Machine Learning Models for Predicting Molecular UV-Vis Spectra with Quantum Mechanical Properties.

Accurate understanding of ultraviolet-visible (UV-vis) spectra is critical for the high-throughput synthesis of compounds for drug discovery. Experimentally determining UV-vis spectra can become expensive when dealing with a large quantity of novel compounds. This provides us an opportunity to drive computational advances in molecular property predictions using quantum mechanics and machine learning methods. In this work, we use both quantum mechanically (QM) predicted and experimentally measured UV-vis spectra as input to devise four different machine learning architectures, UVvis-SchNet, UVvis-DTNN, UVvis-Transformer, and UVvis-MPNN, and assess the performance of each method. We find that the UVvis-MPNN model outperforms the other models when using optimized 3D coordinates and QM predicted spectra as input features. This model has the highest performance for predicting UV-vis spectra with a training RMSE of 0.06 and validation RMSE of 0.08. Most importantly, our model can be used for the challenging task of predicting differences in the UV-vis spectral signatures of regioisomers.

Near Infrared Fluorescence Imaging to Demonstrate Reflux in the Superficial Microvenous Network of the Leg.

OBJECTIVE: Reflux within the superficial microvenous network may play a critical role in the development of skin changes which can be associated with chronic venous insufficiency. This study aimed to determine if near infrared fluorescence (NIRF) imaging could be used to accurately determine superficial venous reflux in the leg. METHODS: A total of nine limbs were examined ex vivo from patients undergoing limb amputation for peripheral arterial disease. Cannulation of the distal great saphenous vein was used to sequentially perform Xray contrast enhanced venography, NIRF imaging, and venous corrosion casts. RESULTS: Fluorescence imaging visualised a range of different microvenous reflux patterns ex vivo, which were generally not evident by Xray venography but were consistent with retrograde resin vascular casts. These included both focal and diffuse regions of fluorescence within the skin and, consistent with previous observations, the vascular casts indicated that regions of venous reflux were typically associated with incompetent valves. CONCLUSION: The findings from this study suggest a potential method for investigating early stage superficial venous disease, prior to the appearance of visible signs of advanced venous disease, such as skin changes. However, further studies are required to confirm the in vivo clinical utility of these observations.

Could the median-palate accommodate wide-bodied implants in order to support maxillary over-dentures? A radiomorphometric study of human cadavers.

INTRODUCTION: Atrophy of the alveolar bone is an irreversible multifactorial phenomenon, the rate of which varies between individuals and between the jaws. This atrophy of the alveolar ridges presents severe limitations for the oral rehabilitation of the edentulous patients and poses a clinical challenge to the prosthodontists and implant surgeons. The present research aimed to investigate whether the median-palate of elderly edentulous subjects is anatomically suitable for implant placement. MATERIALS AND METHODS: A total of 32 samples were harvested from the maxillae of 16 human cadavers. One dentate male subject was included for contrast. Bone quality and quantity were analysed at two regions: the median-palate and the edentulous maxillary alveolar ridge. Samples were scanned through micro-CT, and the region of analysis (ROA) identified and dissected. Bone volume to tissue volume ratio (%BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp) and trabecular bone pattern factor (Tb.Pf) were evaluated for the two regions using Skyscan CTAn(®). RESULTS: The results of bone volume fraction obtained from CTAn(®) of the median-palatal region show higher values than the respective premolar sites in 12 of 15 (80%) edentulous samples. However, this difference was statistically non-significant (P = 0.06). Similarly, the trabecular number for 10 of 15 samples (66.6%) from the median-palate shows greater values than the respective premolar site (P = 0.07). Trabecular thickness of 10 of 15 (66.6%) premolar samples is larger than in the median-palatal region. However, these differences were also statistically non-significant (P = 0.25). Statistically significant difference (P = 0.04) was found between the Tb.Sp values of the two regions. CONCLUSION: The results indicate that the anterior median-palate is structurally better than their respective maxillary premolar region in elderly edentulous persons, and an implant can be placed to anchor an overdenture. The best site for a wide-body implant was established to be 6-8 mm posterior to the incisive foramen in elderly edentulous patients.

Leveraging Artificial Intelligence to Expedite Antibody Design and Enhance Antibody-Antigen Interactions.

