Possible Strategies to Reduce the Tumorigenic Risk of Reprogrammed Normal and Cancer Cells.

The reprogramming of somatic cells to pluripotent stem cells has immense potential for use in regenerating or redeveloping tissues for transplantation, and the future application of this method is one of the most important research topics in regenerative medicine. These cells are generated from normal cells, adult stem cells, or neoplastic cancer cells. They express embryonic stem cell markers, such as OCT4, SOX2, and NANOG, and can differentiate into all tissue types in adults, both in vitro and in vivo. However, tumorigenicity, immunogenicity, and heterogeneity of cell populations may hamper the use of this method in medical therapeutics. The risk of cancer formation is dependent on mutations of these stemness genes during the transformation of pluripotent stem cells to cancer cells and on the alteration of the microenvironments of stem cell niches at genetic and epigenetic levels. Recent reports have shown that the generation of induced pluripotent stem cells (iPSCs) derived from human fibroblasts could be induced using chemicals, which is a safe, easy, and clinical-grade manufacturing strategy for modifying the cell fate of human cells required for regeneration therapies. This strategy is one of the future routes for the clinical application of reprogramming therapy. Therefore, this review highlights the recent progress in research focused on decreasing the tumorigenic risk of iPSCs or iPSC-derived organoids and increasing the safety of iPSC cell preparation and their application for therapeutic benefits.

Forecasting fish mortality from water and air quality data using deep learning models.

The high rate of aquatic mortality incidents recorded in Taiwan and worldwide is creating an urgent demand for more accurate fish mortality prediction. Present study innovatively integrated air and water quality data to measure water quality degradation, and utilized deep learning methods to predict accidental fish mortality from the data. Keras library was used to build multilayer perceptron and long short-term memory models for training purposes, and the models' accuracies in fish mortality prediction were compared with that of the naïve Bayesian classifier. Environmental data from the 5 days before a fish mortality event proved to be the most important data for effective model training. Multilayer perceptron model reached an accuracy of 93.4%, with a loss function of 0.01, when meteorological and water quality data were jointly considered. It was found that meteorological conditions were not the sole contributors to fish mortality. Predicted fish mortality rate of 4.7% closely corresponded to the true number of fish mortality events during the study period, that is, four. A significant surge in fish mortality, from 20% to 50%, was noted when the river pollution index increased from 5.36 to 6.5. Moreover, the probability of fish mortality increased when the concentration of dissolved oxygen dropped below 2 mg/L. To mitigate fish mortality, ammonia nitrogen concentrations should be capped at 5 mg/L. Dissolved oxygen concentration was found to be the paramount factor influencing fish mortality, followed by the river pollution index and meteorological data. Results of the present study are expected to aid progress toward achieving the Sustainable Development Goals and to increase the profitability of water resources.

Imputation accuracy across global human populations.

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of references from non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative improved the imputation of admixed African-ancestry and Hispanic/Latino samples, but imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we imputed the genotypes of over 43,000 individuals across 123 populations around the world and identified numerous populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for variants with minor allele frequencies between 1% and 5% in Saudi Arabians (n = 1,061), Vietnamese (n = 1,264), Thai (n = 2,435), and Papua New Guineans (n = 776) were 0.79, 0.78, 0.76, and 0.62, respectively, compared to 0.90-0.93 for comparable European populations matched in sample size and SNP array content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European-ancestry reference increased, as predicted. Using sequencing data as ground truth, we also showed that Rsq may over-estimate imputation accuracy for non-European populations more than European populations, suggesting further disparity in accuracy between populations. Using 1,496 sequenced individuals from Taiwan Biobank as a second reference panel to TOPMed, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, but this design did not improve accuracy across frequency spectra. Taken together, our analyses suggest that we must ultimately strive to increase diversity and size to promote equity within genetics research.

Association of the AhR, ARNT, and AhRR gene polymorphisms and cord blood AhR levels with elevated cord blood IgE susceptibility in Taiwan mother-infant pairs: a nested case-control study.

