Integrating AI/ML Models for Patient Stratification Leveraging Omics Dataset and Clinical Biomarkers from COVID-19 Patients: A Promising Approach to Personalized Medicine.

The COVID-19 pandemic has presented an unprecedented challenge to the healthcare system. Identifying the genomics and clinical biomarkers for effective patient stratification and management is critical to controlling the spread of the disease. Omics datasets provide a wealth of information that can aid in understanding the underlying molecular mechanisms of COVID-19 and identifying potential biomarkers for patient stratification.

In Silico Development of Combinatorial Therapeutic Approaches Targeting Key Signaling Pathways in Metabolic Syndrome.

Purpose: Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome.

Effects of Magnesium, Calcium, and Aluminum Chelation on Fluoroquinolone Absorption Rate and Bioavailability: A Computational Study.

Fluoroquinolones (FQs) are a widespread class of broad-spectrum antibiotics prescribed as a first line of defense, and, in some cases, as the only treatment against bacterial infection. However, when administered orally, reduced absorption and bioavailability can occur due to chelation in the gastrointestinal tract (GIT) with multivalent metal cations acquired from diet, coadministered compounds (sucralfate, didanosine), or drug formulation. Predicting the extent to which this interaction reduces in vivo antibiotic absorption and systemic exposure remains desirable yet challenging.

Accelerated Repurposing and Drug Development of Pulmonary Hypertension Therapies for COVID-19 Treatment Using an AI-Integrated Biosimulation Platform.

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca-mediated SARS-CoV-2 cellular entry and replication are noteworthy.

In Silico Simulation of the Systemic Drug Exposure Following the Topical Application of Opioid Analgesics in Patients with Cutaneous Lesions.

The use of opioid analgesics in treating severe pain is frequently associated with putative adverse effects in humans. Topical agents that are shown to have high efficacy with a favorable safety profile in clinical settings are great alternatives for pain management of multimodal analgesia. However, the risk of side effects induced by transdermal absorption and systemic exposure is of great concern as they are challenging to predict.

Driving success in personalized medicine through AI-enabled computational modeling.

The development of successful drugs is expensive and time-consuming because of high clinical attrition rates. This is caused partially by the rupture seen in the translatability of the drug from the bench to the clinic in the context of personalized medicine. Artificial intelligence (AI)-driven platforms integrated with mechanistic modeling have become instrumental in accelerating the drug development process by leveraging data ubiquitously across the various phases.

Molecular Simulation and Statistical Learning Methods toward Predicting Drug-Polymer Amorphous Solid Dispersion Miscibility, Stability, and Formulation Design.

Amorphous solid dispersions (ASDs) have emerged as widespread formulations for drug delivery of poorly soluble active pharmaceutical ingredients (APIs). Predicting the API solubility with various carriers in the API-carrier mixture and the principal API-carrier non-bonding interactions are critical factors for rational drug development and formulation decisions. Experimental determination of these interactions, solubility, and dissolution mechanisms is time-consuming, costly, and reliant on trial and error.

RNAseq Analysis of Rodent Spaceflight Experiments Is Confounded by Sample Collection Techniques.

To understand the physiological changes that occur in response to spaceflight, mice are transported to the International Space Station (ISS) and housed for variable periods of time before euthanasia on-orbit or return to Earth. Sample collection under such difficult conditions introduces confounding factors that need to be identified and addressed. We found large changes in the transcriptome of mouse tissues dissected and preserved on-orbit compared with tissues from mice euthanized on-orbit, preserved, and dissected after return to Earth.

Author Correction: Multi-omics analysis of multiple missions to space reveal a theme of lipid dysregulation in mouse liver.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Multi-omics analysis of multiple missions to space reveal a theme of lipid dysregulation in mouse liver.

Spaceflight has several detrimental effects on the physiology of astronauts, many of which are recapitulated in rodent models. Mouse studies performed on the Space Shuttle showed disruption of lipid metabolism in liver. However, given that these animals were not sacrificed on-orbit and instead returned live to earth, it is unclear if these disruptions were solely induced by space stressors (e.

Peripheral reduction of FGFR4 with antisense oligonucleotides increases metabolic rate and lowers adiposity in diet-induced obese mice.

