Systematic identification of ACE2 expression modulators reveals cardiomyopathy as a risk factor for mortality in COVID-19 patients

Background Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for SARS-CoV-2. It plays critical roles in both the transmission and the pathogenesis of COVID-19. Comprehensive profiling of ACE2 expression patterns could reveal risk factors of severe COVID-19 illness. While the expression of ACE2 in healthy human tissues has been well characterized, it is not known which diseases and drugs might be associated with ACE2 expression. Results We develop GENEVA (GENe Expression Variance Analysis), a semi-automated framework for exploring massive amounts of RNA-seq datasets. We apply GENEVA to 286,650 publicly available RNA-seq samples to identify any previously studied experimental conditions that could be directly or indirectly associated with ACE2 expression. We identify multiple drugs, genetic perturbations, and diseases that are associated with the expression of ACE2, including cardiomyopathy, HNF1A overexpression, and drug treatments with RAD140 and itraconazole. Our joint analysis of seven datasets confirms ACE2 upregulation in all cardiomyopathy categories. Using electronic health records data from 3936 COVID-19 patients, we demonstrate that patients with pre-existing cardiomyopathy have an increased mortality risk than age-matched patients with other cardiovascular conditions. GENEVA is applicable to any genes of interest and is freely accessible at http://genevatool.org. Conclusions This study identifies multiple diseases and drugs that are associated with the expression of ACE2. The effect of these conditions should be carefully studied in COVID-19 patients. In particular, our analysis identifies cardiomyopathy patients as a high-risk group, with increased ACE2 expression in the heart and increased mortality after SARS-COV-2 infection.

Differential diagnosis of tinnitus

Tinnitus is a common clinical symptomthat can be debilitating. Risk factors forits development are hearing loss, use of ototoxic drugs, head injury and depression. At the onset of the disease, the likelihood of ear pathology, the presence of anxiety and depression should be considered. There are no effective drug treatments for tinnitus, although a number of scientific studies are ongoing to determine the mechanisms of the development of this condition and to search for possible options for its treatment. When ear pathology is detected, surgical interventions can be effective, but tinnitus associated with this disease persists. Available treatment approaches include hearing aids for diagnosed hearing loss (even mild or unilateral), broadband sound therapy, and counseling. Cognitive-behavioral therapy is indicated for some patients, but availability remains inadequate. The evidence base is most significant for the combination of sound therapy and CBT-based counseling, although clinical trials are complicated by the heterogeneity of the tinnitus patient population.

Inter Molecular Level Interaction Studies of Combination Drug Crizotinib And Temozolomide in Glioblastoma Multiforme Targets: An In-silico Approach

Combination drug treatments are frequently used in many diseases, including cancers and AIDS. The main aims of these treatments are to reduce toxicity, decrease or delay drug resistance, and improve drug efficacy by inhibiting the activity of a specific target or groups of targets in a cell. The net effect of combination drug efficacy is mainly quantified and interpreted by various terminologies like synergy, additive, agonism, and antagonism based on drugs dose ratio. In single or combination drug treatment, drug action occurs on cells due to the intermolecular level interaction of drugs with protein/DNA/RNA/Enzyme. This type of inter molecular level interaction can be detected with the help of docking software. The current study aims to identify the inter-molecular level interaction of combination drug Crizotinib and Temozolomide with C-MET, C-ROS1, and ALK targets in Glioblastoma Multiforme(GBM). To identify this, we performed forward and reverse docking of drugs with these proteins, and the results were evaluated by drug properties and the complex energy. From the analysis study, we recognized that first, Crizotinib and then, after Temozolomide bounded docked complexes showed the least complex energy in all the docked complex structures, and the better complexes were identified from the result by MD simulation.

Cost-Effectiveness and Guidelines for Opioid Substitution Treatment

There was evidence indicating that in the treatment of opioid use disorder, injectable hydromorphone, or injectable methadone provided more benefit at less cost compared with injectable diacetylmorphine over a 6-month time horizon. Evidence suggests that in the treatment of opioid use disorder, both injectable hydromorphone and injectable diacetylmorphine are likely to provide more benefit at less cost than methadone maintenance treatment. Treatment with injectable hydromorphone was more cost-effective than injectable diacetylmorphine in opioid use disorder patients who do not respond to or relapse from drug treatments. The evidence is limited because observed data were collected during a short-term follow-up, and long-term cost-effectiveness outcomes were based on extrapolations beyond data from the actual studies. One guideline provided a weak recommendation, supported by low-quality evidence, for using slow-release oral morphine in older adults with adequate renal function in whom buprenorphine and methadone maintenance have been ineffective to treat opioid use disorder or could not be tolerated. Another guideline recommends using injectable hydromorphone or injectable diacetylmorphine for individuals with severe opioid use disorders who relapsed previous treatments failed. No relevant cost-effectiveness evidence or guidelines with recommendations regarding the use of oral hydromorphone, fentanyl patches, or fentanyl buccal tablets for opioid use disorder treatment were identified; therefore, no summary can be provided.