The roles of aryl hydrocarbon receptor (AhR), AhR-nuclear translocator (ARNT), and AhR repressor (AhRR) genes in the elevation of cord blood IgE (CbIgE) remained unclear. Our aims were to determine the polymorphisms of AhR, ARNT, and AhRR genes, cord blood AhR (CBAhR) level, and susceptibility to elevation of CbIgE. 206 infant-mother pairs with CbIgE>=0.35 IU/ml and 421 randomly selected controls recruited from our previous study. Genotyping was determined using TaqMan assays. Statistical analysis showed AhR rs2066853 (GG vs. AA+AG: adjusted OR (AOR)=1.5, 95%CI=1.10-2.31 and AOR=1.60, 95%CI=1.06-2.43, respectively) and the combination of AhR rs2066853 and maternal total IgE (mtIgE)>=100 IU/ml were significantly correlated with CbIgE>=0.35 IU/ml or CbIgE>=0.5 IU/ml. CBAhR in a random subsample and CbIgE levels were significantly higher in infants with rs2066853GG genotype. We suggest that infant AhR rs2066853 and their interactions with mtIgE>=100 IU/ml significantly correlate with elevated CbIgE, but AhRR and ARNT polymorphisms do not.

Di-n-butyl phthalate promotes the neural differentiation of mouse embryonic stem cells through neurogenic differentiation 1.

An understanding of the risk of gene deletion and mutation posed by endocrine-disrupting chemicals (EDCs) is necessary for the identification of etiological reagents for many human diseases. Therefore, the characterization of the genetic traits caused by developmental exposure to EDCs is an important research subject. A new regenerative approach using embryonic stem cells (ESCs) holds promise for the development of stem-cell-based therapies and the identification of novel therapeutic agents against human diseases. Here, we focused on the characterization of the genetic traits and alterations in pluripotency/stemness triggered by phthalate ester derivatives. Regarding their in vitro effects, we reported the abilities of ESCs regarding proliferation, cell-cycle control, and neural ectoderm differentiation. The expression of their stemness-related genes and their genetic changes toward neural differentiation were examined, which led to the observation that the tumor suppressor gene product p53/retinoblastoma protein 1 and its related cascades play critical functions in cell-cycle progression, cell death, and neural differentiation. In addition, the expression of neurogenic differentiation 1 was affected by exposure to di-n-butyl phthalate in the context of cell differentiation into neural lineages. The nervous system is one of the most sensitive tissues to exposure to phthalate ester derivatives. The present screening system provides a good tool for studying the mechanisms underlying the effects of EDCs on the developmental regulation of humans and rodents, especially on the neuronal development of ESCs.

Acute high-intensity interval exercise improves food-related cognition in young adults with obesity: An ERP study / El ejercicio agudo en intervalos de alta intensidad mejora la cognición relacionada con los alimentos en adultos jóvenes con obesidad: un estudio ERP

Purpose Cognitive function, particularly food-related cognition, is critical for maintaining a healthy weight and preventing the acceleration of obesity. High-Intensity Interval Exercise (HIIE) is an increasingly popular form of exercise and has been shown to improve physical fitness and cognitive function. However, there is limited research on the effects and underlying mechanisms of HIIE on general and food-related cognition among adults with obesity. The aim of the current study was to examine the influence of a single bout of HIIE on food-related cognition among young adults with obesity. Methods Fifteen young men with obesity (BMI = 33.88 ± 4.22, age = 24.60 ± 5.29 years) were recruited. Participants took part in a HIIE condition consisting of 30 minutes of stationary cycle exercise (5-min warm-up, 20-min HIIE and 5-min cool down), and a control session consisting of a time and attention-matched period of sedentary rest in a counterbalanced order. Behavioral (reaction time and accuracy) and event-related potential measures (P3 and the late positive potential, LPP) elicited during a food-related Flanker task were measured after the HIIE and control session. Results Shorter response times were observed following HIIE, regardless of congruency or picture type, with no change in accuracy. Increased P3 and LPP amplitudes were observed following HIIE relative to the control session. Conclusion The findings suggest a single bout of HIIE has a beneficial effect on general and food-related cognition among young adults with obesity, with increased recruitment of cognitive resources to support cognitive control. Future research is warranted to examine the dose-response relationship between acute bouts or longer participation in HIIE on food-related cognition in obesity.(AU)

