Ethnic variation and structure-function analysis of tauopathy-associated PERK alleles.

EIF2AK3, also known as PERK, plays a pivotal role in cellular proteostasis, orchestrating the Unfolded Protein Response (UPR) and Integrated Stress Response (ISR) pathways. In addition to its central position in intracellular stress regulation, human GWAS identify EIF2AK3 as a risk factor in tauopathies, neurodegenerative diseases caused by aberrant tau protein accumulation. Guided by these genomic indicators, our investigation systematically analyzed human PERK variants, focusing on those with potential tauopathy linkages. We assembled a comprehensive data set of human PERK variants associated with Wolcott Rallison Syndrome (WRS), tauopathies, and bioinformatically predicted loss-of-function, referencing the gnomAD, Ensembl, and NCBI databases. We found extensive racial/ethnic variation in the prevalence of common PERK polymorphisms linked to tauopathies. Using SWISS-MODEL, we identified structural perturbations in the ER stress-sensing luminal domain dimers/oligomers of tauopathy-associated PERK variants, Haplotypes A and B, in combination with another tauopathy-linked R240H mutation. Recombinant expression of disease-associated variants in vitro revealed altered PERK signal transduction kinetics in response to ER stress compared to the predominant non-disease variant. In summary, our data further substantiates that human PERK variants identified in tauopathy genetic studies negatively impact PERK structure, function, and downstream signaling with significant variations in prevalence among different racial and ethnic groups.

Retinal detachment.

Retinal detachment (RD) occurs when the neurosensory retina, the neurovascular tissue responsible for phototransduction, is separated from the underlying retinal pigment epithelium (RPE). Given the importance of the RPE for optimal retinal function, RD invariably leads to decreased vision. There are three main types of RD: rhegmatogenous, tractional and exudative (also termed serous) RD. In rhegmatogenous RD, one or more retinal breaks enable vitreous fluid to enter the subretinal space and separate the neurosensory retina from the RPE. In tractional RD, preretinal, intraretinal or subretinal membranes contract and exert tangential forces and elevate the retina from the underlying RPE. Finally, in exudative RD, an underlying inflammatory condition, vascular abnormality or the presence of a tumour causes exudative fluid to accumulate in the subretinal space, exceeding the osmotic pump function of the RPE. The surgical management of RD usually involves pars plana vitrectomy, scleral buckling or pneumatic retinopexy. The approach taken often depends on patient characteristics as well as on practitioner experience and clinical judgement. Advances in surgical technology and continued innovation have improved outcomes for many patients. However, even if retinal re-attachment is achieved, some patients still experience decreased vision or other visual symptoms, such as metamorphopsia, that diminish their quality of life. Continued research in the areas of neuroprotection and retinal biology as well as continued surgical innovation are necessary to enhance therapeutic options and outcomes for these patients.

Acute spontaneous vortex vein occlusion: clinical features, multimodal imaging and natural course.

AIMS: To describe the clinical features, multimodal imaging, treatments and natural course of acute spontaneous vortex vein occlusion. METHODS: Clinical data were collected on nine patients with acute vortex vein occlusion. The symptoms and signs, multimodal imaging, treatments and follow-up results were summarised. RESULTS: Six patients (66.7%) were men and three (33.3%) were women. The mean age was 47.8±15.4 years. Patients were initially misdiagnosed as having choroidal tumour (66.7%), scleritis (22.2%) and peripheral exudative haemorrhagic chorioretinopathy (11.1%). The related clinical characteristics included choroidal pseudo-tumour (100%), anterior segment injection (88.9%), acute ocular pain (77.8%), transient blurred vision (66.7%) and subsequent scleral icterus (66.7%). Six patients (66.7%) experienced a definite Valsalva manoeuvre prior to the onset. In acute phase, ultrasonography showed a low-to-medium reflective lesion without inside blood flow signal (mean thickness, 2.7±0.6 mm). Swept-source optical coherence tomography angiography (SS-OCTA) demonstrated the dilated vortex veins and ampulla with suprachoroidal haemorrhage and exudation. Indocyanine green angiography (ICGA) demonstrated choroidal circulation abnormalities in the affected quadrant. MRI showed a well-defined mass with enhancement. The main treatment was medical observation (44.5%). The choroidal pseudo-tumour spontaneously resolved with a mean course of 4.1±1.9 weeks. CONCLUSIONS: Acute vortex vein occlusion is a rare condition and initial misdiagnosis is not uncommon. It is mainly identified as an evanescent choroidal pseudo-tumour with acute pain, red eye and blurred vision. Widefield ICGA and SS-OCTA can offer valuable diagnostic clues. Medical observation may be a treatment option.

