Molecular Mechanisms Underlying Single Nucleotide Polymorphism-Induced Reactivity Decrease in CYP2D6.

Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes involved in drug metabolism. Genetic polymorphism can influence drug metabolism by CYP2D6 such that a therapy is seriously affected by under- or overdosing of drugs. However, a general explanation at the atomistic level for poor activity is missing so far. Here we show for the 20 most common single nucleotide polymorphisms (SNPs) of CYP2D6 that poor metabolism is driven by four mechanisms. We found in extensive all-atom molecular dynamics simulations that the rigidity of the I-helix (central helix), distance between central phenylalanines (stabilizing bound substrate), availability of basic residues on the surface of CYP2D6 (binding of cytochrome P450 reductase), and position of arginine 132 (electron transfer to heme) are essential for an extensive function of the enzyme. These results were applied to SNPs with unknown effects, and potential SNPs that may lead to poor drug metabolism were identified. The revealed molecular mechanisms might be important for other drug-metabolizing cytochrome P450 enzymes.

Single cell regulatory architecture of human pancreatic islets suggests sex differences in ß cell function and the pathogenesis of type 2 diabetes.

Type 2 and type 1 diabetes (T2D, T1D) exhibit sex differences in insulin secretion, the mechanisms of which are unknown. We examined sex differences in human pancreatic islets from 52 donors with and without T2D combining single cell RNA-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), hormone secretion, and bioenergetics. In nondiabetic (ND) donors, sex differences in islet cells gene accessibility and expression predominantly involved sex chromosomes. Islets from T2D donors exhibited similar sex differences in sex chromosomes differentially expressed genes (DEGs), but also exhibited sex differences in autosomal genes. Comparing ß cells from T2D vs. ND donors, gene enrichment of female ß cells showed suppression in mitochondrial respiration, while male ß cells exhibited suppressed insulin secretion. Thus, although sex differences in gene accessibility and expression of ND ß cells predominantly affect sex chromosomes, the transition to T2D reveals sex differences in autosomes highlighting mitochondrial failure in females.

Materials descriptors for advanced water dissociation catalysts in bipolar membranes.

The voltage penalty driving water dissociation (WD) at high current density is a major obstacle in the commercialization of bipolar membrane (BPM) technology for energy devices. Here we show that three materials descriptors, that is, electrical conductivity, microscopic surface area and (nominal) surface-hydroxyl coverage, effectively control the kinetics of WD in BPMs. Using these descriptors and optimizing mass loading, we design new earth-abundant WD catalysts based on nanoparticle SnO2 synthesized at low temperature with high conductivity and hydroxyl coverage. These catalysts exhibit exceptional performance in a BPM electrolyser with low WD overvoltage (ηwd) of 100 ± 20 mV at 1.0 A cm-2. The new catalyst works equivalently well with hydrocarbon proton-exchange layers as it does with fluorocarbon-based Nafion, thus providing pathways to commercializing advanced BPMs for a broad array of electrolysis, fuel-cell and electrodialysis applications.

Laser-Assisted Lingual Frenectomy: A Case Report.

A lingual frenectomy is a surgical procedure aimed at addressing "tongue-tie" or ankyloglossia, where a strip of tissue restricting tongue movement is removed. Typically, this strip extends from the bottom of the mouth to the underside of the tongue. The procedure, often performed using a diode laser, offers several advantages including simplicity and safety for patients. It can significantly improve speech articulation and eating for individuals with ankyloglossia. This case report highlights the successful treatment of a female patient experiencing speech difficulties with diode laser therapy for tongue-tie.

Laser-Assisted Treatment for Maxillary Peripheral Odontogenic Fibroma: A Case Report.

Most odontogenic tumors are intraosseous growths. A peripheral odontogenic fibroma presents as a slow-growing and firm swelling on the gingiva. It develops more commonly on the mandibular than the maxillary region. It can be found on either the palatal or lingual and on the labial or buccal surface of the jaw. It usually does not ulcerate. The most common type is a peripheral odontogenic fibroma, which is a benign odontogenic neoplasm of the periodontal soft tissues. In this case report, a 53-year-old male patient with peripheral odontogenic fibroma was treated using a laser.