This perspective sheds light on the transformative impact of recent computational advancements in the field of protein therapeutics, with a particular focus on the design and development of antibodies. Cutting-edge computational methods have revolutionized our understanding of protein-protein interactions (PPIs), enhancing the efficacy of protein therapeutics in preclinical and clinical settings. Central to these advancements is the application of machine learning and deep learning, which offers unprecedented insights into the intricate mechanisms of PPIs and facilitates precise control over protein functions. Despite these advancements, the complex structural nuances of antibodies pose ongoing challenges in their design and optimization. Our review provides a comprehensive exploration of the latest deep learning approaches, including language models and diffusion techniques, and their role in surmounting these challenges. We also present a critical analysis of these methods, offering insights to drive further progress in this rapidly evolving field. The paper includes practical recommendations for the application of these computational techniques, supplemented with independent benchmark studies. These studies focus on key performance metrics such as accuracy and the ease of program execution, providing a valuable resource for researchers engaged in antibody design and development. Through this detailed perspective, we aim to contribute to the advancement of antibody design, equipping researchers with the tools and knowledge to navigate the complexities of this field.

Trabecular bone microarchitecture in the median palate and maxillary premolar alveolar sites of edentulous elderly cadavers.

PURPOSE: The median palate has been proposed as an alternative site for implant placement supporting maxillary overdentures. The aim of our research was to compare the histologic bone microarchitecture of the median palatal and the maxillary premolar alveolar ridge in edentulous elderly human cadavers. MATERIALS AND METHODS: The bone quality and quantity were analyzed at two regions of analysis (ROA) in 16 maxilla of human cadavers: the median palate (ROA I) and edentulous maxillary alveolar premolar ridge (ROA II). Histomorphometry of the scanned images was performed using image analysis software (National Institutes of Health ImageJ). The bone volume/tissue volume ratio, trabecular thickness, trabecular separation, and trabecular number were evaluated for the two regions. RESULTS: The bone volume fraction of the median-palatal region (ROA I) was greater than at the respective premolar sites (ROA II) in 10 of 15 samples (66.6%), with mean values ranging from 19.3-61.3%. However, the results were not statistically significant (P = .151). Similarly, the trabecular number of ROA II showed greater values than that for ROA II (mean TbN for ROA I, 1.03 mm(-1) and for ROA II, 0.96 mm(-1)). However, these differences were not statistically significant (P = .454). CONCLUSIONS: These results have indicated that the anterior median palate is structurally similar to the corresponding maxillary premolar region in elderly edentulous persons. Therefore, it can be used as an implant site to anchor a maxillary overdenture in patients with atrophic maxillary ridges.

Exceptional T CD4+ Recovery Post-antiretroviral Is Linked to a Lower HIV Reservoir with a Specific Immune Differentiation Pattern.

We present a cohort of individuals who reached CD4+ T cell counts of greater than 1,000 cells/mm3 (Hypers) after starting antiretroviral treatment (ART) and compared them with those who reached between 350 and 999 CD4+ T cells/mm3 (Concordants). Demographic data, immune recovery kinetics, T CD4+ subset phenotypes, and integrated HIV DNA were analyzed. Data from individuals living with HIV on their first ART regimen and after 48 months of follow-up were obtained. Immune phenotype by Flow Cytometry analysis on whole blood was performed, cytokines were measured, and integrated HIV-1 DNA was measured by polymerase chain reaction. From a total of 424 individuals, 26 Hypers (6.1%), 314 Concordants (74.1%), and 84 (19.8%) discordants were identified. Hypers had a higher proportion of CD4+-naive (Nv) T cells (37.6 vs. 24.8, p < .05), and a low proportion of CD4+ effector memory T cells (27.9 vs. 39.4, p < .05), with similar results found in CD8+ T cells. Hypers demonstrated a higher percentage of CD4+CD45RA+CD31neg cells with a lower response to interleukin-2 stimulation and a lower integrated HIV-1 DNA/CD4 ratio (1.2 vs. 2.89, p < .05). In Hypers, T cell recovery occurs very early after initiation of ART. Following this initial recovery state, their CD4+ T cell level homeostasis seems to be driven by nonthymic-central-Nv cells. This exceptional recovery is associated with a lower HIV reservoir, which may be related to an increase in noninfected CD4+ T cells. These patients could then be eligible candidates for cure trials.

Quantum Mechanical Methods Predict Accurate Thermodynamics of Biochemical Reactions.

