United States

Background
In 2015, 3.4 million people in the US had active epilepsy. Despite numerous pharmacologic treatments available, only 44% report seizure control consistent with reported rates of drug-resistance. This highlights the need for better defined pathophysiology and mechanism-targeted therapy. Among the numerous implicated mechanisms, mutations in NMDA receptors have been causally implicated in pathogenesis. NMDA receptors are glutamate-gated Ca2+-permeable ion channels with essential roles in the physiology of central excitatory synapses and their dysfunc-tion cause severe neuropsychiatric symptoms. More than 4000 genetic variants have been identi-fied across the seven genes encoding NMDA receptor subunits, however, functional information about these variants is sparse and their role in pathogenesis insufficiently known. Here we reveal the structural mechanism by which two GluN2A variants may be pathogenic. 
Methods
We use all-atom targeted molecular dynamics simulations to build a structural model of channel opening as no structural data yet exists for these channels in the open conformation. This allowed us to screen and identify residues comprising critical allosteric interfaces that strengthen during activation. We identify a conserved structural element that single-molecule electrophysiology to examine the contribution of GluN2A subunit-residues, P552 and F652, and their pathogenic sub-stitutions, P552R and F652V, affect receptor functions.
Results
We found that P552 and F652 interact during the receptors’ normal activity cycle; the interaction stabilizes receptors in open conformations and is required for a normal electrical response. Engi-neering shorter side-chains at these positions (P552A and/or F652V) caused a loss of interaction energy and produced receptors with severe gating, conductance, and permeability deficits. In contrast, the P552R sidechain resulted in stronger interaction and produced a distinct, yet still drastically abnormal electrical response.
Conclusion
These results identify the dynamic contact between P552 and F652 as a critical step in the NMDA receptor activation, and show that both increased and reduced communication through this interaction cause dysfunction. Results show that subtle differences in NMDA receptor pri-mary structure can generate complex phenotypic alterations whose binary classification is too simplistic to serve as a therapeutic guide.

AMA Research Challenge 2022

Neurology - Rethinking NMDA Receptor Disease Variant Classification in Epilepsy - Neurology

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Previous studies demonstrated that increasing a protein’s thermostability may increase its resistance to protease digestion. Given recent efforts at evolutionary redesign of lysosomal enzymes to treat lysosomal storage diseases, we sought to identify orthologs of tripeptidyl-peptidase 1 (TPP1) with enhanced thermostability for potential use in improving the existing enzyme replacement therapy for late-infantile neuronal ceroid lipofuscinosis (LINCL), a neurodegenerative disease. TPP1 orthologs from Rattus norvegicus, Heterocephalus glaber, Danio rerio, and Gallus gallus domesticus exhibited increased thermal half-life at 60oC, suggesting that these proteins may confer increased in vivo stability via evolutionary redesign of human TPP1. Structure-function analysis is required to identify residues for mutation in human TPP1 to confer this enhanced stability.

Neurology - Thermostability of TPP1 Animal Orthologs: Potential for Drug Development via Evolutionary Redesign - Neurology

Background: Ovarian Cancer (OC) is the leading cause of death from gynecologic malignancies in the United States largely due to the advanced stage at the time of diagnosis. The identification of metastatic triggers is the significant and unmet need in OC therapy. The epithelial-to-mesenchymal transition (EMT), a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, or mesenchymal properties, has been well-described in OC. Discovering the “trigger/s,” its downstream targets, and therapeutic targeting are essential to substantively improve the survival of women with OC. The objective of our study is to evaluate the role of Connective Tissue Growth Factor (CTGF), a member of a family of extracellular matrix (ECM) associated heparin-binding proteins in EMT in OC. 

Methods: R182 and R2615 are well-described epithelial OC cell and MR182 and MR2615 are the mesenchymal counterparts. R182/R2615 CTGF knock outs (KO) were derived utilizing a Cas9/CRISPR-Cas9 lentivirus plasmid vector and verified by indel sequencing. Invasion, anoikis resistance, and chemosensitivity assays were performed in wild-type (WT) and KO cells. RNA sequence analysis was performed and analyzed using iPathway guide. Top five upregulated and downregulated genes involved in ECM organization pathway were validated by quantitative PCR (qPCR). Immunofluorescence was performed for F-actin. 

