Serialized on-grid lift-in sectioning for tomography (SOLIST) enables a biopsy at the nanoscale.

Cryo-focused ion beam milling has substantially advanced our understanding of molecular processes by opening windows into cells. However, applying this technique to complex samples, such as tissues, has presented considerable technical challenges. Here we introduce an innovative adaptation of the cryo-lift-out technique, serialized on-grid lift-in sectioning for tomography (SOLIST), addressing these limitations. SOLIST enhances throughput, minimizes ice contamination and improves sample stability for cryo-electron tomography. It thereby facilitates the high-resolution imaging of a wide range of specimens. We illustrate these advantages on reconstituted liquid-liquid phase-separated droplets, brain organoids and native tissues from the mouse brain, liver and heart. With SOLIST, cellular processes can now be investigated at molecular resolution directly in native tissue. Furthermore, our method has a throughput high enough to render cryo-lift-out a competitive tool for structural biology. This opens new avenues for unprecedented insights into cellular function and structure in health and disease, a 'biopsy at the nanoscale'.

Paraoxonase 2 Facilitates Pancreatic Cancer Growth and Metastasis by Stimulating GLUT1-Mediated Glucose Transport.

Metabolic deregulation is a hallmark of human cancers, and the glycolytic and glutamine metabolism pathways were shown to be deregulated in pancreatic ductal adenocarcinoma (PDAC). To identify new metabolic regulators of PDAC tumor growth and metastasis, we systematically knocked down metabolic genes that were overexpressed in human PDAC tumor samples using short hairpin RNAs. We found that p53 transcriptionally represses paraoxonase 2 (PON2), which regulates GLUT1-mediated glucose transport via stomatin. The loss of PON2 initiates the cellular starvation response and activates AMP-activated protein kinase (AMPK). In turn, AMPK activates FOXO3A and its transcriptional target, PUMA, which induces anoikis to suppress PDAC tumor growth and metastasis. Pharmacological or genetic activation of AMPK, similar to PON2 inhibition, blocks PDAC tumor growth. Collectively, our results identify PON2 as a new modulator of glucose transport that regulates a pharmacologically tractable pathway necessary for PDAC tumor growth and metastasis.

Clonal Evolution in 207 Cases of Refractory or Relapsed Acute Myeloid Leukemia.

Clonal evolution (CE) is a driving force behind the development and progression of acute myeloid leukemia (AML). Advances in molecular and cytogenetic assays have improved the depth and breadth of detection of CE in AML, which is defined here as a detected change in cytogenetic or molecular profile at relapsed or refractory (RR) disease. In this study, we demonstrate the clinical impact of CE in a cohort of patients with RR AML treated between 2013 and 2023. We discovered CE is significantly more frequent in relapsed disease (58.2%, [46.6%, 69.2%]) than in refractory disease (21.1%, [14.4%, 29.2%], p < 0.001). CE negatively impacts prognosis when detected by conventional karyotyping in refractory disease (4.2 vs. 13.9 months, p < 0.011). In contrast with prior literature, CE had no impact on overall survival if detected in relapsed disease. Surprisingly, those who achieved negative measurable residual disease (MRD) were no more likely to eliminate their original clone than those who did not (p = 1). We found several cytogenetic and molecular signatures which may predispose to CE: aberrations of chromosome 17, trisomy 8, TP53, KRAS, and FLT3-TKD. Finally, physicians were less likely to retreat those with CE with IC after receiving IC as first-line therapy (35.0% vs. 70.9%, p = 0.004). This study illustrates the role of CE in chemotherapy-resistant AML; we identify unique cytogenetic and molecular signatures that define a subset of patients associated with a dismal prognosis. As next-generation sequencing panels expand and new methods to characterize cytogenetic abnormalities emerge, our findings establish a basis for future studies investigating the prognostic and therapeutic impact of CE.

