexes reveal extensive structural similarities with their CI counterparts. The results indicate that the CE and CI spliceosome assembly pathways converge already at the pre-B stage. Add-back experiments using purified CE pre-B complexes, coupled with cryo-electron microscopy, elucidate the order of the extensive remodelling events that accompany the formation of B complexes and B-like complexes. The molecular triggers and roles of B-specific proteins in these rearrangements are also identified. We show that CE pre-B complexes can productively bind in trans to a U1 snRNP-bound 5' splice site. Together, our studies provide new mechanistic insights into the CE to CI switch during spliceosome assembly and its effect on pre-mRNA splice site pairing at this stage.

Cryo-EM analyses of dimerized spliceosomes provide new insights into the functions of B complex proteins.

The B complex is a key intermediate stage of spliceosome assembly. To improve the structural resolution of monomeric, human spliceosomal B (hB) complexes and thereby generate a more comprehensive hB molecular model, we determined the cryo-EM structure of B complex dimers formed in the presence of ATP γ S. The enhanced resolution of these complexes allows a finer molecular dissection of how the 5' splice site (5'ss) is recognized in hB, and new insights into molecular interactions of FBP21, SNU23 and PRP38 with the U6/5'ss helix and with each other. It also reveals that SMU1 and RED are present as a heterotetrameric complex and are located at the interface of the B dimer protomers. We further show that MFAP1 and UBL5 form a 5' exon binding channel in hB, and elucidate the molecular contacts stabilizing the 5' exon at this stage. Our studies thus yield more accurate models of protein and RNA components of hB complexes. They further allow the localization of additional proteins and protein domains (such as SF3B6, BUD31 and TCERG1) whose position was not previously known, thereby uncovering new functions for B-specific and other hB proteins during pre-mRNA splicing.

Structural insights into how Prp5 proofreads the pre-mRNA branch site.

During the splicing of introns from precursor messenger RNAs (pre-mRNAs), the U2 small nuclear ribonucleoprotein (snRNP) must undergo stable integration into the spliceosomal A complex-a poorly understood, multistep process that is facilitated by the DEAD-box helicase Prp5 (refs. 1-4). During this process, the U2 small nuclear RNA (snRNA) forms an RNA duplex with the pre-mRNA branch site (the U2-BS helix), which is proofread by Prp5 at this stage through an unclear mechanism5. Here, by deleting the branch-site adenosine (BS-A) or mutating the branch-site sequence of an actin pre-mRNA, we stall the assembly of spliceosomes in extracts from the yeast Saccharomyces cerevisiae directly before the A complex is formed. We then determine the three-dimensional structure of this newly identified assembly intermediate by cryo-electron microscopy. Our structure indicates that the U2-BS helix has formed in this pre-A complex, but is not yet clamped by the HEAT domain of the Hsh155 protein (Hsh155HEAT), which exhibits an open conformation. The structure further reveals a large-scale remodelling/repositioning of the U1 and U2 snRNPs during the formation of the A complex that is required to allow subsequent binding of the U4/U6.U5 tri-snRNP, but that this repositioning is blocked in the pre-A complex by the presence of Prp5. Our data suggest that binding of Hsh155HEAT to the bulged BS-A of the U2-BS helix triggers closure of Hsh155HEAT, which in turn destabilizes Prp5 binding. Thus, Prp5 proofreads the branch site indirectly, hindering spliceosome assembly if branch-site mutations prevent the remodelling of Hsh155HEAT. Our data provide structural insights into how a spliceosomal helicase enhances the fidelity of pre-mRNA splicing.

Nonsense-mediated mRNA decay pathway in plants under stress: general gene regulatory mechanism and advances.