Results: CTGF was expressed in the epithelial and not in the mesenchymal OC cell lines. Loss of CTGF was associated with anoikis resistance, where KO and WT cells displayed 75% and 10% viability, respectively. KO cells were significantly more invasive than WT cells. Administration of exogeneous CTGF in KO cells decreased invasion in a dose dependent manner. No change was seen in chemosensitivity to Cisplatin in KO cells. RNA seq analysis identified ECM organization as the biologic process most affected by loss of CTGF. Upregulated (FREM2, LAMC2, ITGB4) and downregulated (SPP1, SV2A, RELN, COL6A3, COL4A6) genes were validated by qPCR. Immunofluorescence staining demonstrated increased F-actin expression in KO cells.

Conclusion: Our data suggests that CTGF expression maintains the epithelial phenotype in OC and that loss of CTGF may be one of the early triggers of EMT in OC. Loss of CTGF should be further evaluated as a poor prognostic marker in OC.


Loss of Connective Tissue Growth Factor Expression Promotes Remodeling of the Extracellular Matrix and Epithelial-to-Mesenchymal Transition in Ovarian Cancer

Background: The Renin Angiotensin System has a protective axis involving Angiotensin Converting Enzyme 2 (ACE2) and its product, Ang-1-7. ACE2 has received attention as a host cell receptor for the SARS-CoV-2 virus, but it also has a protective role regulating inflammatory pathways in tissues including the retina. This review summarizes what the current literature determines the role of ACE2 to be in the retina, and how this information can be used to develop therapies for treating retinopathies. 

Methods: Medical Subject Headings (MeSH) inquiry in the Medline/PubMed databases was used to search for papers. The Mesh topics used are “Angiotensin Converting Enzyme 2,” “ACE2 protein,” “angiotensin I (1-7),” “Retina”, “Retinal Pigment Epithelium,” and “Macula.” This review includes animal studies, postmortem studies, and studies using primary human retinal pigment epithelium cell cultures (hRPE) and human induced pluripotent stem-cell derived retinal organoids.

Results: The literature indicated that ACE2 is expressed in retinal ganglion cells extending to photoreceptors and the Retinal Pigment Epithelium (RPE) layer, indicating that it spans the entire retina. It has been shown that ACE2 co-localizes with Müller cells, which also stretch across the thickness of the retina. Additionally, the pathways influenced by ACE2 have been investigated. Animal and human studies found that ACE2 attenuates inflammation by regulating MAPK and NF-kB pathways. Human studies additionally found the STAT3 pathway to be another way ACE2 prevents inflammation. ACE2/Ang-1-7’s protective properties have been tested and it was found that it can reduce retinal damage caused by diabetes. It has been suggested to explore ACE2/Ang-1-7 as possible therapy for various retinopathies. 

Conclusion: ACE2 and its product, Ang-1-7, have been shown to have anti-inflammatory effects on the retina. This can be used in the treatment of pathologies that affect the retina, including diabetic retinopathy. Ang-1-7 has a short half-life which may be why it has not been used as a therapeutic intervention. The challenge is to find a way to deliver Ang-1-7 effectively, or to induce endogenous ACE2 to produce more Ang-1-7. Overall, the ACE2/Ang-1-7 protective axis of RAS is involved in the entire retina, affects various anti-inflammatory pathways, and can be used in therapeutic interventions in managing retinopathies. 


A Review of Angiotensin Converting Enzyme 2 and the Retina

Purpose: Glaucoma is a group of optic neuropathies characterized by retinal ganglion cell (RGC) death and visual field loss. A degenerative mechanism associated with RGC death is disrupted delivery of neurotropic factors due to glaucomatous axonal damage. This transport is critical for protection of long-term neuronal function. Thus, we investigate a potential therapeutic target, human Neuritin 1 (NRN1), which has demonstrated neuroprotective effects in rodent axonal injury models. Further, the advent of induced pluripotent stem cell (iPSC) technology allows iPSC-RGCs to be generated in-vitro from commercial iPSCs and reprogrammed corneal fibroblasts. We hypothesize delivery of NRN1 and transplantation of iPSC-RGCs will sustain survival of RGCs and ultimately slow progression of glaucoma-induced neuronal death in our ocular translaminar autonomous system (TAS) perfusion model system. This will allow us to analyze a potential therapeutic approach for both early-stage glaucoma (NRN1 therapy) to protect dying RGCs, and late-stage (iPSC-RGCs), when most RGCs are lost. 

Methods: Human donor eyes were obtained from eye banks according to Declaration of Helsinki. The iPSC-RGCs transfected with AAV2-GFP were seeded into human posterior cups with NRN1 and cultured in TAS model under pressurized conditions for 2 days. Survival of iPSC-RGCs, gliotic and fibrotic pathways were measured through expression by qRT-PCR and immunohistochemistry. Retinal function post-treatment was measured through electroretinogram analysis. 