Acute high-intensity interval exercise improves food-related cognition in young adults with obesity: An ERP study.

Purpose Cognitive function, particularly food-related cognition, is critical for maintaining a healthy weight and preventing the acceleration of obesity. High-Intensity Interval Exercise (HIIE) is an increasingly popular form of exercise and has been shown to improve physical fitness and cognitive function. However, there is limited research on the effects and underlying mechanisms of HIIE on general and food-related cognition among adults with obesity. The aim of the current study was to examine the influence of a single bout of HIIE on food-related cognition among young adults with obesity. Methods Fifteen young men with obesity (BMI = 33.88 ± 4.22, age = 24.60 ± 5.29 years) were recruited. Participants took part in a HIIE condition consisting of 30 minutes of stationary cycle exercise (5-min warm-up, 20-min HIIE and 5-min cool down), and a control session consisting of a time and attention-matched period of sedentary rest in a counterbalanced order. Behavioral (reaction time and accuracy) and event-related potential measures (P3 and the late positive potential, LPP) elicited during a food-related Flanker task were measured after the HIIE and control session. Results Shorter response times were observed following HIIE, regardless of congruency or picture type, with no change in accuracy. Increased P3 and LPP amplitudes were observed following HIIE relative to the control session. Conclusion The findings suggest a single bout of HIIE has a beneficial effect on general and food-related cognition among young adults with obesity, with increased recruitment of cognitive resources to support cognitive control. Future research is warranted to examine the dose-response relationship between acute bouts or longer participation in HIIE on food-related cognition in obesity.

Effect of acute concurrent exercise training and the mediating role of lactate on executive function: An ERP study.

Both acute aerobic (AE) and resistance exercise (RE) have been acknowledged to be effective methods in enhancing executive function and brain-related P3 amplitudes. Nevertheless, the effect of acute concurrent exercise training (CET), combining both AE and RE, on executive function remains subject to speculation. Moreover, investigation of the mechanisms that underlie improvements in executive function would facilitate scientific understanding. Notably, lactate has emerged as a candidate among several potential mechanisms. Therefore, the main aim of the present study was to investigate the effect of acute CET on the cognitive flexibility dimension of executive function using behavioural and neuro-electric measures. A secondary aim was to determine the mediating effect of blood lactate in the acute exercise-executive function relationship. Seventy-eight young adults (38 women, 40 men; 22.8 ± 1.8 years) were randomly assigned to one of the following groups: CET, AE, or reading control (RC). Cognitive flexibility was evaluated using the Task-Switching Test and its derived electroencephalography (EEG) was assessed immediately prior to and following each treatment. Fingertip lactate assays were taken prior to, at the midpoint, and after each treatment. Both acute CET and AE shortened response time regardless of test conditions when compared to the RC group. Greater P3 amplitude was observed following CET in the heterogeneous condition and under AE in the switch condition. A significant mediation of blood lactate for response time emerged in both the CET and AE groups for the heterogeneous and switch conditions. The blood lactate mediation was not reflected in P3 amplitude. The present findings suggest that acute CET leads to positive behavioural and neuro-electric alterations of cognitive flexibility, and its effect is similar to AE. Additionally, blood lactate serves as a mediator of the effects of acute exercise on executive function from a behavioural, but not neuro-electric standpoint.

Heterogeneity of Phase II Enzyme Ligands on Controlling the Progression of Human Gastric Cancer Organoids as Stem Cell Therapy Model.