Thermodynamics plays a crucial role in regulating the metabolic processes in all living organisms. Accurate determination of biochemical and biophysical properties is important to understand, analyze, and synthetically design such metabolic processes for engineered systems. In this work, we extensively performed first-principles quantum mechanical calculations to assess its accuracy in estimating free energy of biochemical reactions and developed automated quantum-chemistry (QC) pipeline (https://appdev.kbase.us/narrative/45710) for the prediction of thermodynamics parameters of biochemical reactions. We benchmark the QC methods based on density functional theory (DFT) against different basis sets, solvation models, pH, and exchange-correlation functionals using the known thermodynamic properties from the NIST database. Our results show that QC calculations when combined with simple calibration yield a mean absolute error in the range of 1.60-2.27 kcal/mol for different exchange-correlation functionals, which is comparable to the error in the experimental measurements. This accuracy over a diverse set of metabolic reactions is unprecedented and near the benchmark chemical accuracy of 1 kcal/mol that is usually desired from DFT calculations.

Bayesian Inference for Integrating Yarrowia lipolytica Multiomics Datasets with Metabolic Modeling.

Optimizing the metabolism of microbial cell factories for yields and titers is a critical step for economically viable production of bioproducts and biofuels. In this process, tuning the expression of individual enzymes to obtain the desired pathway flux is a challenging step, in which data from separate multiomics techniques must be integrated with existing biological knowledge to determine where changes should be made. Following a design-build-test-learn strategy, building on recent advances in Bayesian metabolic control analysis, we identify key enzymes in the oleaginous yeast Yarrowia lipolytica that correlate with the production of itaconate by integrating a metabolic model with multiomics measurements. To this extent, we quantify the uncertainty for a variety of key parameters, known as flux control coefficients (FCCs), needed to improve the bioproduction of target metabolites and statistically obtain key correlations between the measured enzymes and boundary flux. Based on the top five significant FCCs and five correlated enzymes, our results show phosphoglycerate mutase, acetyl-CoA synthetase (ACSm), carbonic anhydrase (HCO3E), pyrophosphatase (PPAm), and homoserine dehydrogenase (HSDxi) enzymes in rate-limiting reactions that can lead to increased itaconic acid production.

An in vitro ovarian explant culture system to examine sex change in a hermaphroditic fish.

Many teleost fishes undergo natural sex change, and elucidating the physiological and molecular controls of this process offers unique opportunities not only to develop methods of controlling sex in aquaculture settings, but to better understand vertebrate sexual development more broadly. Induction of sex change in some sequentially hermaphroditic or gonochoristic fish can be achieved in vivo through social manipulation, inhibition of aromatase activity, or steroid treatment. However, the induction of sex change in vitro has been largely unexplored. In this study, we established an in vitro culture system for ovarian explants in serum-free medium for a model sequential hermaphrodite, the New Zealand spotty wrasse (Notolabrus celidotus). This culture technique enabled evaluating the effect of various treatments with 17ß-estradiol (E2), 11-ketotestosterone (11KT) or cortisol (CORT) on spotty wrasse ovarian architecture for 21 days. A quantitative approach to measuring the degree of ovarian atresia within histological images was also developed, using pixel-based machine learning software. Ovarian atresia likely due to culture was observed across all treatments including no-hormone controls, but was minimised with treatment of at least 10 ng/mL E2. Neither 11KT nor CORT administration induced proliferation of spermatogonia (i.e., sex change) in the cultured ovaries indicating culture beyond 21 days may be needed to induce sex change in vitro. The in vitro gonadal culture and analysis systems established here enable future studies investigating the paracrine role of sex steroids, glucocorticoids and a variety of other factors during gonadal sex change in fish.

Induction of osteopenia during experimental tooth movement in the rat: alveolar bone remodelling and the mechanostat theory.

Increases in bone strains above a certain threshold have a positive effect on bone mass, whereas reductions in strain magnitude lead to bone loss and osteopenia; the term 'mechanostat' has been introduced to describe this tissue-level negative feedback mechanism. The mechanobiology of bone and particularly alveolar bone is poorly understood, and whether the mechanostat theory has any relevance to explaining the osseous changes that occur during orthodontic tooth movement remains unclear. To investigate the relationship further, an expansile force of 0.2 N was applied to the maxillary molars of 36, 6-week-old Wistar rats by helical coil springs. The animals were sacrificed at 1, 2, 4, and 8 days and the tissue response analyzed by histological, biochemical, and finite element (FE) methods. Differences between groups were determined by Student's t-test (two-tailed). The appliance produced an increase in the intermolar width averaging 0.5 mm after 8 days. Tetracycline uptake in the control rats suggested a rapid turnover of bone in both the interradicular domain and the bone-periodontal ligament interface. In the experimental group, however, incorporation of tetracycline into the interradicular domain was reduced and conventional histology revealed evidence of bone loss and osteopenia, in both the experimental and a group of sham-treated positive controls (with inactive, annealed springs). Serum alkaline phosphatase declined significantly in both experimental and sham-treated groups over the 8-day time course, indicating decreased bone formation. Serum acid phosphatase also declined, suggesting a concomitant decrease in bone resorption. Three-dimensional FE analysis of the stresses generated in the bone following occlusal (2 N) and orthodontic loading showed that the orthodontic force created a constant loading condition shielding some areas of bone from mechanical stress. Areas of low mechanical stimulation were coincident with sites of bone loss observed histologically, while bone mass was preserved in areas with higher levels of loading. These findings suggest that (1) the osteopenia resulted from stress shielding of the interradicular bone by the appliance, and a consequent reduction in occlusal loading below the critical threshold required for maintaining normal osseous architecture and (2) the mechanostat model can be employed to explain, at least in part, the response of the bone to orthodontic loading.