Promoting High-Oxidation-State Metal Active Sites in a Hollow Ternary Metal Fluoride Nanoflake Array for Urea Electrolysis.

The adsorption ability of hydrogen, hydroxide, and oxygenic intermediates plays a crucial role in electrochemical water splitting. Electron-deficient metal-active sites can prompt electrocatalytic activity by improving the adsorption ability of intermediates. However, it remains a significant challenge to synthesize highly abundant and stable electron-deficient metal-active site electrocatalysts. Herein, we present a general approach to synthesizing a hollow ternary metal fluoride (FeCoNiF2) nanoflake array as an efficient and robust bifunctional electrocatalyst for the hydrogen evolution reaction (HER) and urea oxidation reaction (UOR). We find that the F anion withdraws electrons from the metal centers, inducing an electron-deficient metal center catalyst. The rationally designed hollow nanoflake array exhibits the overpotential of 30 mV for HER and 130 mV for UOR at a current density of 10 mA cm-2 and superior stability without decay events over 150 h at a large current density of up to 100 mA cm-2. Remarkably, the assembled urea electrolyzer using a bifunctional hollow FeCoNiF2 nanoflake array catalyst requires cell voltages of only 1.352 and 1.703 V to afford current densities of 10 and 100 mA cm-2, respectively, which are 116 mV less compared with that required for overall water splitting.

Predictive In Vitro-In Vivo Extrapolation for Time Dependent Inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 Using Pooled Human Hepatocytes, Human Liver Microsomes, and a Simple Mechanistic Static Model.

Inactivation of Cytochrome P450 (CYP450) enzymes can lead to significant increases in exposure of comedicants. The majority of reported in vitro to in vivo extrapolation (IVIVE) data have historically focused on CYP3A, leaving the assessment of other CYP isoforms insubstantial. To this end, the utility of human hepatocytes (HHEP) and human liver microsomes (HLM) to predict clinically relevant drug-drug interactions was investigated with a focus on CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. Evaluation of IVIVE for CYP2B6 was limited to only weak inhibition. A search of the University of Washington Drug-Drug Interaction Database was conducted to identify a clinically relevant weak, moderate, and strong inhibitor for selective substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2D6, resulting in 18 inhibitors for in vitro characterization against 119 clinical interaction studies. Pooled human hepatocytes and HLM were preincubated with increasing concentrations of inhibitors for designated timepoints. Time dependent inhibition was detected in HLM for four moderate/strong inhibitors, suggesting that some optimization of incubation conditions (i.e., lower protein concentrations) is needed to capture weak inhibition. Clinical risk assessment was conducted by incorporating the in vitro derived kinetic parameters maximal rate of enzyme inactivation (min-1) (kinact) and concentration of inhibitor resulting in 50% of the maximum enzyme inactivation (KI) into static equations recommended by regulatory authorities. Significant overprediction was observed when applying the basic models recommended by regulatory agencies. Mechanistic static models, which consider the fraction of metabolism through the impacted enzyme, using the unbound hepatic inlet concentration lead to the best overall prediction accuracy with 92% and 85% of data from HHEPs and HLM, respectively, within twofold of the observed value. SIGNIFICANCE STATEMENT: Coupling time-dependent inactivation parameters derived from pooled human hepatocytes and human liver microsomes (HLM) with a mechanistic static model provides an easy and quantitatively accurate means to determine clinical drug-drug interaction risk from in vitro data. Optimization is needed to evaluate time-dependent inhibition (TDI) for weak and moderate inhibitors using HLM. Recommendations are made with respect to input parameters for in vitro to in vivo extrapolation (IVIVE) of TDI with non-CYP3A enzymes using available data from HLM and human hepatocytes.

Effects of career development learning on students' perceived employability: a longitudinal study.