Gastric cancer (GC) organoids are frequently used to examine cell proliferation and death as well as cancer development. Invasion/migration assay, xenotransplantation, and reactive oxygen species (ROS) production were used to examine the effects of antioxidant drugs, including perillaldehyde (PEA), cinnamaldehyde (CA), and sulforaphane (SFN), on GC. PEA and CA repressed the proliferation of human GC organoids, whereas SFN enhanced it. Caspase 3 activities were also repressed on treatment with PEA and CA. Furthermore, the tumor formation and invasive activities were repressed on treatment with PEA and CA, whereas they were enhanced on treatment with SFN. These results in three-dimensional (3D)-GC organoids showed the different cancer development of phase II enzyme ligands in 2D-GC cells. ROS production and the expression of TP53, nuclear factor erythroid 2-related factor (NRF2), and Jun dimerization protein 2 were also downregulated on treatment with PEA and CA, but not SFN. NRF2 knockdown reversed the effects of these antioxidant drugs on the invasive activities of the 3D-GC organoids. Moreover, ROS production was also inhibited by treatment with PEA and CA, but not SFN. Thus, NRF2 plays a key role in the differential effects of these antioxidant drugs on cancer progression in 3D-GC organoids. PEA and CA can potentially be new antitumorigenic therapeutics for GC.

Clostridium innocuum, an emerging pathogen that induces lipid raft-mediated cytotoxicity.

Clostridium innocuum is an emerging spore-forming anaerobe that is often observed in Clostridioides difficile-associated inflammatory bowel disease (IBD) exacerbations. Unlike C. difficile, C. innocuum neither produces toxins nor possesses toxin-encoding genetic loci, but is commonly found in both intestinal and extra-intestinal infections. Membrane lipid rafts are composed of dynamic assemblies of cholesterol and sphingolipids, allowing bacteria to gain access to cells. However, the direct interaction between C. innocuum and lipid rafts that confers bacteria the ability to disrupt the intestinal barrier and induce pathogenesis remains unclear. In this study, we investigated the associations among nucleotide-binding oligomerization domain containing 2 (NOD2), lipid rafts, and cytotoxicity in C. innocuum-infected gut epithelial cells. Our results revealed that lipid rafts were involved in C. innocuum-induced NOD2 expression and nuclear factor (NF)-κB activation, triggering an inflammatory response. Reducing cholesterol by simvastatin significantly dampened C. innocuum-induced cell death, indicating that the C. innocuum-induced pathogenicity of cells was lipid raft-dependent. These results demonstrate that NOD2 mobilization into membrane rafts in response to C. innocuum-induced cytotoxicity results in aggravated pathogenicity.

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWASs), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study, we constructed and evaluated genomic PRS models based on either non-Latino White (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR2 = 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR2 = 0.116 ± 0.026) or multi-ancestry samples (PseudoR2 = 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR2 = 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWASs may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligogenic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.

Study of Atomic Layer Deposition Nano-Oxide Films on Corrosion Protection of Al-SiC Composites.

In recent years, aluminum matrix composites (AMCs) have attracted attention due to their promising properties. However, the presence of ceramic particles in the aluminum matrix renders AMCs a high corrosion rate and makes it challenging to use traditional corrosion protection methods. In this study, atomic layer deposition (ALD) techniques were used to deposit HfO2, ZrO2, TiO2, and Al2O3 thin films on AMC reinforced with 20 vol.% SiC particles. Our results indicate that the presence of micro-cracks between the Al matrix and SiC particles leads to severe micro-crack-induced corrosion in Al-SiC composites. The ALD-deposited films effectively enhance the corrosion resistance of these composites by mitigating this micro-crack-induced corrosion. Among these four atomic-layer deposited films, the HfO2 film exhibits the most effective reduction in the corrosion current density of Al-SiC composites in a 1.5 wt% NaCl solution from 1.27 × 10-6 A/cm2 to 5.89 × 10-11 A/cm2. The electrochemical impedance spectroscopy (EIS) investigation shows that HfO2 deposited on Al-SiC composites has the largest Rp value of 2.0 × 1016. The HfO2 film on Al-SiC composites also exhibits effective inhibition of pitting corrosion, remaining at grade 10 even after 96 h of a salt spray test.

