Computational Compensatory Mutation Discovery Approach: Predicting a PARP1 Variant Rescue Mutation

The prediction of protein mutations that affect function may be exploited for multiple uses. In the context of disease variants, the prediction of compensatory mutations that reestablish functional phenotypes could aid in the development of genetic therapies. In this work, we present an integrated approach that combines coevolutionary analysis and molecular dynamics (MD) simulations to discover functional compensatory mutations. This approach is employed to investigate possible rescue mutations of a poly(ADP-ribose) polymerase 1 (PARP1) variant, PARP1 V762A, associated with lung cancer and follicular lymphoma. MD simulations show PARP1 V762A exhibits noticeable changes in structural and dynamical behavior compared with wild type PARP1. Our integrated approach predicts A755E as a possible compensatory mutation based on coevolutionary information, and molecular simulations indicate that the PARP1 A755E/V762A double mutant exhibits similar structural and dynamical behavior to WT PARP1. Our methodology can be broadly applied to a large number of systems where SNPs have been identified as connected to disease and can shed light on the biophysical effects of such changes as well as provide a way to discover potential mutants that could restore wild type-like functionality. This can in turn be further utilized in the design of molecular therapeutics that aim to mimic such compensatory effect.

Molecular Insights of SARS-CoV-2 Infection and Molecular Treatments

: The coronavirus disease emerged in December 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome-related coronavirus 2 (SARS-CoV-2) and its rapid global spread has brought an international health emergency and urgent responses for seeking efficient prevention and therapeutic treatment. This has led to imperative needs for illustration of the molecular pathogenesis of SARS-CoV-2, identification of molecular targets or receptors, and development of antiviral drugs, antibodies, and vaccines. In this study, we investigated the current research progress in combating SARS-CoV-2 infection. Based on the published research findings, we first elucidated, at the molecular level, SARS-CoV-2 viral structures, potential viral host-cell-invasion and pathogenic mechanisms, main virus-induced immune responses, and emerging SARS-CoV-2 variants. We then focused on the main virus- and host-based potential targets, summarized and categorized effective inhibitory molecules based on drug development strategies for COVID-19, that can guide efforts for the identification of new drugs and treatment for this problematic disease. Current research and development of antibodies and vaccines were also introduced and discussed. We concluded that the main virus entry route- SARS-CoV-2 spike protein interaction with ACE2 receptors has played a key role in guiding the development of therapeutic treatments against COVID-19, four main therapeutic strategies may be considered in developing molecular therapeutics, and drug repurposing is likely to be an easy, fast and low-cost approach in such a short period of time with urgent need of antiviral drugs. Additionally, the quick development of antibody and vaccine candidates has yielded promising results, but the wide-scale deployment of safe and effective COVID-19 vaccines remains paramount in solving the pandemic crisis. As new variants of the virus begun to emerge, the efficacy of these vaccines and treatments must be closely evaluated. Finally, we discussed the possible challenges of developing molecular therapeutics for COVID-19 and suggested some potential future efforts. Despite the limited availability of literatures, our attempt in this work to provide a relatively comprehensive overview of current SARS-CoV-2 studies can be helpful for quickly acquiring the key information of COVID-19 and further promoting this important research to control and diminish the pandemic.

Annotation of Putative Circadian Rhythm-Associated Genes in Diaphorina citri (Hemiptera : Liviidae)

The circadian rhythm is a process involving multiple genes that generates an internal molecular clock, allowing organisms to anticipate environmental conditions produced by the earth's rotation on its axis. This report presents the results of the manual curation of twenty-seven genes likely associated with circadian rhythm in the genome of Diaphorina citri, the Asian citrus psyllid. This insect acts as the vector of the bacterial pathogen Candidatus Liberibacter asiaticus (CLas), the causal agent of citrus greening disease (Huanglongbing). This disease is the most severe detriment to citrus industries and has drastically decreased crop yields worldwide. Based on the genes identified in the psyllid genome, namely cry1 and cry2, D. citri likely possesses a circadian model similar to that of the lepidopteran butterfly, Danaus plexippus. Manual annotation of these genes will allow future molecular therapeutics to be developed that can disrupt the psyllid biology.

Advances in Lymphedema

Lymphedema is a common, complex, and inexplicably underappreciated human disease. Despite a history of relative neglect by health care providers and by governmental health care agencies, the last decade has seen an explosive growth of insights into, and approaches to, the problem of human lymphedema. The current review highlights the significant advances that have occurred in the investigative and clinical approaches to lymphedema, particularly over the last decade. This review summarizes the progress that has been attained in the realms of genetics, lymphatic imaging, and lymphatic surgery. Newer molecular insights are explored, along with their relationship to future molecular therapeutics. Growing insights into the relationships among lymphedema, obesity, and other comorbidities are important to consider in current and future responses to patients with lymphedema.