Characterization of the Fishing Lines in Titiwai (=Arachnocampa luminosa Skuse, 1890) from New Zealand and Australia.

Animals use adhesive secretions in a plethora of ways, either for attachment, egg anchorage, mating or as either active or passive defence. The most interesting function, however, is the use of adhesive threads to capture prey, as the bonding must be performed within milliseconds and under unsuitable conditions (movement of prey, variable environmental conditions, unfavourable attack angle, etc.) to be nonetheless successful. In the following study a detailed characterization of the prey capture system of the world-renowned glowworm group Arachnocampa from the macroscopic to the ultrastructural level is performed. The data reveal that the adhesive droplets consist mostly of water and display hygroscopic properties at varying humidity levels. The droplet core of Arachnocampa luminosa includes a certain amount of the elements sodium, sulphur and potassium (beside carbon, oxygen and nitrogen), while a different element composition is found in the two related species A. richardsae and A. tasmaniensis. Evidence for lipids, carbohydrates and proteins was negative on the histochemical level, however X-ray photoelectron spectroscopy confirm the presence of peptides within the droplet content. Different to earlier assumptions, the present study indicates that rather than oxalic acid, urea or uric acid are present in the adhesive droplets, presumably originating from the gut. Comparing the capture system in Arachnocampa with those of orb-spiders, large differences appear not only regarding the silky threads, but also, in the composition, hygroscopic properties and size of the mucous droplets.

Infection of apical dentin and root-end cavity disinfection.

INTRODUCTION: The purpose of this study was to assess Enterococcus faecalis penetration into the dentin of the apical 3 mm and bacterial death after the application of either chlorhexidine or laser to root-end cavities. METHODS: Root canals of 60 single-rooted teeth were prepared. In part 1, cementum was removed semicircumferentially from 21 roots, and the smear layer was removed from 15 roots using 17% EDTA/cetrimide. Teeth were inoculated and incubated with E. faecalis for 10 days, rinsed, and live/dead stained. The effect of cementum and smear on bacterial penetration was assessed by confocal laser scanning microscopy (CLSM). In part 2, 39 teeth had root ends resected and cavities ultrasonically prepared. Inoculated roots were assigned to 1 of the following 3 groups: (1) root-end cavities irrigated with 0.2 % chlorhexidine, (2) root-end cavities irradiated with a laser for 20 seconds at 1.5 W, or (3) root-end cavities that received no treatment. Roots were live/dead stained, sectioned, and examined by CLSM. The depth of the bacterial penetration and bacterial survival were compared using the Mann-Whitney U test. RESULTS: The presence of a smear layer and/or cementum did not significantly affect bacterial penetration. In root-end cavities, chlorhexidine was more effective than laser (P < .001), reducing bacterial viability by 93% versus 70% with a laser. CONCLUSIONS: E. faecalis invaded the entire width of dentin in the apical 3 mm irrespective of the smear layer and/or cementum. Chlorhexidine was more effective than laser in disinfecting root-end cavities.

Bacterial viability determination in a dentinal tubule infection model by confocal laser scanning microscopy.

Dentinal tubule invasion protects bacteria from chemo-mechanical disinfection and frequently results in root canal treatment failures. Enterococcus faecalis is a primary causative agent, particularly in persistent, asymptomatic, and chronic apical periodontitis. In order to assess and compare the efficacies of endodontic antimicrobial agents and application strategies, we have developed a convenient and robust method to measure bacterial viability and assess distribution in an ex vivo tubule infection model. Following infection and antimicrobial treatment of prepared ex vivo roots, the tubule bacteria are exposed to nucleic acid-binding fluorescent stains (LIVE/DEAD BacLight stain), sectioned, and examined by confocal laser scanning microscopy. The proportion of red-fluorescing (dead) and green-fluorescing (live) bacteria is then visualized in situ and quantified with image analysis software.