Domestication in dry-cured meat Penicillium fungi: Convergent specific phenotypes and horizontal gene transfers without strong genetic subdivision.

Some fungi have been domesticated for food production, with genetic differentiation between populations from food and wild environments, and food populations often acquiring beneficial traits through horizontal gene transfers (HGTs). Studying their adaptation to human-made substrates is of fundamental and applied importance for understanding adaptation processes and for further strain improvement. We studied here the population structures and phenotypes of two distantly related Penicillium species used for dry-cured meat production, P. nalgiovense, the most common species in the dry-cured meat food industry, and P. salamii, used locally by farms. Both species displayed low genetic diversity, lacking differentiation between strains isolated from dry-cured meat and those from other environments. Nevertheless, the strains collected from dry-cured meat within each species displayed slower proteolysis and lipolysis than their wild conspecifics, and those of P. nalgiovense were whiter. Phenotypically, the non-dry-cured meat strains were more similar to their sister species than to their conspecific dry-cured meat strains, indicating an evolution of specific phenotypes in dry-cured meat strains. A comparison of available Penicillium genomes from various environments revealed HGTs, particularly between P. nalgiovense and P. salamii (representing almost 1.5 Mb of cumulative length). HGTs additionally involved P. biforme, also found in dry-cured meat products. We further detected positive selection based on amino acid changes. Our findings suggest that selection by humans has shaped the P. salamii and P. nalgiovense populations used for dry-cured meat production, which constitutes domestication. Several genetic and phenotypic changes were similar in P. salamii, P. nalgiovense and P. biforme, indicating convergent adaptation to the same human-made environment. Our findings have implications for fundamental knowledge on adaptation and for the food industry: the discovery of different phenotypes and of two mating types paves the way for strain improvement by conventional breeding, to elucidate the genomic bases of beneficial phenotypes and to generate diversity.

Effects of hypochlorous acid mouthwash on salivary bacteria including Staphylococcus aureus in patients with periodontal disease: a randomized controlled trial.

BACKGROUND: The effects of a low concentration of hypochlorous acid (HOCl) mouthwash on salivary bacteria remained unclear. We aimed to evaluate the antibacterial effects of 100 ppm HOCl mouthwash on salivary bacteria, including Staphylococcus aureus (S. aureus), in patients with periodontal disease (PD). METHODS: Patients with PD were randomized into mouthwash-only (MW, n = 26) and mouthwash with periodontal flosser (MWPF, n = 27) groups. Patients without PD were selected for the control group (n = 30). S. aureus culture and saliva samples (before and after the intervention) were collected for bacterial DNA extraction. A real-time polymerase chain reaction assay and serial dilutions of S. aureus culture and saliva samples were used to measure the salivary bacteria total count (SBTC) and confirm the antibacterial effects of the mouthwash using S. aureus. RESULTS: No significant difference in demographic data was observed among the three groups. Before the intervention, the baseline SBTC of the MW and MWPF groups was significantly higher than that of the control group. After the mouthwash rinses, the SBTC data significantly changed in the MW and MWPF groups only (by 62.4% and 77.4%, respectively). After the base-2 log-transformation of the SBTC data, a similar trend was observed. Linear regression revealed that baseline SBTC and the MWPF intervention significantly affected SBTC reduction percentage by volume. After incubation with 10% (v/v) of mouthwash, the survival rates of 106 and 107 colony-forming units/mL of S. aureus were 0.51% ± 0.06% and 1.42% ± 0.37%, respectively. CONCLUSIONS: These study results indicated that 100 ppm HOCl mouthwash treatment could effectively reduce SBTC in patients with PD and the abundance of S. aureus. It provides that the HOCl mouthwash can be an option for individuals to help control SBTC, especially in patients with PD. TRIAL REGISTRATION: The study protocol was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-F(I)-20200042) on 20/03/2020 and retrospectively registered at ClinicalTrial.gov (NCT05372835) on 13/05/2022.