MAIN CONCLUSION: Nonsense-mediated mRNA decay in eukaryotes is vital to cellular homeostasis. Further knowledge of its putative role in plant RNA metabolism under stress is pivotal to developing fitness-optimizing strategies. Nonsense-mediated mRNA decay (NMD), part of the mRNA surveillance pathway, is an evolutionarily conserved form of gene regulation in all living organisms. Degradation of mRNA-bearing premature termination codons and regulation of physiological RNA levels highlight NMD's role in shaping the cellular transcriptome. Initially regarded as purely a tool for cellular RNA quality control, NMD is now considered to mediate various aspects of plant developmental processes and responses to environmental changes. Here we offer a basic understanding of NMD in eukaryotes by explaining the concept of premature termination codon recognition and NMD complex formation. We also provide a detailed overview of the NMD mechanism and its role in gene regulation. The potential role of effectors, including ABCE1, in ribosome recycling during the translation process is also explained. Recent reports of alternatively spliced variants of corresponding genes targeted by NMD in Arabidopsis thaliana are provided in tabular format. Detailed figures are also provided to clarify the NMD concept in plants. In particular, accumulating evidence shows that NMD can serve as a novel alternative strategy for genetic manipulation and can help design RNA-based therapies to combat stress in plants. A key point of emphasis is its function as a gene regulatory mechanism as well as its dynamic regulation by environmental and developmental factors. Overall, a detailed molecular understanding of the NMD mechanism can lead to further diverse applications, such as improving cellular homeostasis in living organisms.

Breaking the Barriers: Machine-Learning-Based c-RASAR Approach for Accurate Blood-Brain Barrier Permeability Prediction.

The intricate nature of the blood-brain barrier (BBB) poses a significant challenge in predicting drug permeability, which is crucial for assessing central nervous system (CNS) drug efficacy and safety. This research utilizes an innovative approach, the classification read-across structure-activity relationship (c-RASAR) framework, that leverages machine learning (ML) to enhance the accuracy of BBB permeability predictions. The c-RASAR framework seamlessly integrates principles from both read-across and QSAR methodologies, underscoring the need to consider similarity-related aspects during the development of the c-RASAR model. It is crucial to note that the primary goal of this research is not to introduce yet another model for predicting BBB permeability but rather to showcase the refinement in predicting the BBB permeability of organic compounds through the introduction of a c-RASAR approach. This groundbreaking methodology aims to elevate the accuracy of assessing neuropharmacological implications and streamline the process of drug development. In this study, an ML-based c-RASAR linear discriminant analysis (LDA) model was developed using a dataset of 7807 compounds, encompassing both BBB-permeable and -nonpermeable substances sourced from the B3DB database (freely accessible from https://github.com/theochem/B3DB), for predicting BBB permeability in lead discovery for CNS drugs. The model's predictive capability was then validated using three external sets: one containing 276,518 natural products (NPs) from the LOTUS database (accessible from https://lotus.naturalproducts.net/download) for data gap filling, another comprising 13,002 drug-like/drug compounds from the DrugBank database (available from https://go.drugbank.com/), and a third set of 56 FDA-approved drugs to assess the model's reliability. Further diversifying the predictive arsenal, various other ML-based c-RASAR models were also developed for comparison purposes. The proposed c-RASAR framework emerged as a powerful tool for predicting BBB permeability. This research not only advances the understanding of molecular determinants influencing CNS drug permeability but also provides a versatile computational platform for the rapid assessment of diverse compounds, facilitating informed decision-making in drug development and design.

Excited Charge Separation in a π-Interacting Phenothiazine-Zinc Porphyrin-Fullerene Donor-Acceptor Conjugate.