Technological prospecting of music therapy in Alzheimer's disease

Alzheimer's disease (AD) is characterized by cognitive impairment and progressive memory loss and drug treatments have limited efficacy. Thus, non-pharmacological interventions, such as music therapy, have shown to be promising as supporting pharmacological treatment and, therefore, may arouse commercial interest regarding the development of this type of product. Thus, this study aims to carry out a patentometric survey on patent registrations with music therapy in the treatment of AD. A systematic search was carried out from 2000 to 2020 on the Orbti-Questel website, searching for documents referring to music therapies in AD. The terms “Alzheimer music methodology active therapy” and “Alzheimer music methodology passive therapy” were used. After searching, reading, and excluding duplicate results, we found four patent families referring to music therapy in AD and all were selected as a result, which was considered little compared to the number of studies published on the subject.

The population genetics of collateral resistance and sensitivity

Resistance mutations against one drug can elicit collateral sensitivity against other drugs. Multi-drug treatments exploiting such trade-offs can help slow down the evolution of resistance. However, if mutations with diverse collateral effects are available, a treated population may evolve either collateral sensitivity or collateral resistance. How to design treatments robust to such uncertainty is unclear. We show that many resistance mutations in Escherichia coli against various antibiotics indeed have diverse collateral effects. We propose to characterize such diversity with a joint distribution of fitness effects (JDFE) and develop a theory for describing and predicting collateral evolution based on simple statistics of the JDFE. We show how to robustly rank drug pairs to minimize the risk of collateral resistance and how to estimate JDFEs. In addition to practical applications, these results have implications for our understanding of evolution in variable environments.

RoPod, a customizable toolkit for non-invasive root imaging, reveals cell type-specific dynamics of plant autophagy

Autophagy is the major catabolic process in eukaryotes and a key regulator of plant fitness. It enables rapid response to stress stimuli, essential for plastic adaptation of plants to changes in the environment. Fluorescent reporters and confocal microscopy are among the most frequently used methods for assessing plant autophagic activity. However, detection of dynamic changes in the pathway activity has been hampered by stresses imposed on living plant tissues during sample mounting and imaging. Here we implemented RoPod, a toolkit optimized for minimally-invasive time-lapse imaging of Arabidopsis roots, to reveal a time-resolved response of plant autophagy to drug treatments typically used for pathway modulation and discovered previously overlooked cell type-specific changes in the pathway response. These results not only give an insight into the complex dynamics of plant autophagy, but also provide necessary information for choosing sampling time for the end-point assays currently employed in plant autophagy research. RoPods are inexpensive and easy-to-use devices that are based on commercial or custom designed chambers, compatible with inverted microscopes. We describe a detailed protocol for the fabrication and use of RoPods and provide a complete pipeline including semi-automated image analysis for root hair growth assays, demonstrating the broader applicability of the RoPod toolkit.

Genes Contributing to Resilience and Sensitivity to Lisinopril at Old Age: Clinical Translation of GWA in Drosophila

Despite impressive results in restoring physical performance in rodent models, treatment with Renin-Angiotensin System (RAS) inhibitors such as Lisinopril have highly mixed results in humans, likely, in part, due to genetic variation in human populations. To date, the genetic determinants of responses to drugs such as RAS inhibitors remain unknown. Given the complexity of the relationship between physical traits and genetic background, genomic studies which predict genotype- and age-specific responses to drug treatments in humans or vertebrate animals are difficult. Here, using 126 genetically distinct lines of Drosophila, we tested the effects of Lisinopril on climbing speed and endurance at young and old age (N=14,310). Our data show that functional response and sensitivity to Lisinopril ranges from significant protection against physical decline (8–100% faster, P< 0.0001) to increased weakness (P< 0.0001) depending on both genotype and age (P< 0.0001). Genome-wide analyses revealed little to no overlap in candidate polymorphisms influencing sensitivity between ages nor between treatments within each age. Furthermore, network analyses led to identification of evolutionarily conserved genes in the WNT signaling pathway as being significantly associated with variations in sensitivity to Lisinopril. Genetic knockdown of Axin, frizzled, nemo, and wingless, genes with human orthologs AXIN1, FZD1, NLK, and WNT1, respectively, abolished the effects of Lisinopril treatment. Our results implicate these genes as contributors to the genotype- and age-specific effects of Lisinopril treatment and as potential therapeutic targets for improvement of resiliency. Our approach should be widely applicable for identifying genomic variants that predict age-dependent responses to pharmaceutical treatments.