This study investigates the relationship between career development learning (CDL) and students' perceived employability (SPE) with the mediating role of human capital. Using a quantitative method based on structured questionnaires to collect data from 512 Vietnamese students before starting their internship at businesses and 322 of them after 4 months, the results of the partial least square Structural Equational Model analysis showed that CDL positively affects SPE over time. Besides, the study explored the mediating effect of human capital in the relationship between CDL and SPE. In particular, scholastic capital and cultural capital play mediating roles while social capital failed to be in the relationship between CDL and SPE. This study is expected to enrich current literature on students' employability and human capital theory. From practical aspects, the findings of this work can be of benefit to higher education institutions in supporting their students to enhance their employability in labour market.

Redox Modification of the Iron-Sulfur Glutaredoxin GRXS17 Activates Holdase Activity and Protects Plants from Heat Stress.

Heat stress induces misfolding and aggregation of proteins unless they are guarded by chaperone systems. Here, we examined the function of the glutaredoxin GRXS17, a member of thiol reductase families in the model plant Arabidopsis (Arabidopsis thaliana). GRXS17 is a nucleocytosolic monothiol glutaredoxin consisting of an N-terminal thioredoxin domain and three CGFS active-site motif-containing GRX domains that coordinate three iron-sulfur (Fe-S) clusters in a glutathione-dependent manner. As an Fe-S cluster-charged holoenzyme, GRXS17 is likely involved in the maturation of cytosolic and nuclear Fe-S proteins. In addition to its role in cluster biogenesis, GRXS17 presented both foldase and redox-dependent holdase activities. Oxidative stress in combination with heat stress induced loss of its Fe-S clusters followed by subsequent formation of disulfide bonds between conserved active-site cysteines in the corresponding thioredoxin domains. This oxidation led to a shift of GRXS17 to a high-molecular-weight complex and thus activated its holdase activity in vitro. Moreover, GRXS17 was specifically involved in plant tolerance to moderate high temperature and protected root meristematic cells from heat-induced cell death. Finally, GRXS17 interacted with a different set of proteins upon heat stress, possibly protecting them from heat injuries. Therefore, we propose that the Fe-S cluster enzyme GRXS17 is an essential guard that protects proteins against moderate heat stress, likely through a redox-dependent chaperone activity. We reveal the mechanism of an Fe-S cluster-dependent activity shift that converts the holoenzyme GRXS17 into a holdase, thereby preventing damage caused by heat stress.

Premaxillary Injection for Perioral Rejuvenation and Lip Enhancement.

BACKGROUND: This is the first study to evaluate the effect of premaxillary filler injection on nasal tip projection, upper lip projection, and upper lip vermilion height. OBJECTIVES: The primary objective of this study was to analyze the change in nasal tip projection (measured by the Goode ratio) and the change in upper lip projection (measured by the Z angle) following premaxillary hyaluronic acid injection. A secondary objective was to measure the change in upper lip vermilion height. We hypothesized that treated subjects will show an increase in nasal tip projection, upper lip projection, and upper lip vermilion height. METHODS: Twenty volunteer patients with signs of perioral aging or poor upper lip projection were enrolled in this prospective cohort study and underwent premaxillary hyaluronic acid filler injection between November 2017 and June 2018. Nasal tip projection, upper lip projection, and upper lip vermilion height were assessed from baseline and posttreatment photographs based on the Goode ratio, Z angle, and lip vermilion height ratio, respectively. RESULTS: No significant change was noted between pre- and posttreatment Goode ratio measurements (P = 0.841). There was a significant decrease in Z angle and therefore significant increase in upper lip projection with treatment (P < 0.001). The lip vermilion height ratio demonstrated a trend of increased upper lip vermilion height but this did not achieve statistical significance (P = 0.561). CONCLUSIONS: Premaxillary filler treatment resulted in a significant increase in upper lip projection. Premaxillary filler injection when performed in a safe manner is a valuable treatment option for perioral rejuvenation.

Metformin prescription status and abdominal aortic aneurysm disease progression in the U.S. veteran population.

