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Use of inhibitors and cell based therapies to combat a fatal immune response in COVID-19

UC researchers sought to define the host immune response, the “cytokine storm” , that has been implicated in fatal COVID-19 using an AI-based approach. Over 45,000 publicly available transcriptomic datasets of viral pandemics were analyzed to extract a 166-gene signature. The signature was surprisingly conserved in all viral pandemics, including COVID-19, inspiring the nomenclature ViP-signature. A subset of 20-genes classified disease severity in respiratory pandemics. The ViP signatures pinpointed airway epithelial and myeloid cells as the major contributors of an IL-15 cytokine storm, and epithelial and NK cell destruction as determinants of severity/fatality. They also helped formulate precise therapeutic goals to reduce disease symptoms and severity. Thus, the ViP signatures provide a quantitative and qualitative framework for titrating the immune response in viral pandemics and may serve as a powerful unbiased tool in our armamentarium to rapidly assess disease severity and vet candidate drugs. 

Mammalian Milk Oligosaccharides as a Potential Prophylactic and Treatment for Viral Respiratory Diseases

Researchers at the University of California, Davis have developed a method of using mammalian milk oligosaccharides as a potential prevention or treatment for viral respiratory diseases - including COVID-19 and influenza.

Reversing COVID-19 associated ARDS and cytokine storm with N-acetylglucosamine

The rapid emergence and spread of a novel coronavirus disease (COVID-19) has caused a global pandemic. Excessive inflammation leading to acute respiratory distress syndrome (ARDS) is the primary driver of mortality in severe COVID-19 cases, and is yet to be addressed by current therapeutics. Researchers at UCI and Mt. Sinai Hospital have therefore developed an anti-inflammatory treatment using N-acetylglucosamine to lower the mortality and need for ventilators in critically ill COVID-19 patients.

The Vaccushield Aka Slacc (Suction-Assisted Local Aerosol Containment Chamber)

UCLA researchers in the Department of Anesthesiology and Perioperative Medicine have developed a device that can act as a protective barrier for healthcare workers from patients with contagious respiratory pathogens.

Fluorescence Lifetime Imaging Microscopy Device for Antibiotic Susceptibility Testing (FLIM-AST)

Antibiotic resistant bacterial infection is a global public health threat leading to prolonged hospital stays, higher medical costs, and increased mortality rates. UCI researchers developed a device to rapidly determine antibiotic susceptibility of bacteria from patient samples to determine more effective antibiotic treatments.

Method to Enhance the Effectiveness of HIV Vaccines

Researchers at the University of California, Davis have developed adjuvants that promotes the efficacy of HIV vaccines.

Chronic Wound Mouse Model

Prof. Manuela Martins-Green and colleagues from the University of California, Riverside have developed a mouse model for chronic wounds in db/db-/- diabetic mice. Wounds are considered chronic when the body is unable to properly facilitate every stage of the healing process due to Oxidative Stress (OS), which occurs when an imbalance of redox chemicals exists in the damaged tissues. To create the chronic  wounds the mice were treated with inhibitors of antioxidant enzymes (IAE) at the time of wounding only. The wounds were then covered with tegaderm membranes and allowed to become chronic. Control wounds were treated with placebo. Fig 1: Percent open wound area over time in wounds of C57BL/6 and db/db-/- mice.  

COMPOSITIONS AND METHODS FOR IDENTIFYING HOST CELL TARGET PROTEINS FOR TREATING RNA VIRUS INFECTIONS

Viral infection is a multistep process involving complex interplay between viral life cycle and host immunity. One defense mechanism that hosts use to protect cells against the virus are nucleic-acid-mediated surveillance systems, such as RNA interference-driven gene silencing and CRISPR-Cas mediated gene editing. Another important stage for host cells to combat virus replication is translational regulation, which is particular important for the life cycle of RNA viruses, such as Hepatitis C virus and Coronavirus.  While efforts to characterize structural features of viral RNA have led to a better understanding of translational regulation, no systematical approaches to identify important host genes for controlling viral translation have been developed and little is known about how to regulate host-virus translational interaction to prevent and treat infections caused by RNA viruses.   UC Berkeley researchers have developed a high-throughput platform using CRISPR-based target interrogation to identify new therapeutics targets or repurposed drug targets for blocking viral RNA translation.  The new kits can also be used to identify important domains within target proteins that are required for regulating (viral RNA translation) and can inform drug design and development for treating RNA viruses.