Results: We successfully maintained the human posterior eye cups in translaminar differentials for 2 days. In contrast to controls, we observed increased RGC survival and retinal function after combination therapy of NRN1 and iPSC-RGC. Additionally, we found differential gene expression of apoptosis, inflammation, and gliotic markers.

Conclusion: Our study identified that NRN1 in conjunction with iPSC-RGC transplantation treatment promotes RGC survival under glaucomatous conditions. This suggests that NRN1 and iPSC-RGCs could be utilized as a potential combination therapy to save retinal neurons and prevent neurodegeneration in glaucoma patients. 


Combinatorial Therapeutic Strategy of Stem Cell Retinal Organoids and Neurotrophic Factor for Glaucoma

Background
Diabetic retinopathy (DR) is one of the leading complications of diabetes mellitus (DM) and is a progressive neovascular disease that causes pathological changes in neuronal, vascular, and immune systems. Inflammation and inflammasome activation have been associated with multiple neurovascular conditions and are implicated in the pathogenesis of diabetic retinopathy. NLRP3 is a well-studied inflammasome made up of the constituents NLRP3, Asc, and Caspase-1. This inflammasome has been demonstrated to be activated by a multitude of danger signals including elevated glucose and free fatty acids, which are present in diabetes mellitus. However, there remains uncertainty regarding the role of the NLRP3 inflammasome in DR development.

Methods
Diabetes was induced using the streptozotocin (STZ) model in C57BL/6J wild type (WT) male mice (N=40) and knock out (KO) male mice lacking certain NLRP3 inflammasome constituents (Caspase-1 KO (N=7) and ASC KO (N=9)). Vehicle control was injected for control (CTL) mice of each genotype. After one and three months of hyperglycemia, retinal neurodegeneration was evaluated using scotopic electroretinography (ERG) and bilateral eyes were harvested for immunoblotting to evaluate the neuroretina for inflammasome activity. 

Results
Immunoblotting of whole retinal lysates showed minimal increase of inflammasome activation in WT DM mice compared to WT CTL mice. However, on ERG evaluation at three months, there was a 23.1% decrease in a-wave and a 32.3% decrease in b-wave between DM and CTL WT mice. For both strains of KO mice, there was a lesser decrease of 10.8% and 21.8% in a- and b-waves respectively (Caspase-1 KO), and of 5% and 18.3% in a- and b-waves respectively (ASC KO) between DM and CTL mice.

Conclusion
Our results suggest that while NLRP3 inflammasome activation may not be evident on protein analysis, the decrease in readings on ERG evaluation may be indicative of a reduction in neuroretinal function by three months of DR. Additionally, the reduced loss of electrical function in both Caspase-1 KO and ASC KO mice may represent a partial rescue of neuroretinal function when components of the NLRP3 inflammasome are absent. This finding helps to establish a direct connection between NLRP3 inflammasome constituents to the pathological processes of DR. 


NLRP3 inflammasome activation in diabetic retinopathy affects neuroretinal function.

Background
Sig1R is a pluripotent modulator of cell survival, the activation of which by the high-affinity, high-specificity ligand pentazocine ((+)-PTZ), has marked retinal neuroprotective effects in the RhoP23H/+ model of adRP compared to non-treated mutants. These findings were obtained in mice administered (+)-PTZ beginning at postnatal day 14 (P14); whether prenatal administration of (+)-PTZ would afford retinal protection was not known and was investigated in the current study. 

Methods
RhoP23H/+ mice were administered (+)-PTZ 3X/week beginning at either (a) P14 (“post”-RhoP23H/+) or (b) RhoP23H/+ mouse dams received (+)-PTZ during adolescence, throughout pregnancy, and pups were treated beginning at P14 (“pre”-RhoP23H/+). Pups from both groups were administered (+)-PTZ through P180 at which time rod and cone photoreceptor function was evaluated by scotopic and photopic electroretinography (ERG), visual acuity by OptoMotry (OMR), in vivo retinal architecture in dorsal and ventral retina by optical coherence tomography (OCT). Retinal structure was examined post-mortem by light microscopy; the thickness of the outer nuclear layer (ONL) of rod/cone nuclei was quantified. Data were analyzed by 2-way ANOVA.