Conventional Scalpel Technique for Frenectomy During Orthodontic Treatment: A Case Report.

Frenum aberrations in the maxillary and mandibular regions are pivotal concerns, particularly regarding midline diastema and gingival health. The frenum is composed predominantly of collagenous and elastic fibers. There are various frenal attachment anomalies that may result in gingival recession. Amidst treatment options, conventional scalpel frenectomy emerges as a viable solution, showcasing its efficacy in addressing deviant frena. Ultimately, our findings underscore the imperative for personalized interventions to alleviate aesthetic apprehensions and uphold periodontal integrity in adult populations.

Monovalent cation binding to model systems and the macrocyclic depsipeptide, emodepside.

This study focuses on the systematic exploration of the emodepside conformations bound to monovalent K+ ion using quantum mechanical density functional theory (DFT) calculations at the M06-2X/6-31+G(d,p) level of theory. Nine conformers of emodepside and their complexes with K+ ion were characterized as stationary points on the potential energy surface. The conformational isomers were examined for their 3D structures, bonding, energetics, and interactions with the cation. A cavitand-like structure (CC) is identified to be the energetically most stable arrangement. To arrive at a better understanding of the K+ ion binding, calculations were initially performed on complexes formed by the K+ and Na+ ions with model ligands (methyl ester and N,N-dimethyl acetamide). Both the natural bond orbital (NBO) method and the block-localized wavefunction (BLW) energy decomposition approach was employed to assess the bonding and energetic contributions stabilizing the ion-bound model complexes. Finally, the solvent effect was evaluated through complete geometry optimizations and energy minimizations for the model ion-ligand complexes and the emodepside-K+ bound complexes using an implicit solvent model mimicking water and DMSO.

Role of Oxidative Stress in Periodontal Diseases.

Periodontal disease, a significant worldwide health burden, is characterized by chronic inflammation and destruction of periodontal tissues, including the cementum, periodontal ligament (PDL), alveolar bone, and gingival tissue. Recent research has linked the development and progression of periodontal disease to oxidative stress. This study provides comprehensive explanations of the mechanisms behind oxidative stress in periodontal disease, with a focus on the generation of reactive oxygen species (ROS) and their effects on periodontal tissues. Oxidative stress triggers a number of detrimental reactions, including lipid peroxidation, protein oxidation, and damage to deoxyribonucleic acid (DNA). Alveolar bone resorption, connective tissue degradation, and periodontal inflammation are further conditions exacerbated by these processes. In addition, the delicate balance between antioxidants and oxidants is upset by oxidative stress, which impairs antioxidant defense systems and exacerbates periodontal tissue damage. This review highlights the negative effects of oxidative stress and enhances periodontal health outcomes.

Augmenting authenticity for non-invasive in vivo detection of random blood glucose with photoacoustic spectroscopy using Kernel-based ridge regression.

Photoacoustic Spectroscopy (PAS) is a potential method for the noninvasive detection of blood glucose. However random blood glucose testing can help to diagnose diabetes at an early stage and is crucial for managing and preventing complications with diabetes. In order to improve the diagnosis, control, and treatment of Diabetes Mellitus, an appropriate approach of noninvasive random blood glucose is required for glucose monitoring. A polynomial kernel-based ridge regression is proposed in this paper to detect random blood glucose accurately using PAS. Additionally, we explored the impact of the biological parameter BMI on the regulation of blood glucose, as it serves as the primary source of energy for the body's cells. The kernel function plays a pivotal role in kernel ridge regression as it enables the algorithm to capture intricate non-linear associations between input and output variables. Using a Pulsed Laser source with a wavelength of 905 nm, a noninvasive portable device has been developed to collect the Photoacoustic (PA) signal from a finger. A collection of 105 individual random blood glucose samples was obtained and their accuracy was assessed using three metrics: Root Mean Square Error (RMSE), Mean Absolute Difference (MAD), and Mean Absolute Relative Difference (MARD). The respective values for these metrics were found to be 10.94 (mg/dl), 10.15 (mg/dl), and 8.86%. The performance of the readings was evaluated through Clarke Error Grid Analysis and Bland Altman Plot, demonstrating that the obtained readings outperformed the previously reported state-of-the-art approaches. To conclude the proposed IoT-based PAS random blood glucose monitoring system using kernel-based ridge regression is reported for the first time with more accuracy.