We have designed, synthesized, and characterized a donor-acceptor triad, SPS-PPY-C60, that consists of a π-interacting phenothiazine-linked porphyrin as a donor and sensitizer and fullerene as an acceptor to seek charge separation upon photoexcitation. The optical absorption spectrum revealed red-shifted Soret and Q-bands of porphyrin due to charge transfer-type interactions involving the two ethynyl bridges carrying electron-rich and electron-poor substituents. The redox properties suggested that the phenothiazine-porphyrin part of the molecule is easier to oxidize and the fullerene part is easier to reduce. DFT calculations supported the redox properties wherein the electron density of the highest molecular orbital (HOMO) was distributed over the donor phenothiazine-porphyrin entity while the lowest unoccupied molecular orbital (LUMO) was distributed over the fullerene acceptor. TD-DFT studies suggested the involvement of both the S2 and S1 states in the charge transfer process. The steady-state emission spectrum, when excited either at porphyrin Soret or visible band absorption maxima, revealed quenched emission both in nonpolar and polar solvents, suggesting the occurrence of excited state events. Finally, femtosecond transient absorption spectral studies were performed to witness the charge separation by utilizing solvents of different polarities. The transient data was further analyzed by GloTarAn by fitting the data with appropriate models to describe photochemical events. From this, the average lifetime of the charge-separated state calculated was found to be 169 ps in benzonitrile, 319 ps in dichlorobenzene, 1.7 ns in toluene for Soret band excitation, and ∼320 ps for Q-band excitation in benzonitrile.

Identification of potential JNK3 inhibitors through virtual screening, molecular docking and molecular dynamics simulation as therapeutics for Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurological disorder and no effective drug is available for its treatment. Numerous pathological conditions are believed to be responsible for the initiation and development of AD including c-Jun N-terminal kinases (JNKs). The JNKs are one of the enzymes from the mitogen-activated protein kinase (MAPK) family that controls the phosphorylation of various transcription factors on serine and threonine residues, and hold significant responsibilities in tasks like gene expression, cell proliferation, differentiation, and apoptosis. Since, JNK3 is primarily expressed in the brain hence its increased levels in the brain are associated with the AD pathology promoting neurofibrillary tangles, senile plaques, neuroinflammation, and nerve cell apoptosis. The current research work is focused on the development of novel JNK inhibitors as therapeutics for AD employing a structure-based virtual screening (SBVS) approach. The ZINC database (14634052 compounds) was investigated after employing pan assay interference (PAINs), drug-likeness, and diversity picking filter to distinguish molecules interacting with JNK3 by following three docking precision criteria: High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP) & MMGBSA. Five lead molecules showed a better docking score in the range of -13.091 to -14.051 kcal/mol better than the reference compound (- 11.828 kcal/mol). The lead compounds displayed acceptable pharmacokinetic properties and were subjected to molecular dynamic simulations of 100 ns and binding free energy calculations. All the lead molecules showed stable RMSD and hydrogen bond interactions throughout the trajectory. The ∆GMM/PBSA_total score for the lead compounds ZINC220382956, ZINC147071339, ZINC207081127, ZINC205151456, ZINC1228819126, and CC-930 was calculated and found to be - 31.39, - 42.8, - 37.04, - 39.01, - 36.5, - 34.16 kcal/mol, respectively. Thus, it was concluded that the lead molecules identified in these studies have the potential to be explored as potent JNK3 inhibitors.

One-stage prosthodontically driven jaw reconstruction in patients with benign and malignant pathologies: A 7- to 11-year cohort study.

OBJECTIVES: One stage functional jaw reconstruction is defined as the resection and reconstruction of segmental defects in conjunction with the placement of dental implants in an ideal prosthetic position and loaded with a provisional restoration, during one surgical procedure. The aim of the study is to describe clinical outcomes of patients who underwent one stage functional jaw reconstruction. METHODS: Patients who underwent one-stage functional jaw reconstruction, from January 2013 to March 2016 were recalled in 2022 and 2023. Planning and execution for the reconstruction utilized either analogue or digital techniques. Outcome parameters recorded were treatment-related outcomes at patient level, implant-related outcomes and patient-reported outcome measures. RESULTS: Eighteen patients underwent one-stage jaw reconstruction with a total of 57 implants. Four patients had maxillary and 14 had mandibular reconstructions. Ten patients underwent postoperative radiotherapy. Ten patients were planned using analogue and eight by digital planning. Three patients had partial flap necrosis, three patients had plate fractures, implant loss was seen in one patient and four patients died during the period. A functional prosthesis was provided in 16 out of the 18 patients. CONCLUSION: One-stage functional jaw reconstruction is a predictable method for providing rehabilitation with successful outcomes at 7-11 years. However, caution should be exercised when the treatment modality is carried out in patients with malignant pathologies who have undergone radiotherapy.

