United States

Plasmodium spp., the causative pathogen of malaria infected over 200 million people in the past year and killed over 600,000 of those—mostly children and women in Sub-Saharan Africa. A malaria vaccine that can prevent both symptomatic disease and infection is desperately needed if we are to eradicate the disease. Current vaccine candidates that target the major surface protein CSP have proven unable to provide such infection-blocking protection. The Wilder lab has identified another antigen (UIS3), which when targeted by passive transfer (injection) of antibodies can reduce parasite burden during the multi-day intracellular liver stage. Although they do not completely block infection on their own, passively transferred anti-UIS3 polyclonal antibodies can work synergistically with anti-CSP antibodies to increase infection-blocking protection from 0% to 64% in a stringent murine challenge model. These results were not replicated when this combination was tested via active vaccination using RNA-based vaccines, which is likely due to the failure of this vaccine platform to elicit anti-UIS3 antibodies. In addition to understanding why UIS3 was not amenable to RNA-based vaccination, we will need understand how these antibodies are functioning mechanistically to better design future vaccines. To this end, we created a panel of monoclonal antibodies against UIS3 and found that 1 of 6 was able to reduce parasite liver burden in the mice. To determine if this function correlated with the ability of the antibody to the region of UIS3 known to sequester host autophagy protein LC3, we performed ELISA against the full-length UIS3 protein and simply the LC3 binding domain. We found that the one antibody with function in vivo bound for FL and BD the best, leaving open the possibility that either affinity and/or LC3 binding dictate function. Our next experiments include screening new monoclonals while also using the existing set to determine if the single functional antibody works by allowing autophagy-mediated killing of the parasite or other immune mechanisms.


AMA Research Challenge 2022

Understanding the Mechanism of Action of Intracellularly acting anti-pyUIS3 Antibodies in Liver-stage Malaria Infection 

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Charles Lopresto, DO

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poster

Background
COVID-19 has had severe impacts both in terms of human health and disruption to society since appearing in December 2019. Our project aims to look at changes in biophysical properties of the surface glycoprotein (S) of SARS-COV-2 to understand the evolution of variants within the human population. 

Methods
We obtained SARS-COV-2 amino acid sequences from the NIH NCBI Virus database and imported them into Microsoft Excel. Each amino acid residue within the full-length sequences was assigned a parametric value based on total accessible surface area (ASAtot), non-polar accessible surface area (ASAnp), polar accessible surface area (ASApol), and net charge at pH 7.0 (Charge). These values were used to quantify differences between these properties in sequences. PYMOL was then used to plot areas of interest onto the molecular structure in both the open (RBD – “Up”) and closed (RBD – “Down”) conformations. Furthermore, changes in parametric values observed in the sequences were compared to a random amino acid sequence data set using KaleidaGraph to determine statistical significance. 

Results
Our analysis revealed evidence of sporadic changes occurring at amino acids at the surface of S. Interestingly, different regions seem to be mutated in different variants. The S2 domain, particularly in Delta and Zeta lineages, appears to be inherently mutable. Despite the fact mutations are well-tolerated in many parts of S, very few of these become fixed in the population, indicating these individual changes do not provide a global selective advantage. In the Delta linage, for example, we observed numerous sporadic mutations occurring particularly in the N domain, whereas in the Omicron lineage, a greater proportion of mutations become fixed in the population.

Conclusion
We conclude that mutations in SARS-COV-2 S may confer fitness in the infected individual, but may not be advantageous in an outbred population. The biophysical property changes observed can be applied to predicting T- and B-cell interactions with S, helping us assess the effectiveness of current vaccines against circulating variants and help formulate future vaccine targets to protect against a wider range of SARS-COV-2 variants.