Bioprospecting of multi-stress tolerant Pseudomonas sp. antagonistic to Rhizoctonia solani for enhanced wheat growth promotion.

Salt affected cotton rhizospheric soil was explored for multi-stress resistance microbes to obtain 46 rhizobacteria. Of these, seven strains strongly inhibited the growth of phytopathogenic fungus Rhizoctonia solani by virtue of antifungal compound 2,4-diacetylphloroglucinol (DAPG) production. These seven strains demonstrated an array of plant growth-promoting activities as follows: (i) production of indole-3-acetic acid, ammonia, siderophore; (ii) solubilisation of phosphate, while two isolates showed Zn solubilisation. The phenetic and 16S ribotyping revealed affiliation of all the isolates to Pseudomonas guariconensis and presence of phlD gene marker for DAPG production. Among the seven isolates, strain VDA8 showed the highest DAPG production (0.16 µg ml-1) in liquid synthetic medium under aerobic conditions at 28 °C. Furthermore, sucrose, peptone, sodium hydrogen phosphate, ZnSO4, pH 8.0, and NaCl (1%) were observed as the best carbon, nitrogen, phosphate, trace element, pH, and salt concentration, respectively for maximum production of DAPG by strain VDA8 (3.62 ± 0.04 µg ml-1). The strain VDA8 was further assessed for wheat (Triticum aestivum) growth promotion by seed biopriming under laboratory (plate assay) and field condition in alkaline saline soil with pH 8.5. The field scale (324 m2) trials demonstrated 28.6% enhanced grain production compared to control demonstrating the newly isolated Pseudomonas sp. as multi-potent bioinoculant.

Single cell regulatory architecture of human pancreatic islets suggests sex differences in ß cell function and the pathogenesis of type 2 diabetes.

Biological sex affects the pathogenesis of type 2 and type 1 diabetes (T2D, T1D) including the development of ß cell failure observed more often in males. The mechanisms that drive sex differences in ß cell failure is unknown. Studying sex differences in islet regulation and function represent a unique avenue to understand the sex-specific heterogeneity in ß cell failure in diabetes. Here, we examined sex and race differences in human pancreatic islets from up to 52 donors with and without T2D (including 37 donors from the Human Pancreas Analysis Program [HPAP] dataset) using an orthogonal series of experiments including single cell RNA-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), dynamic hormone secretion, and bioenergetics. In cultured islets from nondiabetic (ND) donors, in the absence of the in vivo hormonal environment, sex differences in islet cell type gene accessibility and expression predominantly involved sex chromosomes. Of particular interest were sex differences in the X-linked KDM6A and Y-linked KDM5D chromatin remodelers in female and male islet cells respectively. Islets from T2D donors exhibited similar sex differences in differentially expressed genes (DEGs) from sex chromosomes. However, in contrast to islets from ND donors, islets from T2D donors exhibited major sex differences in DEGs from autosomes. Comparing ß cells from T2D and ND donors revealed that females had more DEGs from autosomes compared to male ß cells. Gene set enrichment analysis of female ß cell DEGs showed a suppression of oxidative phosphorylation and electron transport chain pathways, while male ß cell had suppressed insulin secretion pathways. Thus, although sex-specific differences in gene accessibility and expression of cultured ND human islets predominantly affect sex chromosome genes, major differences in autosomal gene expression between sexes appear during the transition to T2D and which highlight mitochondrial failure in female ß cells.

Radiographic Evaluation in Implant Patients: A Review.

Diagnostic imaging is crucial in assessing dental implant patients. The height, width, and shape of the bone are precisely depicted and measured by these tests, which help pinpoint the locations of significant anatomical structures adjacent to the implant placement sites. The type of implant to be utilized, the positioning of the remaining dentition, and the degree to which bone quality or quantity is in question all play a role in determining the radiologic approach that is most suited for a given patient. This review is an update on the current knowledge in the field of radiographic evaluation in implant placement. Considering the radiation exposure and the expense of each test, it is important to carefully determine whether pre-implant imaging is acceptable in each situation. Although multislice computed tomography is the gold standard from the authors' perspective, not every implant situation can justify such a test.