BACKGROUND: Identification of a safe and effective medical therapy for abdominal aortic aneurysm (AAA) disease remains a significant unmet medical need. Recent small cohort studies indicate that metformin, the world's most commonly prescribed oral hypoglycemic agent, may limit AAA enlargement. We sought to validate these preliminary observations in a larger cohort. METHODS: All patients with asymptomatic AAA disease managed in the Veterans Affairs Health Care System between 2003 and 2013 were identified by International Classification of Diseases, Ninth Revision codes. Those with a concomitant diagnosis of diabetes mellitus who also received two or more abdominal imaging studies (computed tomography, magnetic resonance imaging, or ultrasound) documenting the presence and size of an AAA, separated by at least 1 year, were included for review. Maximal AAA diameters were determined from radiologic reports. Further data acquisition was censored after surgical AAA repair, when performed. Comorbidities, active smoking status, and outpatient medication records (within 6 months of AAA diagnosis) were also queried. Yearly AAA enlargement rates, as a function of metformin treatment status, were compared using two statistical models expressed in millimeters per year: a multivariate linear regression (model 1) and a multivariate mixed-effects model with random intercept and random slope (model 2). RESULTS: A total of 13,834 patients with 58,833 radiographic records were included in the analysis, with radiology imaging follow-up of 4.2 ± 2.6 years (mean ± standard deviation). The average age of the patients at AAA diagnosis was 69.8 ± 7.8 years, and 39.7% had a metformin prescription within ±6 months of AAA. The mean growth rate for AAAs in the entire cohort was 1.4 ± 2.0 mm/y by model 1 analysis and 1.3 ± 1.6 mm/y by model 2 analysis. The unadjusted mean rate of AAA growth was 1.2 ± 1.9 mm/y for patients prescribed metformin compared with 1.5 ± 2.2 mm/y for those without (P < .001), a 20% decrease. This effect remained significant when adjusted for variables relevant on AAA progression: metformin prescription was associated with a reduction in yearly AAA growth rate of -0.23 mm (95% confidence interval, -0.35 to -0.16; P < .001) by model 1 analysis and 0.20 mm/y (95% confidence interval, -0.26 to -0.14; P < .001) by model 2 analysis. A subset analysis of 7462 patients with baseline AAA size of 35 to 49 mm showed a similar inhibitory effect (1.4 ± 2.0 mm/y to 1.7 ± 2.2 mm/y; P < .001). Patients' factors associated with an increased yearly AAA growth rate were baseline AAA size, metastatic solid tumors, active smoking, chronic obstructive pulmonary disease, and chronic renal disease. Factors associated with decreased yearly AAA growth rates included prescriptions for angiotensin II type 1 receptor blockers or sulfonylureas and the presence of diabetes-related complications. CONCLUSIONS: In a nationwide analysis of diabetic Veterans Affairs patients, prescription for metformin was associated with decreased AAA enlargement. These findings provide further support for the conduct of prospective clinical trials to test the ability of metformin to limit progression of early AAA disease.

Adipose tissue-derived stem cells prevent fibrosis in murine steatohepatitis by suppressing IL-17-mediated inflammation.