Using Biophysical Properties of SARS-COV-2 Surface Glycoprotein to Determine its Ongoing Structural Evolution

Anesthesiology - Effects of Electric Spinal Cord Stimulation on Post-Surgical Pain in Mice - Anesthesiology

Introduction: 
Propofol gains popularity (from 16.7% to 58.1% in the USA during the decade 2006-15) in anesthesia services for outpatient colonoscopy1. Recently, two randomized control trials (RCTs) with large study sizes show propofol’s positive impact in patient satisfaction in comparison to tradition sedation (midazolam) for elective colonoscopy.2,3 A recent review evaluated patient satisfaction but their study’s inclusion criteria omitted similar RCTs comparing propofol with midazolam in elective colonoscopy. This meta-analysis attempted to know the numerical effect size between propofol and midazolam, with or without opioids, to understand the magnitude of propofol’s impact in patient satisfaction compared to tradition sedatives such as midazolam. 
Methods:
We searched PubMed, EMBASE, and Web of Science (WOS) for publications that reported RCTs in which adults undergoing elective colonoscopy were randomly assigned to propofol with or without opioids or midazolam sedation with or without opioids. Male and female adults with ASA scores I-III having outpatient colonoscopy were included, while patients receiving patient-controlled anesthesia and ASA IV-V were excluded (Figure 1). The process of identifying study trials is summarized in the PRISMA flow diagram (Figure 2). Satisfaction scales were converted to 10-point scales with mean and standard deviation calculated. Validated data were transferred to specialized software (RevMan 5, www.cochrane.org) for statistical analysis and preparation of forrest plots. Mean difference i.e., difference in means, random-effects model with 95% confidence interval was calculated and compared with a larger and positive mean difference indicating more patient satisfaction to propofol. 
Results:
The patients with propofol sedation and midazolam sedation totaled (n=925 vs. n=939) n = 1,864. Patient satisfaction was significantly higher in propofol with mean difference 0.71 [0.41-1.01] CI 95% (Figure 3). The meta-analysis showed no publication bias, but statistical heterogeneity was high I2 = 88% (Figure 3,4).
Conclusion:
Anesthetists appreciate propofol’s rapid onset, ease of titration, and anti-emetic properties. This meta-analysis helps understand the magnitude of propofol’s impact in patient satisfaction compared to traditional sedatives such as midazolam. 


Anesthesiology - The Effect Size of Patient Satisfaction in a Meta-Analysis of Randomized Controlled Trials Between Propofol and Midazolam in Elective Colonoscopy - Anesthesiology

Background: Sinoatrial node (SAN) cells, the natural pacemakers of the heart, determine the rate and rhythm of the heart’s electrical conduction system. Damage to these cells can lead to conditions such as arrhythmias and Sick Sinus Syndrome. These conditions are commonly treated with electronic pacemaker implants which can lead to risks of complications, such as infection. A more biologically compatible therapeutic alternative that could reduce the risk of complications could eventually include cell transplantation with SAN cells derived from human pluripotent stem cells (hPSCs). However, a protocol for the generation of SAN cells from hPSCs in vitro has not been well-established, although there are well-established protocols for the generation of other cardiomyocytes, such as ventricular and atrial cells. Our study aims to generate SAN-like cells in vitro by using the hPSC model.

Methods: To generate the SAN-like cells, we combined aspects of protocols for the generation of ventricular and atrial cells from hPSCs with a newer, published, successful protocol by Protze et al. proposed for generating SAN-like cells from hPSCs. By incorporating these protocols, SAN-like cells were generated by selective induction of cardiac progenitors and controlled maturation of the SAN lineage by mimicking their in vivo development. The cells were then characterized via light and fluorescent microscopy, flow cytometry, and immunofluorescence, and viability was assessed via light microscopy and flow cytometry.

Results: We successfully generated SAN-like cells as demonstrated by their faster beating pattern on light and fluorescent microscopy and a lack of NKX2-5 expression on immunofluorescence, two characteristics that distinguish SAN cells from other cardiomyocytes. However, flow cytometry demonstrated a small proportion of live cells and light microscopy observations demonstrated increased cellular debris and cell death morphology of the SAN-like cells, suggesting that viability of these cells was greatly reduced compared to other cardiomyocytes generated in vitro.

Conclusion: The successful generation of SAN-like cells from hPSCs provides a promising avenue in the development of novel biologic therapies that could improve outcomes in the most susceptible populations for rhythm disorders. Future studies need to address the issue of reduced viability of these cells compared to other in vitro generated cardiomyocytes.