Obesity is a primary risk factor for multiple metabolic disorders. Many drugs for the treatment of obesity, which mainly act through CNS as appetite suppressants, have failed during development or been removed from the market due to unacceptable adverse effects. Thus, there are very few efficacious drugs available and remains a great unmet medical need for anti-obesity drugs that increase energy expenditure by acting on peripheral tissues without severe side effects.

Pharmacodynamics and subchronic toxicity in mice and monkeys of ISIS 388626, a second-generation antisense oligonucleotide that targets human sodium glucose cotransporter 2.

ISIS 388626, a 2'-methoxyethyl (MOE)-modified antisense oligonucleotide (ASO) that targets human sodium glucose cotransporter 2 (SGLT2) mRNA, is in clinical trials for the management of diabetes. SGLT2 plays a pivotal role in renal glucose reabsorption, and inhibition of SGLT2 is anticipated to reduce hyperglycemia in diabetic subjects by increasing urinary glucose elimination. To selectively inhibit SGLT2 in the kidney, ISIS 388626 was designed as a "shortmer" ASO, consisting of only 12 nucleotides with two 2'-MOE-modified nucleotides at the termini.

Insulin regulation of phosphoenolpyruvate carboxykinase-c gene transcription: the role of sterol regulatory element-binding protein 1c.

The effect of insulin on the regulation of phosphoenolpyruvate carboxykinase C (PEPCK-C) gene transcription, while pivotal for control of carbohydrate metabolism, constitutes only a small part of its overall action in cellular processes. Transcription of the PEPCK-C gene is the target for a number of pathways involved in the signal transduction initiated by insulin, and these processes involve an array of transcription factors and co-regulatory proteins that either alone or in concert bind to a subset of sites in the gene promoter to regulate its expression. This review will focus on a specific transcription factor, sterol regulatory element-binding protein 1c (SREBP-1c), and its role in the control of PEPCK-C gene transcription.

Several transcription factors are recruited to the glucose-6-phosphatase gene promoter in response to palmitate in rat hepatocytes and H4IIE cells.

Fatty acids and glucose are strong modulators of the expression of glucose-6-phosphatase (Glc-6-Pase), an enzyme that plays a key role in glucose homeostasis. PUFA inhibit, whereas SFA and monounsaturated fatty acids induce the expression of the Glc-6-Pase gene. Palmitate and oleate are the most abundant fatty acid species in circulation during food deprivation in mammals.

A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation.

The adaptive response to amino acid limitation in mammalian cells inhibits global protein synthesis and promotes the expression of proteins that protect cells from stress. The arginine/lysine transporter, cat-1, is induced during amino acid starvation by transcriptional and post-transcriptional mechanisms. It is shown in the present study that the transient induction of cat-1 transcription is regulated by the stress response pathway that involves phosphorylation of the translation initiation factor, eIF2 (eukaryotic initiation factor-2).

Glucocorticoids regulate transcription of the gene for phosphoenolpyruvate carboxykinase in the liver via an extended glucocorticoid regulatory unit.

The hepatic transcriptional regulation by glucocorticoids of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C) gene is coordinated by interactions of specific transcription factors at the glucocorticoid regulatory unit (GRU). We propose an extended GRU that consists of four accessory sites, two proximal AF1 and AF2 sites and their distal counterpart dAF1 (-993) and a new site, dAF2 (-1365); together, these four sites form a palindrome. Sequencing and gel shift binding assays of hepatic nuclear proteins interacting with these sites indicated similarity of dAF1 and dAF2 sites to the GRU proximal AF1 and AF2 sites.

Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C.

Transcription of the gene for PEPCK-C occurs in a number of mammalian tissues, with highest expression occurring in the liver, kidney cortex, and white and brown adipose tissue. Several hormones and other factors, including glucagon, epinephrine, insulin, glucocorticoids and metabolic acidosis, control this process in three responsive tissues, liver, adipose tissue, and kidney cortex. Expression of the gene in these three tissues in regulated in a different manner, responding to the specific physiological role of the tissue.

SREBP-1c and Sp1 interact to regulate transcription of the gene for phosphoenolpyruvate carboxykinase (GTP) in the liver.

The sterol regulatory element-binding protein-1c (SREBP-1c), as well as SREBP-1a and SREBP-2, inhibit transcription of the gene encoding the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C). There are two SREBP regulatory elements (SREs) in the PEPCK-C gene promoter (-322 to -313 and -590 to -581). The SRE at -590 overlaps an Sp1 site on the opposite strand of the DNA.