Chronic aquatic toxicity assessment of diverse chemicals on Daphnia magna using QSAR and chemical read-across.

We have modeled here chronic Daphnia toxicity taking pNOEC (negative logarithm of no observed effect concentration in mM) and pEC50 (negative logarithm of half-maximal effective concentration in mM) as endpoints using QSAR and chemical read-across approaches. The QSAR models were developed by strictly obeying the OECD guidelines and were found to be reliable, predictive, accurate, and robust. From the selected features in the developed models, we have found that an increase in lipophilicity and saturation, the presence of electrophilic or electronegative or heavy atoms, the presence of sulphur, amine, and their related functionality, an increase in mean atomic polarizability, and higher number of (thio-) carbamates (aromatic) groups are responsible for chronic toxicity. Therefore, this information might be useful for the development of environmentally friendly and safer chemicals and data-gap filling as well as reducing the use of identified toxic chemicals which have chronic toxic effects on aquatic ecosystems. Approved classes of drugs from DrugBank databases and diverse groups of chemicals from the Chemical and Product Categories (CPDat) database were also assessed through the developed models.

Rethinking underutilized cereal crops: pan-omics integration and green system biology.

MAIN CONCLUSION: Due to harsh lifestyle changes, in the present era, nutritional security is needed along with food security so it is necessary to include underutilized cereal crops (UCCs) in our daily diet to counteract the rising danger of human metabolic illness. We can attain both the goal of zero hunger and nutritional security by developing improved UCCs using advanced pan-omics (genomics, transcriptomics, proteomics, metabolomics, nutrigenomics, phenomics and ionomics) practices. Plant sciences research progressed profoundly since the last few decades with the introduction of advanced technologies and approaches, addressing issues of food demand of the growing population, nutritional security challenges and climate change. However, throughout the expansion and popularization of commonly consumed major cereal crops such as wheat and rice, other cereal crops such as millet, rye, sorghum, and others were impeded, despite their potential medicinal and nutraceutical qualities. Undoubtedly neglected underutilized cereal crops (UCCs) also have the capability to withstand diverse climate change. To relieve the burden of major crops, it is necessary to introduce the new crops in our diet in the way of UCCs. Introgression of agronomically and nutritionally important traits by pan-omics approaches in UCCs could be a defining moment for the population's well-being on the globe. This review discusses the importance of underutilized cereal crops, as well as the application of contemporary omics techniques and advanced bioinformatics tools that could open up new avenues for future study and be valuable assets in the development and usage of UCCs in the perspective of green system biology. The increased and improved use of UCCs is dependent on number of factors that necessitate a concerted research effort in agricultural sciences. The emergence of functional genomics with molecular genetics might gear toward the reawakening of interest in underutilized cereals crops. The need of this era is to focus on potential UCCs in advanced agriculture and breeding programmes. Hence, targeting the UCCs, might provide a bright future for better health and scientific rationale for its use.

Toxicity analysis of endocrine disrupting pesticides on non-target organisms: A critical analysis on toxicity mechanisms.

Endocrine disrupting compounds are the chemicals which mimics the natural endocrine hormones and bind to the receptors made for the hormones. Upon binding they activate the cascade of reaction which leads to permanent activating of the signalling cycle and ultimately leads to uncontrolled growth. Pesticides are one of the endocrine disrupting chemicals which cause cancer, congenital birth defects, and reproductive defects in non-target organisms. Non-target organisms are keen on exposing to these pesticides. Although several studies have reported about the pesticide toxicity. But a critical analysis of pesticide toxicity and its role as endocrine disruptor is lacking. Therefore, the presented review literature is an endeavour to understand the role of the pesticides as endocrine disruptors. In addition, it discusses about the endocrine disruption, neurological disruption, genotoxicity, and ROS induced pesticide toxicity. Moreover, biochemical mechanisms of pesticide toxicity on non-target organisms have been presented. An insight on the chlorpyrifos toxicity on non-target organisms along with species names have been presented.