Results
ERG: Scotopic and photopic highest flash intensity b-wave amplitudes were significantly impaired in pre-RhoP23H/+ mice (123.9±13.7μV; 44.3±5.5μV, respectively) at P180 compared to age-matched post-RhoP23H/+ mice (203.4±12.4μV; 70.9±4.5μV) p <0.0001 and 0.0003, respectively. OMR: Acuity in pre-RhoP23H/+ mice was significantly reduced (0.344±0.013 c/d) compared to post-RhoP23H/+ (0.387±0.003c/d) p <0.0001. OCT: ONL thickness was significantly greater in pre-RhoP23H/+ (15.56±0.29μm) versus post-RhoP23H/+(14.3±0.22μm) along the dorsal retina (p = 0.0155). Microscopy: ONL thickness along the dorsal retina in pre-RhoP23H/+ was significantly less than in post-RhoP23H/+ (24.37±3.19 v. 35.15±1.52μm) (p <0.0001).

Conclusion
We anticipated that prenatal plus postnatal treatment with Sig1R would yield a more beneficial response than postnatal treatment alone. However, in our study design, mice in the prenatal Sig1R activation cohort had diminished ERG responses, reduced visual acuity and decreased ONL thickness by histologic examination, although OCT revealed thicker ONL in the dorsal retina. This pilot study raises compelling questions about pre- versus post-natal Sig1R activation and its effects on retinal development. Sig1R is gaining attention in the field of neurodegenerative diseases requiring careful analysis of optimal administration of its ligands.

Prenatal activation of Sigma 1 Receptor (Sig1R) yields intriguing consequences on photoreceptor (PRC) function in a murine model of autosomal dominant Retinitis Pigmentosa (adRP)

Background
Diabetic retinopathy (DR) is a serious diabetes complication that affects millions worldwide. Current therapies are invasive and only slow late-stage progression, thus the development of less invasive, novel therapies that attenuate progression are paramount. In the diabetic milieu, inducible nitric oxide synthase (iNOS) expression is upregulated in retinal macrophages/microglia, which increases production of inflammatory cytokines and reactive oxygen species, worsening ischemia, blood-retinal-barrier (BRB) compromise, and disease progression. Arginase 1 (Arg1) is a ureohydrolase that competes with iNOS for their common substrate, L-arginine. Recent studies revealed a neuroprotective role of Arg1 in murine models of retinal ischemia/reperfusion injury and ischemic stroke and demonstrated the beneficial effects of Arg1 administration in these models. As DR also involves ischemia and inflammation, we hypothesized that exogenous Arg1 would be similarly beneficial through iNOS substrate depletion, resulting in decreased retinal inflammation and oxidative stress.

Methods
Using the obese, type 2 diabetic db/db mouse model that well-approximates human DR pathophysiology, the visual function, BRB, retinal inflammation, and oxidative stress were characterized in these mice aged 16-24-weeks and compared to lean, littermate controls. Visual function was determined by electroretinography (ERG) responses, visual acuity, and contrast threshold measurements. Retinas were collected for immunofluorescence or western blot analyses for iNOS, inflammatory cytokines (IL-1β, TNF-α), oxidative stress (3-nitrotyrosine, 4-hydroxynonenal), and BRB assessment, determined by both retinal albumin extravasation and co-labeling for ZO-1 (tight junction protein) and CD31 (endothelial cell-specific protein). To assess Arg1 therapeutic potential, recombinant Arg1 conjugated to polyethylene glycol (PEG-Arg1), for improved half-life, or a PEG-5000 vehicle control was administered intraperitoneally (25mg/kg) to 16-24-week-old db/db mice thrice weekly for 2 weeks and the same experiments were performed.

Results
Compared to lean littermate controls, db/db mice exhibited significant visual dysfunction, BRB compromise, and elevated retinal levels of iNOS, IL-1β, TNF-α, 3-nitrotyrosine, and 4-hydroxynonenal. PEG-Arg1 treatment significantly ameliorated visual function impairment and BRB compromise in these mice and markedly reduced iNOS levels, retinal inflammation, and oxidative stress compared to vehicle-treated db/db mice. 

Conclusion
The retinal pathology of db/db mice significantly improved with PEG-Arg1 therapy. Though further investigation is necessary, these results suggest that systemic PEG-Arg1 administration has potential as a novel DR therapeutic.

Systemic Administration of Pegylated Arginase-1 Attenuates Progression of Diabetic Retinopathy in the db/db Mouse

Background
Superior Capsule Reconstruction (SCR) allows for the repair of irreparable rotator cuff tears in the younger active patient population. While the use of various graft materials has been described, the choice of using an autograft versus an allograft currently remains unclear. This study aimed to biomechanically investigate SCR with the use of a long head of the biceps tendon (LHBT) autograft and human dermal (HD) allograft in regard to functional abduction force and superior translation of the humeral head. 