Why the lower stratosphere cools when the troposphere warms.

Observational data have long suggested that in the tropics, when the troposphere locally warms, the lower stratosphere locally cools. Here, the observed anti-correlation between tropospheric and lower stratospheric temperature is confirmed-the lower stratosphere cools by approximately 2 degrees per degree of warming in the mid-troposphere. This anti-correlation is explained through a recently proposed theory holding that there is a quasi-balanced response of the stratosphere to tropospheric heating [J. Lin, K. Emanuel, Tropospheric thermal forcing of the stratosphere through quasi-balanced dynamics. J. Atmos. Sci. (2024).]. The local-scale anti-correlation between tropospheric and lower stratospheric temperature also holds when considering climate change-where the troposphere has been anomalously warming relative to the zonal mean, the lower stratosphere has been anomalously cooling, and vice versa. This suggests that zonally asymmetries in tropospheric temperature trends will be reflected in that of the lower stratospheric temperature trends. The zonally asymmetric trends are also found to be comparable in magnitude to the mean temperature trends in the lower stratosphere, highlighting the importance of the pattern of warming. The results and proposed theory suggest that in addition to forcing via wave-dissipation, the lower stratosphere can also be subject to direct forcing by the troposphere, through quasi-steady, quasi-balanced dynamics.

Mental health, pain and likelihood of opioid misuse among adults with sickle cell disease.

Depressive symptoms are prevalent in individuals living with sickle cell disease (SCD) and may exacerbate pain. This study examines whether higher depressive symptoms are associated with pain outcomes, pain catastrophizing, interference and potential opioid misuse in a large cohort of adults with SCD. The study utilized baseline data from the 'CaRISMA' trial, which involved 357 SCD adults with chronic pain. Baseline assessments included pain intensity, daily mood, the Patient Health Questionnaire (PHQ), the Generalized Anxiety Disorders scale, PROMIS Pain Interference, Pain Catastrophizing Scale, the Adult Sickle Cell Quality of Life Measurement Information System and the Current Opioid Misuse Measure. Participants were categorized into 'high' or 'low' depression groups based on PHQ scores. Higher depressive symptoms were significantly associated with increased daily pain intensity, negative daily mood, higher pain interference and catastrophizing, poorer quality of life and a higher likelihood of opioid misuse (all p < 0.01). SCD patients with more severe depressive symptoms experienced poorer pain outcomes, lower quality of life and increased risk of opioid misuse. Longitudinal data from this trial will determine whether addressing depressive symptoms may potentially reduce pain frequency and severity in SCD.

Evaluation of Verteporfin as a Novel Antifibrotic Agent in a Rabbit Model of Glaucoma Filtration Surgery: A Pilot Study.