Cardiology - In vitro generation of sinoatrial node-like cardiomyocytes derived from human pluripotent stem cells - Cardiology

In this study we define a novel role for the SDF-1/CXCR4 axis in the hibernation and treatment of myocardial tissue in diabetic cardiomyopathy (DCM).
Wild-type and cardiac CXCR4 null (CM-CXCR4 null) mice were randomly assigned to low-fat diet (LFD) or high-fat diet (HFD) for 30 weeks. Serial echocardiography was used to assess cardiac function. SDF-1 plasmid (80 ug) was injected into the LV wall of half group of the HFD mice (27 weeks). SDF-1, CXCR4, SIRT1, SIRT3, and SIRT6 mRNA levels in the hearts were quantified by qPCR at different times.
Compared to age-matched LFD mice, 27-week-old HFD mice showed a 33% decrease in Ejection Fraction (EF). Direct myocardial injection of hSDF-1 plasmid led to a 15% and 30% improvement in EF 1 and 3 weeks later, respectively, compared to control. To determine if CM-CXCR4 expression induces CM hibernation as a mechanism of DCM, we quantified cardiac function in HFD CM-CXCR4 null mice. We observed an early loss of cardiac function in HFD CM-CXCR4 null mice compared to HFD control mice. Interestingly, SIRT1 and SIRT6 were statistically decreased in HFD mice, suggesting that SIRT signaling may be involved in blunted SDF-1 signaling in DCM.
Our data demonstrated that the SDF-1/CXCR4 axis has an important role in DCM. Our data suggests that cardiac myocyte over-expression of CXCR4 is involved in cardiac myocyte hibernation. These data suggest that modulation of SDF-1/CXCR4 expression will delay or alleviate DCM.

Cardiology - Stromal Cell-Derived Factor 1 (SDF-1) and its Receptor CXCR4 Improve Diabetic Cardiomyopathy (DCM) - Cardiology

Dermatology - Association of Mental Health Disorders and Bacterial Cultures in Hidradenitis Suppurativa - Dermatology

Nonmelanoma skin cancer (NMSC), the most common form of cancer worldwide, is caused by chronic exposure to ultraviolet radiation (UV). UV generates reactive oxygen species, which lead to mutations and inflammation that enhance the oncogenic transformation of skin cells. Because current sunscreens have limited efficacy at protecting from UV and preventing skin cancer, there is a need for alternative preventive approaches. To this end, Pro-NP, a nanoparticle formulation consisting of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), was used for sustained delivery of these enzymes. We hypothesized that topical application of Pro-NP would safely deliver SOD and CAT to skin cells and suppress UV-induced DNA damage and skin carcinogenesis. To test this, Pro-NP or vehicle-treated mice were assessed for biomarkers of UV-induced skin cancer after short-term and long-term irradiation, enabling us to determine the photoprotective effects of Pro-NP in vivo. Pro-NP decreased UV-induced DNA damage in male and female mice, yet only protected female mice from UV-induced cancer formation. Interestingly, Pro-NP reduced UV-induced proliferation and inflammation to a greater extent in female skin. Taken together, these findings demonstrate that topical application of antioxidant regimens such as Pro-NP may protect from DNA damage and inflammation following UV exposure and suppress skin cancer formation.

Dermatology - Nanoparticle-mediated Delivery of Antioxidant Enzymesprotects From Uvr Damage and Skin Tumorigenesis - Dermatology

Dermatology - Representation of Skin of Color Images in Dermatological Artificial Intelligence Databases - Dermatology