An inclusive outlook on the fate and persistence of pesticides in the environment and integrated eco-technologies for their degradation.

Intensive and inefficient exploitation of pesticides through modernized agricultural practices has caused severe pesticide contamination problems to the environment and become a crucial problem over a few decades. Due to their highly toxic and persistent properties, they affect and get accumulated in non-target organisms, including microbes, algae, invertebrates, plants as well as humans, and cause severe issues. Considering pesticide problems as a significant issue, researchers have investigated several approaches to rectify the pesticide contamination problems. Several analyses have provided an extensive discussion on pesticide degradation but using specific technology for specific pesticides. However, in the middle of this time, cleaner techniques are essential for reducing pesticide contamination problems safely and environmentally friendly. As per the research findings, no single research finding provides concrete discussion on cleaner tactics for the remediation of contaminated sites. Therefore, in this review paper, we have critically discussed cleaner options for dealing with pesticide contamination problems as well as their advantages and disadvantages have also been reviewed. As evident from the literature, microbial remediation, phytoremediation, composting, and photocatalytic degradation methods are efficient and sustainable and can be used for treatment at a large scale in engineered systems and in situ. However, more study on the bio-integrated system is required which may be more effective than existing technologies.

N-2-Hydroxypropylmethacrylamide-Polycaprolactone Polymeric Micelles in Co-delivery of Proteasome Inhibitor and Polyphenol: Exploration of Synergism or Antagonism.

Breast cancer leads to the highest mortality among women resulting in a major clinical burden. Multidrug therapy is more efficient in such patients compared to monodrug therapy. Simultaneous combinatorial or co-delivery garnered significant interest in the past years. Caffeic acid (CFA) (a natural polyphenol) has received growing attention because of its anticarcinogenic and antioxidant potential. Bortezomib (BTZ) is a proteasome inhibitor and may be explored for treating breast cancer. Despite its high anticancer activity, the low water solubility and chemical instability restrict its efficacy against solid tumors. In the present study, we designed and investigated a HP-PCL (N-2-hydroxypropylmethacrylamide-polycaprolactone) polymeric micellar (PMCs) system for the simultaneous delivery of BTZ and CFA in the treatment of breast cancer. The designed BTZ+CFA-HP-PCL PMCs were fabricated, optimized, and characterized for size, zeta potential, surface morphology, and in vitro drug release. Developed nanosized (174.6 ± 0.24 nm) PMCs showed enhanced cellular internalization and cell cytotoxicity in both MCF-7 and MDA-MB-231 cells. ROS (reactive oxygen species) levels were highest in BTZ-HP-PCL PMCs, while CFA-HP-PCL PMCs significantly (p < 0.001) scavenged the ROS generated in 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay. The mitochondrial membrane potential (MMP) assay revealed intense and significant green fluorescence in both types of cancer cells when treated with BTZ-HP-PCL PMCs (p < 0.001) indicating apoptosis or cell death. The pharmacokinetic studies revealed that BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs exhibited the highest bioavailability, enhanced plasma half-life, decreased volume of distribution, and lower clearance rate than the pure combination of drugs. In the organ biodistribution studies, the combination of BTZ+CFA showed higher distribution in the spleen and the heart. Overall findings of in vitro studies surprisingly resulted in better therapeutic efficiency of BTZ-HP-PCL PMCs than BTZ+CFA-HP-PCL PMCs. However, the in vivo tumor growth inhibition study performed in tumor-induced mice concluded that the tumor growth was inhibited by both BTZ-HP-PCL PMCs and BTZ+CFA-HP-PCL PMCs (p < 0.0001) more efficiently than pure BTZ and the combination (BTZ+CFA), which may be due to the conversion of boronate ester into boronic acid. Henceforth, the combination of BTZ and CFA provides further indications to be explored in the future to support the hypothesis that BTZ may work with polyphenol (CFA) in the acidic environment of the tumor.

Siloxane Emissions and Exposures during the Use of Hair Care Products in Buildings.