Purpose: Verteporfin is a benzoporphyrin derivative which is Food and Drug Administration-approved for treatment of choroidal neovascularization in conjunction with photodynamic therapy. It has been shown to prevent fibrosis and scar formation in several organs and represents a promising novel antifibrotic agent for glaucoma surgery. The goal of this study is to determine the effect of verteporfin on wound healing after glaucoma filtration surgery. Design: Preclinical study using a rabbit model of glaucoma filtration surgery. Subjects: Eight New Zealand white rabbits underwent glaucoma filtration surgery in both eyes. Methods: Eyes were randomized into 4 study groups to receive a postoperative subconjunctival injection of 1 mg/mL verteporfin (n = 4), 0.4 mg/mL mitomycin C (MMC; n = 4), 0.4 mg/mL MMC + 1 mg/mL verteporfin (n = 4), or balanced salt solution (BSS) control (n = 4). Bleb survival, vascularity, and morphology were graded using a standard scale over a 30-day period, and intraocular pressure (IOP) was monitored. At 30 days postoperative or surgical failure, histology was performed to evaluate for inflammation, local toxicity, and scarring. Main Outcome Measures: The primary outcome measure was bleb survival. Secondary outcome measures were IOP, bleb morphology, and bleb histology. Results: Compared to BSS control blebs, verteporfin-treated blebs demonstrated a trend toward increased surgical survival (mean 9.8 vs. 7.3 days, log rank P = 0.08). Mitomycin C-treated blebs survived significantly longer than verteporfin-treated blebs (log rank P = 0.009), with all but 1 MMC-treated bleb still surviving at postoperative day 30. There were no significant differences in survival between blebs treated with combination verteporfin + MMC and MMC alone. Mitomycin C-treated blebs were less vascular than verteporfin-treated blebs (mean vascularity score 0.3 ± 0.5 for MMC vs. 1.0 ± 0.0 for verteporfin, P < 0.01). Bleb histology did not reveal any significant toxicity in verteporfin-treated eyes. There were no significant differences in inflammation or scarring across groups. Conclusions: Although verteporfin remained inferior to MMC with regard to surgical survival, there was a trend toward increased survival compared with BSS control and it had an excellent safety profile. Further studies with variations in verteporfin dosage and/or application frequency are needed to assess whether this may be a useful adjunct to glaucoma surgery. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The endoplasmic reticulum: Homeostasis and crosstalk in retinal health and disease.

The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding, and trafficking, lipid and sterol biosynthesis, carbohydrate metabolism, and calcium storage and gated release. In addition, the ER makes close contact with multiple intracellular organelles such as mitochondria and the plasma membrane to actively regulate the biogenesis, remodeling, and function of these organelles. Therefore, maintaining a homeostatic and functional ER is critical for the survival and function of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can lead to cell death and other detrimental events such as inflammation and oxidative stress; these processes are implicated in the pathogenesis of many human diseases including retinal disorders. In this review manuscript, we discuss the unique features of the ER and ER stress signaling in the retina and retinal neurons and describe recent advances in the research to uncover the role of ER stress signaling in neurodegenerative retinal diseases including age-related macular degeneration, inherited retinal degeneration, achromatopsia and cone diseases, and diabetic retinopathy. In some chapters, we highlight the complex interactions between the ER and other intracellular organelles focusing on mitochondria and illustrate how ER stress signaling regulates common cellular stress pathways such as autophagy. We also touch upon the integrated stress response in retinal degeneration and diabetic retinopathy. Finally, we provide an update on the current development of pharmacological agents targeting the UPR response and discuss some unresolved questions and knowledge gaps to be addressed by future research.

Using a Multi-pronged Behavioral Intervention to Standardize Antibiotic Prophylaxis at the Time of Foley Catheter Removal After Radical Prostatectomy.

OBJECTIVE: To identify antibiotic prescribing patterns at the time of foley catheter removal after radical prostatectomy and implement a multi-pronged behavioral intervention to standardize antibiotic use. METHODS: This was a single-institution study examining the prescribing of antibiotics at the time of foley catheter removal after radical prostatectomy. Pre-intervention data were collected retrospectively to establish baselines for antibiotic prescribing, patient characteristics, and urinary tract infection rates. A single dose of an oral antibiotic taken at the time of foley catheter removal was recommended as the standard antibiotic protocol. A multi-pronged behavioral intervention was used to encourage compliance with our protocol. Adherence to the protocol, quantity of antibiotics prescribed, and rate of urinary tract infection were recorded prospectively. Durability of the intervention was evaluated during a post-intervention phase. RESULTS: A total of 416 patients and 6 surgeons were included in the study. Accordance with the standardized antibiotic protocol was 59% in the pre-intervention phase and 91% in the intervention phase (P = .03). No patients in the intervention or post-intervention phase were prescribed more than one dose of an antibiotic. The rate of urinary tract infection did not differ across the study phases. CONCLUSION: Implementation of a multi-pronged behavioral intervention resulted in a high rate of surgeon compliance with a standardized antibiotic protocol. This led to a significant reduction in antibiotic use with no change in the rate of urinary tract infection after foley catheter removal after radical prostatectomy.

Comparing Outcomes of 45 Xen Implantation Ab Interno With Closed Conjunctiva to Ab Externo With Open Conjunctiva Approaches.