BACKGROUND AND AIM: The pathological features of non-alcoholic steatohepatitis (NASH) have not been determined, so fundamental treatment has not been established. Adipose-tissue-derived stromal/stem cells (ADSCs) are beneficial for repair/regenerative therapy of impaired organs because of their immuno-modulatory capability. In this study, we assessed how liver damage progresses during the early development phase of the murine NASH model and investigated whether ADSCs are preventatively efficacious against the fibrosis progression of NASH. METHODS: C57BL/6J mice were fed with atherogenic high fat or high-fat diet 60 developing into NASH or simple steatosis. Their hepatic inflammatory cells (HICs) were analyzed by cDNA microarray. NASH mice were treated with ADSCs injected into spleen when hepatic inflammation was initially observed, and liver samples were analyzed. The effect of ADSCs on the mice hepatic stellate cell (HSC) line stimulated by recombinant IL-17 and HICs from NASH mice was analyzed. RESULTS: The gene expression features of HICs implicated as humoral cytokine mediators of lymphoid cells during NASH development, compared with a simple steatosis model. One of the featured cytokines was IL-17. The development of hepatic fibrosis was alleviated when NASH mice were treated with ADSCs as well as treated with anti-IL-17 antibody, and the frequency of IL-17-secreting HICs decreased. NASH-HICs enhanced proliferation of HSCs, in which proliferation was sensitive to IL-17 stimulation. The stimulatory effect of NASH-HICs on the activation of HSCs was attenuated by co-culture with ADSCs. CONCLUSION: ADSCs treatment prevented progression of NASH fibrosis by suppressing IL-17-mediated inflammation, which was associated with HSCs activation.

Assessment of the Impact of Perioral Rejuvenation With Hyaluronic Acid Filler on Projected First Impressions and Mood Perceptions.

BACKGROUND: Small-particle hyaluronic acid filler is approved for lip augmentation and correction of perioral rhytides. Treatment with this product may improve facial aesthetics, projected first impression, and self-perception of mood. OBJECTIVE: To determine the effect of perioral rejuvenation with hyaluronic acid on patient perception of mood and projected first impression. MATERIALS AND METHODS: Seventeen subjects underwent perioral rejuvenation treatment with small-particle hyaluronic acid filler. Each subject underwent photography and completed 2 surveys measuring self-perception of mood before treatment and after achieving an optimal cosmetic result. Aesthetic improvement with treatment was assessed using the Global Aesthetic Improvement Scale and the Oral Commissure Severity and Perioral Line Severity scales. Seventeen hundred blinded evaluators rated pre-treatment and post-treatment photographs of the subjects using a First Impressions Questionnaire. RESULTS: Perioral filler treatment significantly improved pre-treatment and post-treatment scores for happiness within the Happiness Measures Scale. This treatment was found to significantly improve projected first impression across all categories. CONCLUSION: Small-particle hyaluronic acid filler treatment for perioral rejuvenation is an effective method for improving physical appearance as well as first impressions. Larger studies are necessary to verify whether perioral rejuvenation with hyaluronic acid offers enhanced self-perception of mood.

Corner of the Mouth-Reversing the Earliest Sign of Aging.

As individuals age, distinct anatomical changes of the bone and soft tissue result in the development of rhytids in the perioral region. Most notably, the oral commissures turn downward, creating the appearance of a perpetual frown and adding years to the facial appearance. The purpose of this article is to review the anatomical changes associated with perioral aging as well as discuss potential treatment options for perioral rejuvenation particularly at the level of the oral commissures. Lastly, this article covers the senior author's technique for improving oral commissures and restoring youthful appearance of the perioral region.

A Randomized Study to Assess the Efficacy of Skin Rejuvenation Therapy in Combination With Neurotoxin and Full Facial Filler Treatments.

BACKGROUND: Although non-surgical treatment options for facial rejuvenation are well-established, the literature remains limited regarding the combined effect of topical skin treatment with filler and neurotoxin on patient appearance and satisfaction. The objectives of this study were to assess the impact of a skin rejuvenation therapy in combination with neurotoxin or hyaluronic acid filler injection on skin quality and general aesthetic improvement as well as on short-term self-esteem.

METHODS: From 2015 to 2017, 20 female patients were enrolled in our study and were randomized into two groups. Patients in Group A used a basic skin care regimen following hyaluronic acid filler and neurotoxin treatment, while those in Group B utilized the Nu-Derm® skin care system (Obagi Medical Products, Inc) afterwards. Each subject and the principal investigator filled out various assessments pre- and post-treatment to evaluate for change in skin quality (Fitzpatrick Wrinkle Assessment Scale [FWAS] and Skin Quality Assessments [SQA]), aesthetic appearance (Global Aesthetic Improvement Scale [GAIS]), patient satisfaction (Subject Satisfaction Assessment [SSA]), and self-esteem (State Self-Esteem Scale [SSES]).