Cyclic volatile methyl siloxanes (cVMS) are ubiquitous in hair care products (HCPs). cVMS emissions from HCPs are of concern, given the potential adverse impact of siloxanes on the environment and human health. To characterize cVMS emissions and exposures during the use of HCPs, realistic hair care experiments were conducted in a residential building. Siloxane-based HCPs were tested using common hair styling techniques, including straightening, curling, waving, and oiling. VOC concentrations were measured via proton-transfer-reaction time-of-flight mass spectrometry. HCP use drove rapid changes in the chemical composition of the indoor atmosphere. cVMS dominated VOC emissions from HCP use, and decamethylcyclopentasiloxane (D5) contributed the most to cVMS emissions. cVMS emission factors (EFs) during hair care routines ranged from 110-1500 mg/person and were influenced by HCP type, styling tools, operation temperatures, and hair length. The high temperature of styling tools and the high surface area of hair enhanced VOC emissions. Increasing the hair straightener temperature from room temperature to 210 °C increased cVMS EFs by 50-310%. Elevated indoor cVMS concentrations can result in substantial indoor-to-outdoor transport of cVMS via ventilation (0.4-6 tons D5/year in the U.S.); thus, hair care routines may augment the abundance of cVMS in the outdoor atmosphere.

Synthesis of amide derivatives of 3-aryl-3H-benzopyrans as osteogenic agent concomitant with anticancer activity.

The present study reports a series of 3-aryl-3H-benzopyran-based amide derivatives as osteogenic agents concomitant with anticancer activity. Six target compounds viz 22e, 22f, 23i, and 24b-d showed good osteogenic activity at 1 pM and 100 pM concentrations. One of the potential molecules, 24b, effectively induced ALP activity and mRNA expression of osteogenic marker genes at 1 pM and bone mineralization at 100 pM concentrations. These molecules also presented significant growth inhibition of osteosarcoma (MG63) and estrogen-dependent and -independent (MCF-7 and MDA-MB-231) breast cancer cells. The most active compound, 24b, inhibited the growth of all the cancer cells within the IC50 10.45-12.66 µM. The mechanistic studies about 24b showed that 24b induced apoptosis via activation of the Caspase-3 enzyme and inhibited cancer cell migration. In silico molecular docking performed for 24b revealed its interaction with estrogen receptor-ß (ER-ß) preferentially.

Efficacy of Bioactive Compounds in the Regulation of Metabolism and Pathophysiology in Cardiovascular Diseases.

PURPOSE OF REVIEW: An imbalance in reactive oxygen species (ROS) homeostasis can wreak damage to metabolic and physiological processes which can eventually lead to an advancement in cardiovascular diseases (CVD). Mitochondrial dysfunction is considered as a key source of ROS. The purpose of the current review is to concisely discuss the role of bioactive compounds in the modulation of cardiovascular metabolism and their potential application in the management of cardiovascular diseases. RECENT FINDINGS: Recently, it has been shown that bioactive compounds exhibit immunomodulatory function by regulating inflammatory pathways and ROS homeostasis. It has also been reported that bioactive compounds regulate mitochondria dynamics, thus modulating the autophagy and energy metabolism in the cells. In the present article, we have discussed the roles of different bioactive compounds in the modulation of different inflammatory drivers. The functional properties of bioactive compounds in mitochondrial dynamics and its impact on cardiac disease protection have been briefly summarized. Furthermore, we have also discussed various aspects of bioactive compounds with respect to metabolism, immune modulation, circadian rhythm, and its impact on CVD's pathophysiology.

Patient-centric outcome assessment of endodontic microsurgery using periapical radiography versus cone beam computed tomography: A randomized clinical trial.