Live Attenuated Vaccine Against Group A Streptococcus Infection

Streptococcus pyogenes (group A Streptococcus [GAS]) is a leading health and economic burden worldwide, with an estimated 700 million infections occurring annually. Among these are 18.1 million severe cases that result in over 500,000 deaths. Despite active research, a protective vaccine remains elusive, leaving antimicrobial agents as the sole pharmacological intervention against GAS. To date, penicillin remains a primary drug of choice for combating GAS infections. However, despite no apparent emergence of resistant isolates, the rate of treatment failures with penicillin has increased to nearly 40% in certain regions of the world. Due to the high prevalence of GAS infection and the decreasing efficacy of the available repertoire of countermeasures, it is critical to investigate alternative approaches against GAS infection. An emerging strategy for combating pathogenic bacteria involves targeting virulence. To avoid immune clearance, GAS expresses a wide variety of secreted and cell-associated virulence factors to facilitate survival during infection. Despite decades of inquiry into the role and regulation of GAS virulence factors, the function and potential importance of many proteins involved in pathogenicity remain unknown.

Novel Methods To Eliminate Dormant HIV Reservoirs

Human immunodeficiency virus type-1 (HIV-1) is a pathogenic retrovirus and the causative agent of acquired immunodeficiency syndrome (AIDS) and AIDS-related disorders. There were 1.7 million new infections globally in 2018, and ~38 million people are currently living with HIV-1. Although the introduction of antiretroviral therapy (ART) has prevented millions of AIDS-related deaths worldwide, patients must continue to receive ART for the remainder of their lives. HIV-1 reservoirs persist even while subjects are on ART, leading to a rapid increase in viral replication when therapy is discontinued. Therefore, eradication of persistent HIV-1 reservoirs remains the main barrier to achieving a cure for HIV-1/AIDS. The prevailing view of persistence suggests that the virus remains in a latent state in memory CD4+ T cells regardless of plasma viral loads, allowing the virus to establish a life-long infection in the host. Since the latent virus is refractory to existing antiretroviral therapies, curative strategies are now focusing on agents that reactivate viral replication and render it susceptible to conventional therapy. Any strategy aimed at controlling and eradicating viral reservoirs in HIV-1-infected individuals must target such latent reservoirs. The mammalian genome encodes thousands of long noncoding RNAs (lncRNAs, >200 nucleotides), including intergenic lncRNAs (lincRNAs), which are increasingly recognized to play major roles in gene regulation. The pathophysiological functions and mechanisms of lncRNAs in gene regulation have started to emerge. Work over the last few years has begun to uncover the role of lncRNAs in modulating HIV-1 gene expression.

Computational Cytometer Based On Magnetically-Modulated Coherent Imaging And Deep Learning

UCLA researchers in the Department of Electrical & Computer Engineering have designed and built a computational cytometer capable of detecting rare cells at low concentration in whole blood samples. This technique and instrumentation can be used for cancer metastasis detection, immune response characterization and many other biomedical applications.

Crosslinkable Polymer Coating Prevents Bacterial Infection on Implant Surface

UCLA researchers in the Department of Orthopedic Surgery have developed a polymer implant coating that mitigates bacterial infections on the implant surface.

TRM:CRAMP Knockout Mice In The C57bl/6 Background

The mouse Camp gene is an ortholog of the human gene CAMP, which encodes the precursor of cathelicidin antimicrobial peptide LL-37 (or CRAMP in mouse). Expressed mucosal epithelial cells, circulating neutrophils, and myeloid bone marrow cells, Camp is an essential part of the first line of defense against infection. In addition to antimicrobial activity, cathelicidin antimicrobial peptide plays a role in NK cell-mediated tumor growth suppression, and when secreted by neutrophils acts, as an attractant for monocytes, promoting wound healing or angiogenesis. Mouse CRAMP is implicated in adaptive immune response regulation and can interfere with TLR function via interactions with hyaluronan. Mice deficient in CRAMP are more susceptible to experimentally induced necrotic skin infection with Group A Streptococcus, urinary tract infection with uropathogenic E. coli, Pseudomonas aeruginosa infection, and meningococcal Neisseria meningitidis infection.

Predicting Cefixime Susceptiblity Using Molecular Genotyping

UCLA researchers in the David Geffen School of Medicine have developed a novel method to detect the susceptibility of Neisseria gonorrhoeae to the antibiotic cefixime.