Acute effect of combined exercise with aerobic and resistance exercises on executive function.

Objective: Recent studies indicate that acute exercise, whether aerobic exercise (AE) or resistance exercise (RE), improves cognitive function. However, the effects on cognitive function of combined exercise (CE), involving both AE and RE in an exercise session, remain unknown. The aim of this study was to investigate the effects of acute CE on cognitive function. Design: Within-subject design with counterbalancing. Methods: Fifteen healthy men with a sedentary lifestyle in the previous three months were recruited. The participants were assessed for muscular fitness after performing four upper body exercises for a 10-repetition maximum and underwent a submaximal aerobic fitness assessment for V̇O2peak and corresponding workload (watts). They were then assigned to a CE, RE, or sitting control (SC) session in counterbalanced order and were assessed with the Stroop Color and Word Test (SCWT) after each session. Results: Acute CE led to a significantly shorter response time compared to SC (p < .05) in the SCWT, wherein there were no significant differences between acute CE and RE (p = 1.00). Additionally, no significant differences in the accuracy rate were observed across the different sessions (ps > .05). Conclusion: A single session of moderate-intensity CE improved response time in the SCWT, comparable to RE. CE shows promise for enhancing cognitive function, warranting further research on its benefits and other exercise modalities.

Jdp2 is a spatiotemporal transcriptional activator of the AhR via the Nrf2 gene battery.

BACKGROUND: Crosstalk between the aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is called the "AhR-Nrf2 gene battery", which works synergistically in detoxification to support cell survival. Nrf2-dependent phase II gene promoters are controlled by coordinated recruitment of the AhR to adjacent dioxin responsive element (DRE) and Nrf2 recruitment to the antioxidative response element (ARE). The molecular interaction between AhR and Nrf2 members, and the regulation of each target, including phase I and II gene complexes, and their mediators are poorly understood. METHODS: Knockdown and forced expression of AhR-Nrf2 battery members were used to examine the molecular interactions between the AhR-Nrf2 axis and AhR promoter activation. Sequential immunoprecipitation, chromatin immunoprecipitation, and histology were used to identify each protein complex recruited to their respective cis-elements in the AhR promoter. Actin fiber distribution, cell spreading, and invasion were examined to identify functional differences in the AhR-Jdp2 axis between wild-type and Jdp2 knockout cells. The possible tumorigenic role of Jdp2 in the AhR-Nrf2 axis was examined in mutant Kras-Trp53-driven pancreatic tumors. RESULTS: Crosstalk between AhR and Nrf2 was evident at the transcriptional level. The AhR promoter was activated by phase I ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the AhR-Jdp2-Nrf2 axis in a time- and spatial transcription-dependent manner. Jdp2 was a bifunctional activator of DRE- and ARE-mediated transcription in response to TCDD. After TCDD exposure, Jdp2 activated the AhR promoter at the DRE and then moved to the ARE where it activated the promoter to increase reactive oxygen species (ROS)-mediated functions such as cell spreading and invasion in normal cells, and cancer regression in mutant Kras-Trp53-driven pancreatic tumor cells. CONCLUSIONS: Jdp2 plays a critical role in AhR promoter activation through the AhR-Jdp2-Nrf2 axis in a spatiotemporal manner. The AhR functions to maintain ROS balance and cell spreading, invasion, and cancer regression in a mouse model of mutant Kras-Trp53 pancreatic cancer. These findings provide new insights into the roles of Jdp2 in the homeostatic regulation of oxidative stress and in the antioxidation response in detoxification, inflammation, and cancer progression.