RESULTS: Subjects in both treatment groups demonstrated significant improvement in skin quality, as illustrated in the change in FWAS and SQA scores, at 12 weeks after initiating full facial rejuvenation treatment. However, there were no significant differences in FWAS and SQA ratings between the treatment groups. Regarding aesthetic appearance, a statistically significant difference in GAIS scores between Groups A and B was observed at 6 weeks after treatment only. In evaluating for patient satisfaction and self-esteem, there were no significant differences in SSA and SSES ratings over time within each treatment group or between the treatment groups.

CONCLUSIONS: Our study confirms that facial rejuvenation therapy involving hyaluronic acid filler and neurotoxin injections combined with a topical skin treatment regimen leads to improvement in skin quality and aesthetic appearance as well as to patient satisfaction. Additional larger studies are needed to better delineate the most ideal combination facial rejuvenation therapy for optimizing patient appearance and satisfaction.

J Drugs Dermatol. 2018;17(1):48-54.

A Pilot Study Evaluating the Efficacy and Safety of ARTISS Human Fibrin Sealant in External Rhinoplasty.

BACKGROUND: Fibrin sealant application in rhytidectomy has previously demonstrated a reduction in adverse events and drainage volume. Fibrin sealant offers multiple potential benefits including decreasing downtime, reducing complication rates, and improving patient satisfaction. In this study, we evaluated the efficacy and safety of ARTISS [fibrin sealant (human)] in external rhinoplasty. METHODS: Nine healthy participants between the ages of 18 and 50 seeking external rhinoplasty completed this study. All subjects were randomized into control and treatment groups and then underwent external rhinoplasty, with only the treatment group receiving ARTISS [fibrin sealant (Human)] during surgery. Photographs were taken before surgery and 1 day, 1 week, 1 month, 3 months and 6 months after surgery and used in a blinded assessment of recovery time and esthetic improvement with ecchymosis and satisfaction scales. Subject recovery time, downtime, and self-esteem were evaluated at 1 day, 1 week, 1 month and 6 months after surgery. Recovery time was determined by live assessment of edema and ecchymosis using categorical scales. Subject downtime was assessed through a 30-day patient diary and a downtime questionnaire. Subject self-esteem was evaluated with the Heatherton & Polivy State Self-Esteem Scale. The degree of technical ease with the product was determined by the treating investigator with a 10-cm Visual Analog Scale. RESULTS: Patients treated with ARTISS intra-operatively reported significantly higher self-esteem 1 month and 6 months following external rhinoplasty. The ARTISS Easyspray™ Spray Set was rated as technically easy to administer. CONCLUSION: The use of ARTISS fibrin sealant in external rhinoplasties is a safe and easy method and may enhance patient self-esteem. Larger studies are warranted to either verify or challenge the validity of our findings. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

An outcome study of a 2-flap pushback palatoplasty used in the treatment of wide cleft palates.

Cleft palate remains a common congenital deformity. The wide cleft palate in particular presents a unique challenge when attempting to restore a competent velopharyngeal mechanism. We present an outcome study of a single surgeon's experience using a modified surgical technique designed to specifically address the wide cleft palate. The surgical technique consisted of a 2-flap pushback palatoplasty without nasal mucosa closure combined with an end-to-end intravelar veloplasty and was used in cleft palates greater than or equal to 10 mm in width. A retrospective, longitudinal outcome study from chart review was then performed where age at surgery, sex, Veau classification of the cleft type, and follow-up length were recorded for each patient. Postsurgery speech outcomes were assessed by standardized speech evaluation performed by a speech language pathologist, and the presence and location of unplanned oronasal fistulas were recorded. Our study revealed an overall incidence of velopharyngeal insufficiency (VPI) of 10.8% and an unplanned symptomatic fistula rate of 16.8%. There was a significant correlation between the Veau classification of the cleft type with the incidence of both VPI and the occurrence of an unplanned oronasal fistula. Application of this surgical technique, specifically to wider cleft palates, resulted in VPI and fistula rates comparable to rates reported with other techniques used in clefts of all widths. Additional information regarding subsequent growth disturbances of the craniofacial skeleton in these patients is currently being collected.