AIM: This study aimed to evaluate whether utilizing additional cone beam computed tomography (CBCT) imaging has any effect on quality of life and healing outcome following periapical surgery compared with periapical radiographs (PR). METHODOLOGY: The study was registered in ClinicalTrials.gov (NCT04333940). In this parallel group randomized controlled trial, 52 patients (88 teeth) with persistent apical periodontitis and periapical radiographic evidence of periapical lesion were randomly assigned to either PR or CBCT group. The primary predictor was the type of the imaging method (PR only or with additional CBCT). The primary outcome was patient's quality of life during the first week after periapical surgery and the secondary outcomes were duration of surgery and healing outcome at 12-month follow-up. Participants of both groups received periapical surgery based on the pre-surgical plan provided by the radiographic imaging methods. Quality of life (QoL) was assessed using Modified Shugars questionnaire. Radiographic analysis for healing was conducted using Molven's criteria and modified PENN 3D criteria. The categorical data between groups were analysed using the Chi-square test, whilst intragroup comparisons were analysed using the McNemar test. The average scores for each component of QoL (oral functions, general functions, pain, swelling and other symptoms), combined QoL scores (overall average of values of 13 variables) and analgesic usage on each day were calculated and analysed. RESULTS: At 12 months of follow-up, fifty patients were evaluated. Participants in PR group reported significantly more swelling on first three days compared with CBCT group. The analgesic use was higher in the PR group on 2nd and 3rd day (Mann-Whitney U test with Bonferroni correction; p < .007). A significant difference in the limitation of general functions was observed at the second day (p < .07) with the higher values in the PR group. The combined QoL score between the two groups was found to be non-significant. However, none of the patients experienced intraoperative complications or neurovascular exposure. The mean surgical time was lesser in the CBCT group (p < .05). Radiographic healing revealed a success rate of 96.2% for the PR group and 95.8% for the CBCT group with no significant difference between the groups. CONCLUSION: Participants in the CBCT group experienced substantially less early postoperative swelling and limitation in general functions, in comparison with the PR group. However, preoperative CBCT had no effect on other QoL parameters and intraoperative complications in medium-risk patients. Furthermore, CBCT did not exhibit any added advantage over periapical radiography in terms of assessing healing outcome following endodontic microsurgery. CBCT offered surgically relevant anatomic information for pre-surgical planning and ensured the treatment rendition with a significantly reduced operative time.

Impact of ligand environment on optical, luminescence and thermometric behavior of A3 (PO4 )2 :Sm3+ (A = Ca, Sr) phosphors.

The present study investigates the impact of the ligand environment on the luminescence and thermometric behavior of Sm3+ doped A3 (PO4 )2 (A = Sr, Ca) phosphors prepared by combustion synthesis. The structural and luminescent properties of Sm3+ ions in the phosphate lattices were investigated using powder X-ray diffraction (PXRD) and photoluminescence (PL) techniques. PXRD results of the synthesized phosphors exhibit the expected phases that are in agreement with their respective standards. Fourier-transform infrared (FTIR) spectroscopy confirms the presence of PO4 vibrational bands. Upon excitation with near ultraviolet light, the PL studies indicated that Sr3 (PO4 )2 :Sm3+ phosphors exhibit a yellow light emission, whereas Ca3 (PO4 )2 :Sm3+ phosphors exhibit an emission of orange light. The PL emission results are in accordance with the CIE coordinates, with the Sr3 (PO4 )2 :Sm3+ phosphors showing coordinates of (0.56, 0.44), and the Ca3 (PO4 )2 :Sm3+ phosphors displaying coordinates of (0.60, 0.40). Thermal analysis shows improved stability of Ca3 (PO4 )2 :Sm3+ based on lower weight reduction in thermogravimetric analysis. The effect of temperature on the luminescence properties of the phosphor has been examined upon a 405 nm excitation. By using the fluorescence intensity ratio (FIR) method, the temperature responses of the emission ratios from the Sm3+ : the 4 F3/2 → 6 H5/2 transition to the 4 G5/2 → 6 H7/2 and 4 F3/2 → 6 H5/2 transition to the 4 G5/2 → 6 H9/2 emissions are characterized. The Ca3 (PO4 )2 :Sm3+ phosphors are more sensitive as compared with the Sr3 (PO4 )2 :Sm3+ phosphors. The earlier research findings strongly indicate that these phosphors hold great promise as ideal candidates for applications in non-invasive optical thermometry and solid-state lighting devices.

