Phage display as a tool for vaccine and immunotherapy development.

Bacteriophages, or phages, are viruses that specifically infect bacteria and coopt the cellular machinery to create more phage proteins, eventually resulting in the release of new phage particles. Phages are heavily utilized in bioengineering for applications ranging from tissue engineering scaffolds to immune signal delivery. Of specific interest to vaccines and immunotherapies, phages have demonstrated an ability to activate both the innate and adaptive immune systems.

Biomaterials as Tools to Decode Immunity.

The immune system has remarkable capabilities to combat disease with exquisite selectivity. This feature has enabled vaccines that provide protection for decades and, more recently, advances in immunotherapies that can cure some cancers. Greater control over how immune signals are presented, delivered, and processed will help drive even more powerful options that are also safe.

Development of A Fission Yeast Cell-Based Platform for High Throughput Screening of HIV-1 Protease Inhibitors.

Background: HIV-1 protease inhibitor (PI) is one of the most potent classes of drugs in combinational antiretroviral therapies (cART). When a PI is used in combination with other anti- HIV drugs, cART can often suppress HIV-1 below detection thus prolonging the patient's lives. However, the challenge often faced by patients is the emergence of HIV-1 drug resistance.

The single-cell transcriptomic landscape of early human diabetic nephropathy.

Diabetic nephropathy is characterized by damage to both the glomerulus and tubulointerstitium, but relatively little is known about accompanying cell-specific changes in gene expression. We performed unbiased single-nucleus RNA sequencing (snRNA-seq) on cryopreserved human diabetic kidney samples to generate 23,980 single-nucleus transcriptomes from 3 control and 3 early diabetic nephropathy samples. All major cell types of the kidney were represented in the final dataset.

Engineering Biomaterials to Direct Innate Immunity.

Small alterations during early stages of innate immune response can drive large changes in how adaptive immune cells develop and function during protective immunity or disease. Controlling these events creates exciting potential in development of immune engineered vaccines and therapeutics. This progress report discusses recent biomaterial technologies exploiting innate immunity to dissect immune function and to design new vaccines and immunotherapies for infectious diseases, cancer, and autoimmunity.

Accuracy of Three Screening Tools for Prenatal Substance Use.

Objective: To compare and evaluate the accuracy of three screening tools in identifying illicit drug use and prescription drug misuse among a diverse sample of pregnant women.

Methods: This prospective cross-sectional study enrolled a consecutive sample of 500 pregnant women, stratified by trimester, receiving care in two prenatal clinical settings in Baltimore, Maryland, from January 2017 to January 2018. All participants were administered three index tests: 4P's Plus, NIDA Quick Screen-ASSIST (Modified Alcohol, Smoking and Substance Involvement Screening Test), and the SURP-P (Substance Use Risk Profile-Pregnancy) scale, and administered reference tests (urine and hair drug testing) at the in-person baseline visit.

Design, Synthesis, and Characterization of Macrocyclic Inhibitors of the Proprotein Convertase Furin.

The activation of viral glycoproteins by the host protease furin is an essential step in the replication of numerous pathogenic viruses. Thus, effective inhibitors of furin could serve as broad-spectrum antiviral drugs. A crystal structure of an inhibitory hexapeptide derivative in complex with furin served as template for the rational design of various types of new cyclic inhibitors.

Engineering Immune Tolerance with Biomaterials.

Autoimmune diseases, rejection of transplanted organs and grafts, chronic inflammatory diseases, and immune-mediated rejection of biologic drugs impact a large number of people across the globe. New understanding of immune function is revealing exciting opportunities to help tackle these challenges by harnessing-or correcting-the specificity of immune function. However, realizing this potential requires precision control over the interaction between regulatory immune cues, antigens attacked during inflammation, and the tissues where these processes occur.

Peptidoglycan Recognition Protein 4 Suppresses Early Inflammatory Responses to and Contributes to Sphingosine-1-Phosphate Receptor Agonist-Mediated Disease Attenuation.

Incidence of whooping cough (pertussis), a bacterial infection of the respiratory tract caused by the bacterium , has reached levels not seen since the 1950s. Antibiotics fail to improve the course of disease unless administered early in infection. Therefore, there is an urgent need for the development of antipertussis therapeutics.

Pencil beam scanning versus passively scattered proton therapy for unresectable pancreatic cancer.

Background: With an increasing number of proton centers capable of delivering pencil beam scanning (PBS), understanding the dosimetric differences in PBS compared to passively scattered proton therapy (PSPT) for pancreatic cancer is of interest.