Ammonia is associated with liver-related complications and predicts mortality in acute-on-chronic liver failure patients.

The relationship between ammonia and liver-related complications (LRCs) in acute-on-chronic liver failure (ACLF) patients is not clearly established. This study aimed to evaluate the association between ammonia levels and LRCs in patients with ACLF. The study also evaluated the ability of ammonia in predicting mortality and progression of LRCs. The study prospectively recruited ACLF patients based on the APASL definition from the ACLF Research Consortium (AARC) from 2009 to 2019. LRCs were a composite endpoint of bacterial infection, overt hepatic encephalopathy (HE), and ascites. A total of 3871 cases were screened. Of these, 701 ACLF patients were enrolled. Patients with LRCs had significantly higher ammonia levels than those without. Ammonia was significantly higher in patients with overt HE and ascites, but not in those with bacterial infection. Multivariate analysis found that ammonia was associated with LRCs. Additionally, baseline arterial ammonia was an independent predictor of 30-day mortality, but it was not associated with the development of new LRCs within 30 days. In summary, baseline arterial ammonia levels are associated with 30-day mortality and LRCs, mainly overt HE and ascites in ACLF patients.

Molecular Property Diagnostic Suite for COVID-19 (MPDSCOVID-19): an open-source disease-specific drug discovery portal.

Molecular Property Diagnostic Suite (MPDS) was conceived and developed as an open-source disease-specific web portal based on Galaxy. MPDSCOVID-19 was developed for COVID-19 as a one-stop solution for drug discovery research. Galaxy platforms enable the creation of customized workflows connecting various modules in the web server. The architecture of MPDSCOVID-19 effectively employs Galaxy v22.04 features, which are ported on CentOS 7.8 and Python 3.7. MPDSCOVID-19 provides significant updates and the addition of several new tools updated after six years. Tools developed by our group in Perl/Python and open-source tools are collated and integrated into MPDSCOVID-19 using XML scripts. Our MPDS suite aims to facilitate transparent and open innovation. This approach significantly helps bring inclusiveness in the community while promoting free access and participation in software development. Availability & Implementation: The MPDSCOVID-19 portal can be accessed at https://mpds.neist.res.in:8085/.

Surgical Excision of Localized Gingival Overgrowth Using Laser: A Case Report.

Gingival overgrowth, localized or generalized, is one of the leading causes of poor maintenance of oral hygiene. Excision of growth using laser should be the choice of treatment because laser helps maintain a blood-free surgical site during treatment and provides more patient comfort during and after the procedure. Lasers are commonly employed in many different applications, including scaling, root planning, cavity preparation, and excision of soft tissue growths in surgery. Laser therapy offers numerous benefits over traditional methods of treatment. These benefits have led to the growing use of lasers as dental treatment options in a variety of dental fields. In this case report, we are presenting a case of excision of localized gingival growth using a laser. Postoperative healing and maintenance of oral health were satisfied after laser surgery.

L→S Coordination Complexes Containing Benzothiazol-2-ylidene Ligand: Quantum Chemical Analysis and Synthesis.

(NHC)→E coordination interactions were known where NHC is an N-heterocyclic carbene, and E is a main group element (B, C, N, Si, P). Recently, it was suggested that compounds with (NHC)→S coordination chemistry are also possible. This work reports quantum chemical analysis and synthesis of (NHC)→S-R(+) complexes in which benzothiazol-2-ylidene acts as a ligand. A Density functional study established that (NHC)→S interaction can best be described as a coordination interaction. Synthetic efforts were made, initially, to generate divalent sulfur compounds containing benzothiazole substituents. N-alkylation of the heterocyclic ring in these sulfides using methyl triflate led to the generation of the desired products with (NHC)→S coordination chemistry, which involves the in situ generation of NHC ring ligands. The observed changes in the 13C NMR spectra, before and after methylation, confirmed the change in the electronic character of the C-S bond from a covalent character to a coordination character.