Endogenous Retrovirus RNA Expression Differences between Race, Stage and HPV Status Offer Improved Prognostication among Women with Cervical Cancer.

Endogenous human retroviruses (ERVs) are remnants of exogenous retroviruses that have integrated into the human genome. Using publicly available RNA-seq data from 63 cervical cancer patients, we investigated the expression of ERVs in cervical cancers. Four aspects of cervical cancer were investigated: patient ancestral background, tumor HPV type, tumor stage and patient survival. Between the racial subgroups, 74 ERVs were significantly differentially expressed, with Black Americans having 30 upregulated and 44 downregulated (including MER21C, HERV9-int, and HERVH-int) ERVs when compared to White Americans. We found that 3313 ERVs were differentially expressed between HPV subgroups, including MER41A, HERVH-int and HERVK9. There were 28 downregulated (including MLT1D and HERVH-int) and 61 upregulated (including MER41A) ERVs in locally advanced-stage compared to early-stage samples. Tissue microarrays of cervical cancer patients were used to investigate the protein expression of ERVs with protein coding potential (i.e., HERVK and ERV3). Significant differences in protein expression of ERV3 (p = 0.000905) were observed between early-stage and locally advanced-stage tumors. No significant differential expression at the protein level was found for HERVK7 (p = 0.243). We also investigated a prognostic model, supplementing a baseline prediction model using FIGO stage, age and HPV positivity with ERVs data. The expression levels of all ERVs in the HERVd were input into a Lasso-Cox proportional hazards model, developing a predictive 67-ERV panel. When ERVs expression levels were supplemented with the clinical data, a significant increase in prognostic power (p = 9.433 × 10-15) relative to that obtained with the clinical parameters alone (p = 0.06027) was observed. In summary, ERV RNA expression in cervical cancer tumors is significantly different among racial cohorts, HPV subgroups and disease stages. The combination of the expression of certain ERVs in cervical cancers with clinical factors significantly improved prognostication compared to clinical factors alone; therefore, ERVs may serve as future prognostic biomarkers and therapeutic targets. Novelty and Impact: When endogenous retroviral (ERV) expression signatures were combined with currently employed clinical prognosticators of relapse of cervical cancer, the combination outperformed prediction models based on clinical prognosticators alone. ERV expression signatures in tumor biopsies may therefore be useful to help identify patients at greater risk of recurrence. The novel ERV expression signatures or adjacent genes possibly impacted by ERV expression described here may also be targets for the development of future therapeutic interventions.

Effects of Secondary Alveolar Bone Grafting on Maxillary Growth in Cleft Lip or Palate Patients: A Systematic Review and Meta-Analysis.

To assess the effect of secondary alveolar bone grafting (SABG) on maxillary growth in patients with unilateral cleft lip or palate (UCL/P).Systematic review and Meta-analysis.Pubmed, Cochrane Library, Embase, Scopus, Web of Science and manual search was performed to assess the maxillary growth following SABG in UCL/P patients.Non-syndromic patients with UCL/P.Comparison of maxillary growth between patients with UCL/P who underwent SABG and UCL/P patients who had not undergone SABG or non-cleft control.39 of the identified 233 articles were assessed for inclusion and exclusion criteria after duplicate removal and title and abstract reading. 7 articles (1 prospective, and 6 retrospective studies) were included in the qualitative analysis and 2 articles were subjected to quantitative analysis. Four studies had a low risk of bias and three studies had a moderate risk of bias. Meta-analysis revealed a significant reduction of SNA and no significant difference in ANB in the SABG group compared to the non-cleft control group(I2 = 0%). There was no significant difference in ANB between SABG and non-cleft control; however, results showed high heterogeneity(I2 = 83%). Meta-analysis of SNA and ANB showed no significant difference between SABG and the cleft control group; however, there was high heterogeneity.The studies showed a low to moderate risk of bias. SABG causes inhibition of maxillary growth in patients with cleft lip or palate when compared to patients with non-cleft control. Due to high heterogeneity, comparison to cleft control showed insufficient evidence.