Methods
8 fresh-frozen cadaveric shoulder specimens were tested in 5 conditions: (1) intact, (2) complete supraspinatus tear, (3) LHBT autograft, (4) LHBT autograft with side-to-side suturing, and (5) HD allograft with side-to-side suturing. Functional abduction force, superior translation of the humeral head, translational range of motion, and rotational range of motion were tested at 0º, 30º, 60º, and 90º of abduction within each condition. Data was analyzed using analysis of variance with post-hoc Tukey testing for pairwise comparison, with a significance value set at 0.05.

Results
Functional abduction force in the LHBT, LHBT+ suture, and HD+ suture conditions was significantly increased compared to the supraspinatus tear condition at abduction angles of 30º (p=0.011, 0.001, and 0.017 respectively), 60º (p=0.004, 0.001, and 0.002 respectively), and 90º (p=0.013, 0.001, and 0.038 respectively). Additionally, superior translation of the humeral head in the LHBT, LHBT+ suture, and HD+ suture conditions was significantly decreased compared to the tear condition at abduction angles of 30º (p=0.03, 0.049, 0.03 respectively) and 60º (p=0.02, 0.04, 0.03 respectively). All 3 reconstructive techniques were statistically identical to the intact rotator cuff condition in regard to translational and rotational range of motion.

Conclusion
SCR with LHBT autograft without side-to-side suturing, LHBT with posterior side-to-side suturing, and HD allograft with posterior side-to-side suturing all equivalently restore functional abduction force and decrease superior translation of the humeral head after a complete supraspinatus tear. Additionally, all three reconstructive techniques display no deficits in both translational and rotational range of motion, resembling the intact rotator cuff state.


Orthopaedic Surgery - Biceps Autograft versus Dermal Allograft for Superior Capsule Reconstruction after Rotator Cuff Tear - Orthopaedic Surgery

Orthopaedic Surgery - Changes to Excursion of Rotator Cuff Muscles during Abduction after Superior Capsular Reconstruction (SCR) and Reverse Total Shoulder Arthroplasty (rTSA) - Orthopaedic Surgery

Background
Volumetric muscle loss (VML) is a traumatic or surgical orthopaedic injury characterized by a significant loss of skeletal muscle mass and function. Clinically there is no treatment that targets skeletal muscle after VML, and lifelong functional impairments lead to musculoskeletal deformity and comorbidities. While mechanisms driving chronic lack of regeneration remain unclear, pathologic fibrotic deposition and loss of myogenic signaling after injury are thought to be involved. One near-term solution to improve function following VML is to repurpose FDA-approved drugs. This study’s objective was to evaluate effectiveness of an anti-fibrotic, nintedanib, and a hypertrophy stimulant, formoterol combined with leucine, to improve muscle function and regeneration after VML. Muscle function after VML is the key clinical outcome; evaluation of torque thus serves as the main measure of success.

Methods
Adult (12-week-old) male C57BL/6 mice (n=29) underwent unilateral VML surgery removing ~15% of the posterior muscle compartment (gastrocnemius, soleus, plantaris) or remained injury-naïve controls. VML-injured mice were randomized to nintedanib (6mg/kg/day), formoterol (3mg/kg/day) and leucine (24g/kg/day), or no treatment. Six weeks post-VML activity and whole-body metabolism were evaluated. Maximal in vivo muscle torque was evaluated 8 weeks post-VML, and tissue was collected terminally. Data were evaluated using a one-way ANOVA and Tukey post-hoc, with significance at p<0.05.

Results
Twenty-four-hour metabolic rate was ~17% and 8% higher in the formoterol+leucine group (16.5kcal/hour) compared to injury naïve and VML alone, respectively (p<0.001); despite no ambulation or respiratory exchange ratio differences (p≥0.069). However, formoterol+leucine treatment increased lipid oxidation (p=0.005). After 8-weeks, gastrocnemius mass:body mass was reduced for VML alone, but both treatments ameliorated this difference (p=0.004). Maximal in vivo torque was greatest in injury naïve mice (609.6mN•m/kg) and ~41% and 49% lower in VML untreated and nintedanib groups, respectively, while formoterol+leucine mitigated this decline (p=0.012).

Conclusion
Understanding the effects of repurposed FDA-approved medications on functional recovery after VML can establish translational options. Formoterol+leucine treatment improved torque of the posterior muscle compartment and muscle mass to a level not statistically different from injury-naïve mice, supporting its role in promoting functional recovery after VML. This strategy warrants further research to consider applications for VML-injured patients.

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