Radiographic assessment of maxillary sinus membrane and lateral wall thickness using cone-beam CT in different facial types in southwestern Saudi Arabia.

The anatomy of the edentulous posterior maxilla and maxillary sinus possess unique challenges in implant dentistry. The purpose of this study was to assess maxillary sinus membrane thickness (MT) and lateral wall thickness (LWT) in different facial index profiles and to describe the clinical implications. A retrospective image analysis of 75 CBCT scans was done, which yielded a total of 150 sinus images. The facial index was calculated as per the formula given in the text and grouped as euryprosopic, mesoprosopic and leptoprosopic. The images obtained were of 36 women (48%) and 39 men (52%), with maximum subjects in 30-39 years age group. MT and LWT were measured at three different points on the radiograph at every 3mm from the base of the sinus floor in premolar and molar regions of each image. Results showed females had significant differences from males in LWT in both premolar and molar regions (p = 0.018 and 0.032 respectively). Subjects in 40-49 years of age had significant differences (p = 0.021) in MT in premolar region only. Also, difference in MT in premolar and molar regions were also statistically significant. Lastly, the present study did not find any statistically significant difference in MT and LWT in all three facial indices groups. It can be concluded that different facial indices have no positive correlation with maxillary sinus membrane thickness and lateral wall thickness. Hence, surgical complications are avoidable with proper detailed knowledge and appropriate identification of the anatomic structures characteristic to the maxillary sinus.

Effect of Differential Surface Anisotropy on Dissolution Behavior of Fenofibrate Crystal Habits: Comparative Study using USP Type 2 and Type 4 Dissolution Apparatuses.

The solid-state properties of active pharmaceutical ingredient (API) have significant impact on its dissolution performance. In the present study, two different crystal habits viz. rod and plate shape of form I of FEN were evaluated for dissolution profile using USP Type 2 and Type 4 apparatuses. Molecular basis of differential dissolution performance of different crystal habits was investigated. Rod (FEN-R) and plate (FEN-P) shaped crystal habits of Form I of FEN were generated using anti-solvent crystallization method. Despite the same polymorphic form and similar particle size distribution, FEN-P demonstrated higher dissolution performance than FEN-R. Crystal face indexation and electrostatic potential (ESP) map provided information on differential relative abundance of various facets and their molecular environment. In FEN-R, the dominant facet (001) is hydrophobic due to the exposure of chlorophenyl moiety. Whereas, in FEN-P the dominant facet (01-1) was hydrophilic due to the presence of chlorine and ester carbonyl groups. Deeper insight on the impact of different facets on dissolution behavior was obtained by energy framework analysis by unveiling strength of intermolecular interactions along various crystallographic facets. Moreover, type 4 apparatus provided higher discriminatory ability over USP Type 2 apparatus, in probing the crystal habit induced differential dissolution performance of FEN. The findings of this study emphasize that crystal habit should be considered as an important critical material attribute (CMA) during formulation development of FEN and due considerations should be given to the selection of the appropriate dissolution testing set-up for establishing in vitro-in vivo correlation.

Tofacitinib use in ulcerative colitis: An expert consensus for day-to-day clinical practice.

Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.

Laser-Assisted Gingival Depigmentation: A Case Report.

The gingiva's colour varies in different individuals and is assumed to be related to cutaneous pigmentation. The most frequent natural pigment causing endogenous gingival pigmentation is melanin, a brown pigment. Depigmentation is a therapy of choice when individuals are concerned about their appearance and demand it for their aesthetic satisfaction. It is not a clinical indication. This article demonstrates gingival depigmentation using a laser diode with a 90-day follow­up. A 23-year-old male patient visited the Periodontology Department, complaining of poor aesthetics owing to dark-coloured gums. Depigmentation with a laser diode was selected as the treatment plan for both the maxillary and mandibular arches, at an interval of a week. The choice of a procedure is largely influenced by the gingival thickness, the clinician's experience, the patient's preferences, and the rate of recurrence. According to reports, using lasers produces better aesthetic outcomes and has a low recurrence rate.