PRCIS: Ab externo with open conjunctiva placement may lead to improved gelatin stent (XEN Gel Stent; Allergan) success rate compared with ab interno with closed conjunctiva because it conferred more favorable intraocular pressure (IOP) and medication burden reduction based on our complete and qualified success criteria. PURPOSE: To compare outcomes of a gelatin stent (XEN 45 Gel Stent; Allergan) placed either ab interno with closed conjunctiva (AIC) or ab externo with open conjunctiva (AEO) with or without cataract surgery in patients with glaucoma. DESIGN: Retrospective, nonrandomized comparative study of 85 eyes from 85 glaucoma patients who received XEN 45 Gel Stent placed either AIC (N=32) or AEO (N=53) with or without cataract surgery between July 2018 and January 2022 at Massachusetts Eye and Ear. Patients were included if they were 18 years of age or above and had at least 30 days of follow-up without any disqualifying event. RESULTS: Baseline demographics were similar between both groups, except for the glaucoma type. Both AIC and AEO procedures resulted in significant patterns of IOP and medication reduction from baseline up to 1 year. At postoperative year (POY)1, mean IOP was reduced to 11.34±4 mmHg on 1.29±1.34 medications after AEO and 13.70±3.32 mmHg on 2±1.81 medications after AIC. The average IOP reduction was significantly greater in the AEO group at all postoperative time points beyond postoperative week 2. There were significant differences in the survival curves of AEO and AIC groups under both the complete success criteria and the qualified success criteria. Under the complete success criteria, the cumulative probability of survival at POY1 was 28.5% in the AEO group and 3.8% in the AIC group. Under the qualified success criteria, the cumulative probability of survival at POY1 was 60.3% in the AEO group and 21.9% in the AIC group. CONCLUSIONS: In our study, we demonstrate that both placements reduce IOP and medication from baseline, with AEO placement having more favorable success rates compared with AIC placement.

Non-Invasive Evaluation of Retinal Vascular Alterations in a Mouse Model of Optic Neuritis Using Laser Speckle Flowgraphy and Optical Coherence Tomography Angiography.

Optic neuritis, a characteristic feature of multiple sclerosis (MS), involves the inflammation of the optic nerve and the degeneration of retinal ganglion cells (RGCs). Although previous studies suggest that retinal blood flow alterations occur during optic neuritis, the precise location, the degree of impairment, and the underlying mechanisms remain unclear. In this study, we utilized two emerging non-invasive imaging techniques, laser speckle flowgraphy (LSFG) and optical coherence tomography angiography (OCTA), to investigate retinal vascular changes in a mouse model of MS, known as experimental autoimmune encephalomyelitis (EAE). We associated these changes with leukostasis, RGC injury, and the overall progression of EAE. LSFG imaging revealed a progressive reduction in retinal blood flow velocity and increased vascular resistance near the optic nerve head in the EAE model, indicating impaired ocular blood flow. OCTA imaging demonstrated significant decreases in vessel density, number of junctions, and total vessel length in the intermediate and deep capillary plexus of the EAE mice. Furthermore, our analysis of leukostasis revealed a significant increase in adherent leukocytes in the retinal vasculature of the EAE mice, suggesting the occurrence of vascular inflammation in the early development of EAE pathology. The abovechanges preceded or were accompanied by the characteristic hallmarks of optic neuritis, such as RGC loss and reduced visual acuity. Overall, our study sheds light on the intricate relationship between retinal vascular alterations and the progression of optic neuritis as well as MS clinical score. It also highlights the potential for the development of image-based biomarkers for the diagnosis and monitoring of optic neuritis as well as MS, particularly in response to emerging treatments.

Patterns of Telemedicine Use and Glycemic Outcomes of Endocrinology Care for Patients With Type 2 Diabetes.