Methods: Optimized PBS plans were retrospectively generated for 11 patients with locally advanced pancreatic cancer previously treated with PSPT to 59.4 Gy on a prospective trial.

Vagus Nerve Stimulation: Changing the Paradigm for Chronic Severe Depression?

Vagus nerve stimulation (VNS) has been studied for its effect on treatment-resistant depression. Open-label studies have shown a significant positive effect in an especially treatment-resistant depressive population. Insurance company support for VNS has been limited but may be reviewed given recent positive open-label data.

Renal sodium and magnesium reabsorption are not coupled in a mouse model of Gordon syndrome.

Active reabsorption of magnesium (Mg ) in the distal convoluted tubule (DCT) of the kidney is crucial for maintaining Mg homeostasis. Impaired activity of the Na -Cl -cotransporter (NCC) has been associated with hypermagnesiuria and hypomagnesemia, while increased activity of NCC, as observed in patients with Gordon syndrome, is not associated with alterations in Mg balance. To further elucidate the possible interrelationship between NCC activity and renal Mg handling, plasma Mg levels and urinary excretion of sodium (Na ) and Mg were measured in a mouse model of Gordon syndrome.

Dominant-Negative DISC1 Alters the Dopaminergic Modulation of Inhibitory Interneurons in the Mouse Prefrontal Cortex.

A truncated () gene increases the risk of psychiatric disorders, probably affecting cortical interneurons. Here, we sought to determine whether this cell population is affected in mice carrying a truncated () allele (DN-DISC1). We utilized whole cell recordings to assess electrophysiological properties and modulation by dopamine (DA) in two classes of interneurons: fast-spiking (FS) and low threshold-spiking (LTS) interneurons in wild-type and DN-DISC1 mice.

Access to and Experiences with, e-Health Technology Among Glaucoma Patients and Their Relationship with Medication Adherence.

t

Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota.

Background: The diversity and composition of the gut microbiota may affect breast cancer risk by modulating systemic levels of oestrogens and inflammation. The current investigation tested this hypothesis in postmenopausal women by identifying breast cancer associations with an inflammation marker, oestrogen levels, and faecal microbes that were or were not coated with mucosal immunoglobulin A (IgA).

Methods: In this population-based study, we compared 48 postmenopausal breast cancer cases (75% stage 0-1, 88% oestrogen-receptor positive) to 48 contemporaneous, postmenopausal, normal-mammogram, age-matched controls.

Optimization of Substrate-Analogue Furin Inhibitors.

The proprotein convertase furin is a potential target for drug design, especially for the inhibition of furin-dependent virus replication. All effective synthetic furin inhibitors identified thus far are multibasic compounds; the highest potency was found for our previously developed inhibitor 4-(guanidinomethyl)phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148). An initial study in mice revealed a narrow therapeutic range for this tetrabasic compound, while significantly reduced toxicity was observed for some tribasic analogues.

Designing biomaterials with immunomodulatory properties for tissue engineering and regenerative medicine.

Recent research in the vaccine and immunotherapy fields has revealed that biomaterials have the ability to activate immune pathways, even in the absence of other immune-stimulating signals. Intriguingly, new studies reveal these responses are influenced by the physicochemical properties of the material. Nearly all of this work has been done in the vaccine and immunotherapy fields, but there is tremendous opportunity to apply this same knowledge to tissue engineering and regenerative medicine.

Control of autoimmune inflammation using liposomes to deliver positive allosteric modulators of metabotropic glutamate receptors.

Multiple sclerosis (MS) is an autoimmune disease where myelin is incorrectly recognized as foreign and attacked by the adaptive immune system. Dendritic cells (DCs) direct adaptive immunity by presenting antigens to T cells, therefore serving as a target for autoimmune therapies. N-Phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator of metabotropic glutamate receptor 4 (mGluR4), can promote regulatory T cells by altering cytokine secretion to bias T cell differentiation.

American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock.

Objectives: The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine "Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock."

Design: Society of Critical Care Medicine members were identified from general solicitation at Society of Critical Care Medicine Educational and Scientific Symposia (2006-2014).

Controlled Release of Second Generation mTOR Inhibitors to Restrain Inflammation in Primary Immune Cells.

Autoimmune disease occurs when the immune system incorrectly targets the body's own tissue. Inflammatory CD4 T cell phenotypes, such as T1 and T17, are key drivers of this attack. Recent studies demonstrate treatment with rapamycin-a key inhibitor of the mTOR pathway-can skew T cell development, moving T cell responses away from inflammatory phenotypes and toward regulatory T cells (T).