Bifunctional N-Aminopyridinium Reagents Enable C–H Amination, Olefin Carboamination Cascades

<div> <div> <div> <p>C–H amination reactions provide streamlined access to nitrogen-containing small molecules. Here, we disclose benzylic C–H amination with N-aminopyridiniums, which are bifunctional reagents that provide avenues for further diversification. Reductive activation of the incipient N–N bonds unveils electrophilic N-centered radicals, which can be engaged by nucleophilic partners such as olefins, silyl enol ethers, and electron-rich heterocycles. We highlight the synthetic potential of these sequences in the synthesis of tetrahydroisoquinolines, which are important heterocycles in molecular therapeutics, via anti-Markovnikov olefin carboamination. Unlike many C–H amination reactions that provide access to protected amines, the current method installs an easily diversifiable synthetic handle that serves as a lynchpin for C–H amination, deaminative N–N functionalization sequences. </p> </div> </div> </div>

Bifunctional N-Aminopyridinium Reagents Enable C–H Amination, Olefin Carboamination Cascades

<div> <div> <div> <p>C–H amination reactions provide streamlined access to nitrogen-containing small molecules. Here, we disclose benzylic C–H amination with N-aminopyridiniums, which are bifunctional reagents that provide avenues for further diversification. Reductive activation of the incipient N–N bonds unveils electrophilic N-centered radicals, which can be engaged by nucleophilic partners such as olefins, silyl enol ethers, and electron-rich heterocycles. We highlight the synthetic potential of these sequences in the synthesis of tetrahydroisoquinolines, which are important heterocycles in molecular therapeutics, via anti-Markovnikov olefin carboamination. Unlike many C–H amination reactions that provide access to protected amines, the current method installs an easily diversifiable synthetic handle that serves as a lynchpin for C–H amination, deaminative N–N functionalization sequences. </p> </div> </div> </div>

Mapping drug-target interactions and synergy in multi-molecular therapeutics for pressure-overload cardiac hypertrophy

Advancements in systems biology have resulted in the development of network pharmacology, leading to a paradigm shift from “one-target, one-drug” to “target-network, multi-component therapeutics”. We employ a chimeric approach involving in-vivo assays, gene expression analysis, cheminformatics, and network biology to deduce the regulatory actions of a multi-constituent Ayurvedic concoction, Amalaki Rasayana (AR) in animal models for its effect in pressure-overload cardiac hypertrophy. The proteomics analysis of in-vivo assays for Aorta Constricted and Biologically Aged rat models identify proteins expressed under each condition. Network analysis mapping protein–protein interactions and synergistic actions of AR using multi-component networks reveal drug targets such as ACADM, COX4I1, COX6B1, HBB, MYH14, and SLC25A4, as potential pharmacological co-targets for cardiac hypertrophy. Further, five out of eighteen AR constituents potentially target these proteins. We propose a distinct prospective strategy for the discovery of network pharmacological therapies and repositioning of existing drug molecules for treating pressure-overload cardiac hypertrophy.

Alzheimer’s Disease Neuropathological Comorbidities are Common in the Younger-Old

Background: Clinicopathological studies have demonstrated that Alzheimer’s disease dementia (ADD) is often accompanied by clinically undetectable comorbid neurodegenerative and cerebrovascular disease that alter the rate of cognitive decline. Aside from causing increased variability in clinical response, it is possible that the major ADD comorbidities may not respond to ADD-specific molecular therapeutics. Objective: As most reports have focused on comorbidity in the oldest-old, its extent in younger age groups that are more likely to be involved in clinical trials is largely unknown; our objective is to provide this information. Methods: We conducted a survey of neuropathological comorbidities in sporadic ADD using data from the US National Alzheimer’s Coordinating Center. Subject data was restricted to those with dementia and meeting National Institute on Aging-Alzheimer’s Association intermediate or high AD Neuropathological Change levels, excluding those with known autosomal dominant AD-related mutations. Results: Highly prevalent ADD comorbidities are not restricted to the oldest-old but are common even in early-onset ADD. The percentage of cases with ADD as the sole major neuropathological diagnosis is highest in the under-60 group, where “pure” ADD cases are still in the minority at 44%. After this AD as a sole major pathology in ADD declines to roughly 20%in the 70s and beyond. Lewy body disease is the most common comorbidity at younger ages but actually is less common at later ages, while for most others, their prevalence increases with age. Conclusion: Alzheimer’s disease neuropathological comorbidities are highly prevalent even in the younger-old.