DNA-encoded chemical libraries yield non-covalent and non-peptidic SARS-CoV-2 main protease inhibitors.

The development of SARS-CoV-2 main protease (Mpro) inhibitors for the treatment of COVID-19 has mostly benefitted from X-ray structures and preexisting knowledge of inhibitors; however, an efficient method to generate Mpro inhibitors, which circumvents such information would be advantageous. As an alternative approach, we show here that DNA-encoded chemistry technology (DEC-Tec) can be used to discover inhibitors of Mpro. An affinity selection of a 4-billion-membered DNA-encoded chemical library (DECL) using Mpro as bait produces novel non-covalent and non-peptide-based small molecule inhibitors of Mpro with low nanomolar Ki values. Furthermore, these compounds demonstrate efficacy against mutant forms of Mpro that have shown resistance to the standard-of-care drug nirmatrelvir. Overall, this work demonstrates that DEC-Tec can efficiently generate novel and potent inhibitors without preliminary chemical or structural information.

Prevalence of peri-implantitis after alveolar ridge preservation at periodontitis and nonperiodontitis extraction sites: A retrospective cohort study.

INTRODUCTION: Periodontitis is the main indication for dental extraction and often leads to peri-implantitis (PI). Alveolar ridge preservation (ARP) is an effective means of preserving ridge dimensions after extraction. However, whether PI prevalence is lower after ARP for extraction after periodontitis remains unclear. This study investigated PI after ARP in patients with periodontitis. MATERIALS AND METHODS: This study explored the 138 dental implants of 113 patients. The reasons for extraction were categorized as periodontitis or nonperiodontitis. All implants were placed at sites treated using ARP. PI was diagnosed on the basis of radiographic bone loss of ≥3 mm, as determined through comparison of standardized bitewing radiographs obtained immediately after insertion with those obtained after at least 6 months. Chi-square and two-sample t testing and generalized estimating equations (GEE) logistic regression model were employed to identify risk factors for PI. Statistical significance was indicated by p < 0.05. RESULTS: The overall PI prevalence was 24.6% (n = 34). The GEE univariate logistic regression demonstrated that implant sites and implant types were significantly associated with PI (premolar vs. molar: crude odds ratios [OR] = 5.27, 95% confidence intervals [CI] = 2.15-12.87, p = 0.0003; bone level vs. tissue level: crude OR = 5.08, 95% CI = 2.10-12.24; p = 0.003, respectively). After adjustment for confounding factors, the risks of PI were significantly associated with implant sites (premolar vs. molar: adjusted OR [AOR] = 4.62, 95% CI = 1.74-12.24; p = 0.002) and implant types (bone level vs. tissue level: AOR = 6.46, 95% CI = 1.67-25.02; p = 0.007). The reason for dental extraction-that is, periodontitis or nonperiodontitis-was not significantly associated with PI. CONCLUSION: ARP reduces the incidence of periodontitis-related PI at extraction sites. To address the limitations of our study, consistent and prospective randomized controlled trials are warranted.

Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWAS), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied. In this study we constructed and evaluated genomic PRS models based on either non-Latino white (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR 2 = 0.086 ± 0.023 in NLW vs. 0.060 ± 0.020 in LAT), and can be improved for LAT if we performed GWAS in LAT-only (PseudoR 2 = 0.116 ± 0.026) or multi-ancestry samples (PseudoR 2 = 0.131 ± 0.025). However, the best genomic models currently do not have better prediction accuracy than a conventional model using all known ALL-associated loci in the literature (PseudoR 2 = 0.166 ± 0.025), which includes loci from GWAS populations that we could not access to train genomic PRS models. Our results suggest that larger and more inclusive GWAS may be needed for genomic PRS to be useful for ALL. Moreover, the comparable performance between populations may suggest a more oligo-genic architecture for ALL, where some large effect loci may be shared between populations. Future PRS models that move away from the infinite causal loci assumption may further improve PRS for ALL.