Evaluation of calibration curve-based approaches to predict clinical inducers and noninducers of CYP3A4 with plated human hepatocytes.

Cytochrome P450 (P450) induction is often considered a liability in drug development. Using calibration curve-based approaches, we assessed the induction parameters R3 (a term indicating the amount of P450 induction in the liver, expressed as a ratio between 0 and 1), relative induction score, Cmax/EC50, and area under the curve (AUC)/F2 (the concentration causing 2-fold increase from baseline of the dose-response curve), derived from concentration-response curves of CYP3A4 mRNA and enzyme activity data in vitro, as predictors of CYP3A4 induction potential in vivo. Plated cryopreserved human hepatocytes from three donors were treated with 20 test compounds, including several clinical inducers and noninducers of CYP3A4. After the 2-day treatment, CYP3A4 mRNA levels and testosterone 6ß-hydroxylase activity were determined by real-time reverse transcription polymerase chain reaction and liquid chromatography-tandem mass spectrometry analysis, respectively. Our results demonstrated a strong and predictive relationship between the extent of midazolam AUC change in humans and the various parameters calculated from both CYP3A4 mRNA and enzyme activity. The relationships exhibited with non-midazolam in vivo probes, in aggregate, were unsatisfactory. In general, the models yielded better fits when unbound rather than total plasma Cmax was used to calculate the induction parameters, as evidenced by higher R(2) and lower root mean square error (RMSE) and geometric mean fold error. With midazolam, the R3 cut-off value of 0.9, as suggested by US Food and Drug Administration guidance, effectively categorized strong inducers but was less effective in classifying midrange or weak inducers. This study supports the use of calibration curves generated from in vitro mRNA induction response curves to predict CYP3A4 induction potential in human. With the caveat that most compounds evaluated here were not strong inhibitors of enzyme activity, testosterone 6ß-hydroxylase activity was also demonstrated to be a strong predictor of CYP3A4 induction potential in this assay model.

RNA therapeutics for treatment of diabetes.

Diabetes is an ongoing global problem as it affects health of more than 537 million people around the world. Diabetes leaves many serious complications that affect patients and can cause death if not detected and treated promptly. Some of the complications of diabetes include impaired vascular system, increased risk of stroke, neurological diseases that cause pain and numbness, diseases related to the retina leading to blindness, and other complications affecting kidneys, heart failure, muscle weakness, muscle atrophy. All complications of diabetes seriously affect the health of patients. Recently, gene therapy has emerged as a viable treatment strategy for various diseases. DNA and RNA are among the target molecules that can change the structure and function of proteins and are effective methods of treating diseases, especially genetically inherited diseases. RNA therapeutics has attracted deep interest as it has been approved for application in the treatment of functional system disorders such as spinal muscular atrophy, and muscular dystrophy. In this review, we cover the types of RNA therapies considered for treatment of diabetes. In particular, we delve into the mechanism of action of RNA therapies for diabetes, and studies involving testing of these RNA therapies. Finally, we have highlighted the limitations of the current understanding in the mechanism of action of RNA therapies.

Drug repurposing for regenerative medicine and cosmetics: Scientific, technological and economic issues.