Abstract Title:
Exploring subcutaneous encapsulated islet cell transplantation as a treatment for Type 1 diabetes.
Background
According to the JDRF, over 1.6 million persons living in the United States live with Type 1 Diabetes (T1D) as of 2020. Current protocols utilize the liver as a transplant site in patients undergoing islet cell transplantation as a treatment for Type 1 diabetes (T1D). However, the need for an alternative and more accessible site is evident with only 50% of patients maintaining insulin independence one year after transplantation. In this study, we set out to evaluate whether transplantation of non- and (PVPON/TA/CTLA-4-Ig)-encapsulated islets can restore normoglycemia to streptozotocin (STZ)-treated diabetic NOD.SCID mice when transplanted into a prevascularized subcutaneous space.
Methods
We took seven mice that were previously implanted with a nylon catheter subcutaneously in order to induce a foreign body response and increase vascularization. After four weeks, these mice were then administered a dose of 190 mg/kg of STZ in order to induce diabetes. All of the mice were confirmed to be diabetic by a blood glucose value of more than 300 mg/dL. Three mice were transplanted with 500 non-encapsulated islets while the remaining four were transplanted with 500 islets that were encapsulated with a poly (N-vinylpyrrolidone (PVPON)/Tannic acid (TA)/CTLA-4-Ig nanolayer coating. Blood glucose values were then taken from the tail vein of each mouse to assess whether normoglycemia could be restored.
Results
Normoglycemia was restored in five out of the seven mice (71.4%) one day after transplantation. Of the two mice (28.6%) in which normoglycemia was not restored, one mouse (14.3%) had an adverse reaction to the STZ treatment and did not survive 24 hours post transplantation. The other mouse (14.3%) was not engrafted with islet cells and remained diabetic.

Conclusion
Transplantation into a prevascularized subcutaneous pocket using both non-encapsulated and encapsulated islet cells was found to restore normoglycemia in NOD.SCID mice. This therapy for T1D presents an alternative option to the current protocol and should be further explored in future studies. Future studies may make use of other techniques such as encapsulation with PD-L1 (CD274) in order to further diminish the T-cell response and facilitate islet cell survival.


Endocrinology - Exploring Subcutaneous Encapsulated Islet Cell Transplantation as a Treatment for Type 1 Diabetes - Endocrinology

Background: The adipocyte-derived hormone leptin is a key mediator in homeostatic appetite regulation and satiety via the arcuate nucleus (ARC) of the hypothalamus. Interestingly, serotonin (5-HT) produced in the dorsal raphe nucleus (DRN) modulates anorectic effects of its own in the ARC, yet the underlying mechanism through which 5-HT acts in tandem with leptin remains inconclusive. Our lab has identified leptin-sensitive serotonergic neurons in the DRN that project to the ARC, and has demonstrated that activation of this circuit significantly decreases food intake. Through the unique co-expression of leptin receptors and 5-HT within these neurons, the current study aimed to elucidate the role of 5-HT in leptin’s regulation of food intake between the DRN and ARC.

Methods: To examine the role of 5-HT on leptin’s action in the DRN, adult male Sprague Dawley rats underwent stereotaxic surgery for guide cannula implantation in the DRN. After recovery, rats received 100 μg of intra-raphe p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, each day for four days. On the fourth day, an additional injection of leptin was administered in the DRN (5 μg/rat) and food intake was measured over a 24-hour time course. To examine the role of 5-HT on leptin’s hypothalamic action, a subsequent experiment was conducted by implanting an additional cannula into the ARC for the administration of leptin on the fourth day of treatment. Post-mortem, DRN tissue sections were immunolabeled to confirm 5-HT depletion and visualize leptin-sensitive serotonergic neurons.

Results: 24-hour food intake analyses across both experiments revealed only vehicle-treated rats administered leptin exhibited a significant decrease in food intake compared to controls, an effect not observed in PCPA-treated rats. These results suggest depletion of 5-HT within the DRN attenuated leptin’s ability to decrease food intake in both the DRN and ARC. 5-HT immunolabeling confirmed PCPA significantly decreased 5-HT in the DRN of all treated rats and displayed co-localization of 5-HT and phosphorylated-STAT3 (a marker for leptin receptor activation) in DRN neurons.

Conclusion: Depleting DRN-derived 5-HT diminishes leptin’s action on hypothalamic and DRN leptin receptors, suggesting 5-HT is a regulator of leptin-mediated food intake control within this novel neuronal circuit.

Next from AMA Research Challenge 2022

Using Biophysical Properties of SARS-COV-2 Surface Glycoprotein to Determine its Ongoing Structural Evolution

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