Pharmacological Mitigation of Late-Stage Toxemia

Anthrax disease, caused by Bacillus anthracis, is a highly lethal infection with patient fatality rate between 45-85% during fulminant, toxemia-related late-stages of infection. Systemic release of anthrax edema toxin during late-stage infection induces vascular collapse through endothelial barrier disruption, culminating in fatal hypovolemic shock, a hallmark of systemic anthrax infection. Existing therapeutic strategies to mitigate the effects of anthrax infections only target early-stage infection vis-à-vis bacterial clearance (antibiotics) and toxin-host cell interactions (anti-toxin antibodies), but are ineffective in preventing toxemic-shock which is induced even after pathogen clearance. In fact, patients with fulminant infection require aggressive, continuous fluid drainage and assisted breathing, and no effective therapeutic interventions exist currently for this critical stage of infection. Pathogen induced cell-cell barrier disruption (anthrax, cholera, traveler’s diarrhea, gastroenteritis, pertussis, pneumonia) account for significant socio-economic impacts each year. Stand-alone antitoxin therapies such as those mentioned here can fulfill the unmet medical need for measures that significantly improve the survival rate of patients with severe infections, and lower the risk for development of antibiotic resistance.   High fatality rate of anthrax infections, despite intense antibiotic and supportive therapies, are primarily due to the continuing activities of anthrax exotoxins (ET and LT) released in the patient's circulatory system. Edema toxin or ET, a highly active adenylate cyclase that induces uncontrolled, pathological elevation in cellular levels of the second messenger cAMP is a major virulence protein of Bacillus anthracis and mediates significant lethality during fulminant stages of infection. ET induces rapid disruption of the endothelial barrier, resulting in irreversible tissue damage and lethality due massive fluid loss resulting in cardiovascular collapse and hypovolemic shock. It is therefore imperative that new therapeutic measures be developed that effectively blocks the intracellular function of ET (i.e. cellular proteins/pathways co-opted to induce barrier instability), to reduce fatalities associated with anthrax toxemia.

Novel Non-Antibody-Based Chimeric Antigen Receptor Against HIV That Also Protects Cells From Infection

UCLA researchers in the Department of Medicine have developed a novel chimeric antigen receptor (CAR) that targets T cells against HIV while protecting T cells from HIV infection.

New Molecular Tweezers Against Neurological Disorders And Viral Infections

UCLA researchers in the Department of Neurology with an international team of scientists have developed several new molecular tweezer derivatives with novel synthesis methods that significantly improved the therapeutic efficacy and pharmacokinetic characteristics of the drug candidates.

Vaccines Against Herpes Simplex Virus Infection

Herpes simplex virus (HSV) infections affect billions of patients worldwide and can manifest its symptoms as painful blisters or ulcers at oral, ocular or genital locations. Symptomatic patients can currently only alleviate their pains with antiviral medication. These technologies propose a shift in focus toward novel protective epitopes as the foundation for new vaccines.

Viral Expression Vector Targeting HIV-1

UCLA researchers from the Department of Microbiology, Immunology, & Molecular Genetics have developed a viral expression vector that combines two reagents effective against HIV-1 infection.

Novel Synthesis of Streptogramin A Antibiotics

A modular, scalable, chemical synthesis platform that produces new Streptogramin A class antibiotic candidates.

Safe Potent Single Platform Vaccine Against Tier 1 Select Agents and Other Pathogens

UCLA researchers in the Department of Medicine have developed a novel vaccine platform against Tier 1 Select Agents to prevent infectious diseases such as tularemia, anthrax, plague, and melioidosis.

Nanoparticles For Specific Detection And Killing of Pathogenic Bacteria

UCLA researchers in the Department of Chemistry and Biochemistry and Department of Medicine have developed novel functionalized mesoporous silica nanoparticles that can specifically identify pathogenic bacteria and deliver on-target drug treatments.

Systems And Methods For Therapeutic Agent Delivery

UCLA researchers at the Department of Physics have developed a system that is capable of delivering a therapeutic agent to a specifically targeted tissue using ultrasound.

Disulfide Bioconjugation

UCLA researchers in the Department of Chemistry and Biochemistry have proposed a one-step radical mechanism for disulfide bioconjugation that overcomes many concerns associated with the free cysteine residues that result from current bioconjugation techniques.

Endogenous Human Protein Nanoparticle-Based Immune-Focusing Antiviral Vaccine

UCLA researchers in the Department of Biological Chemistry have developed a novel nanoparticle based antiviral vaccine capable of targeting many viruses.

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