Regenerative medicine and cosmetics are currently two outstanding fields for drug discovery. Although many pharmaceutical products for regenerative medicine and cosmetics have received approval by official agencies, several challenges are still needed to overcome, especially financial and time issues. As a result, drug repositioning, which is the usage of previously approved drugs for new treatment, stands out as a promising approach to tackle these problems. Recently, increasing scientific evidence is collected to demonstrate the applicability of this novel method in the field of regenerative medicine and cosmetics. Experts in drug development have also taken advantage of novel technologies to discover new candidates for repositioning purposes following computational approach, one of two main approaches of drug repositioning. Therefore, numerous repurposed candidates have obtained approval to enter the market and have witnessed financial success such as minoxidil and fingolimod. The benefits of drug repositioning are undeniable for regenerative medicine and cosmetics. However, some aspects still need to be carefully considered regarding this method including actual effectiveness during clinical trials, patent regulations, data integration and analysis, publicly unavailable databases as well as environmental concerns and more effort are required to overcome these obstacles.

A eutectogels-catalyzed one-pot multi-component reaction: access to pyridine and chromene derivatives.

The demand for a wide array of functional chemicals and materials has experienced a significant surge in tandem with the advancement of civilization. Regrettably, a number of perilous solvents are employed in chemical laboratories and industrial settings, posing significant risks to the well-being of researchers and contributing to environmental degradation through pollution. Eutectogels, which are based on the eutectic concept, may be synthesized by self-assembling or self-polymerization of various components when put under UV irradiation (254 nm). A novel copolymeric deep eutectic solvent (DES) was successfully synthesized, comprising choline chloride (HBA) as the hydrogen bond acceptor, acetamide (HBD) as the hydrogen bond donor, tetraethyl orthosilicate (TEOS), and formic acid. In this study, we present the preparation of four-component ETGs for synthesizing pyridine and chromene derivatives as a reusable catalyst through a multi-component pathway without solvents. The procedure of synthesizing these heterocyclic compounds is free of using toxic solvents and it could be categorized as a green method.

Characterizing Neisseria meningitidis in Southern Vietnam between 2012 and 2021: A predominance of the chloramphenicol-resistant ST-1576 lineage.

Objectives: Our goal was to describe Invasive Meningococcal Disease (IMD) in Southern Vietnam over the last 10 years. We characterized 109 Neisseria meningitidis strains in Southern Vietnam isolated between 1980s to 2021, that were collected from IMD (n = 44), sexually transmitted infections (n = 2), and healthy carriage (n = 63). Methods: IMD were confirmed by bacterial culture and/or real-time polymerase chain reaction at the national reference laboratory in Pasteur Institute of Ho Chi Minh City (PIHCM). Antimicrobial resistance was determined on 31 IMD and two sexually transmitted infection isolates with E-test for chloramphenicol (CHL), penicillin (PEN), ciprofloxacin (CIP), ceftriaxone (CRO), and rifampicin (RIF). Sequencing was performed for analyzing of multilocus-sequence-typing (MLST), porA, fetA, and antibiotic resistance genes, including gyrA, penA, and rpoB. Results: The incidence rate during this period was 0.02 per 100,000 persons/year. Serogroup B accounted for over 90% of cases (50/54). ST-1576 were mainly responsible for IMD, 27/42 MLST profiles, and associated with CHL resistance. Resistance was prevalent among IMD isolates. Thirteen were resistant to CHL (minimum inhibitory concentration [MIC] ≥16 mg/l), 12 were intermediate to PEN (MIC between 0.19 and 0.5 mg/l), and five were CIP-resistant (MIC between 0.19 and 0.5 mg/l). Particularly, one was non-susceptible to CRO (MIC at 0.125 mg/l), belonging to ST-5571 lineage. The resistance was due to carrying resistant alleles of penA and gyrA genes, and catP gene. Notably, seven isolates were resistant/non-susceptible to two or more antibiotics. Conclusion: Our results suggest the persistence of the circulating ST-1576 in Southern Vietnam, with a spread of antimicrobial resistance across the community.