Importance: Telemedicine can increase access to endocrinology care for people with type 2 diabetes (T2D), but patterns of use and outcomes of telemedicine specialty care for adults with T2D beyond initial uptake in 2020 are not known. Objective: To evaluate patterns of telemedicine use and their association with glycemic control among adults with varying clinical complexity receiving endocrinology care for T2D. Design, Setting, and Participants: Retrospective cohort study in a single large integrated US health system. Participants were adults who had a telemedicine endocrinology visit for T2D from May to October 2020. Data were analyzed from June 2022 to October 2023. Exposure: Patients were followed up through May 2022 and assigned to telemedicine-only, in-person, or mixed care (both telemedicine and in-person) cohorts according to visit modality. Main Outcomes and Measures: Multivariable regression models were used to estimate hemoglobin A1c (HbA1c) change at 12 months within each cohort and the association of factors indicating clinical complexity (insulin regimen and cardiovascular and psychological comorbidities) with HbA1c change across cohorts. Subgroup analysis was performed for patients with baseline HbA1c of 8% or higher. Results: Of 11 498 potentially eligible patients, 3778 were included in the final cohort (81 Asian participants [2%], 300 Black participants [8%], and 3332 White participants [88%]); 1182 used telemedicine only (mean [SD] age 57.4 [12.9] years; 743 female participants [63%]), 1049 used in-person care (mean [SD] age 63.0 [12.2] years; 577 female participants [55%]), and 1547 used mixed care (mean [SD] age 60.7 [12.5] years; 881 female participants [57%]). Among telemedicine-only patients, there was no significant change in adjusted HbA1c at 12 months (-0.06%; 95% CI, -0.26% to 0.14%; P = .55) while in-person and mixed cohorts had improvements of 0.37% (95% CI, 0.15% to 0.59%; P < .001) and 0.22% (95% CI, 0.07% to 0.38%; P = .004), respectively. Patients with a baseline HbA1c of 8% or higher had a similar pattern of glycemic outcomes. For patients prescribed multiple daily injections vs no insulin, the 12-month estimated change in HbA1c was 0.25% higher (95% CI, 0.02% to 0.47%; P = .03) for telemedicine vs in-person care. Comorbidities were not associated with HbA1c change in any cohort. Conclusions and Relevance: In this cohort study of adults with T2D receiving endocrinology care, patients using telemedicine alone had inferior glycemic outcomes compared with patients who used in-person or mixed care. Additional strategies may be needed to support adults with T2D who rely on telemedicine alone to access endocrinology care, especially for those with complex treatment or elevated HbA1c.

TDP43 pathology in chronic traumatic encephalopathy retinas.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.

Study of Atomic Layer Deposition Nano-Oxide Films on Corrosion Protection of Al-SiC Composites.

In recent years, aluminum matrix composites (AMCs) have attracted attention due to their promising properties. However, the presence of ceramic particles in the aluminum matrix renders AMCs a high corrosion rate and makes it challenging to use traditional corrosion protection methods. In this study, atomic layer deposition (ALD) techniques were used to deposit HfO2, ZrO2, TiO2, and Al2O3 thin films on AMC reinforced with 20 vol.% SiC particles. Our results indicate that the presence of micro-cracks between the Al matrix and SiC particles leads to severe micro-crack-induced corrosion in Al-SiC composites. The ALD-deposited films effectively enhance the corrosion resistance of these composites by mitigating this micro-crack-induced corrosion. Among these four atomic-layer deposited films, the HfO2 film exhibits the most effective reduction in the corrosion current density of Al-SiC composites in a 1.5 wt% NaCl solution from 1.27 × 10-6 A/cm2 to 5.89 × 10-11 A/cm2. The electrochemical impedance spectroscopy (EIS) investigation shows that HfO2 deposited on Al-SiC composites has the largest Rp value of 2.0 × 1016. The HfO2 film on Al-SiC composites also exhibits effective inhibition of pitting corrosion, remaining at grade 10 even after 96 h of a salt spray test.

Neurofilament Light Chain in Aqueous Humor as a Marker of Neurodegeneration in Glaucoma.

Purpose: Neurofilament light chain (NfL) is a neuronal cytoskeletal protein that has been identified as a marker of neurodegeneration in diseases of the central nervous system. In this study, we investigated whether NfL in the aqueous humor (AH) can serve as a marker of neurodegeneration in glaucoma in a racially diverse North American population. Design: Single-center, case-control study. Participants: We enrolled patients with various types and stages of glaucoma undergoing planned ophthalmic surgery as part of their routine care and compared them with patients without glaucoma undergoing phacoemulsification for age-related cataract. Methods: We collected AH from 39 glaucoma patients and 10 patients without glaucoma. AH NfL was quantified using the Single-Molecule Array (Simoa)® NF-light assay (Quanterix). Demographic information, such as age, body mass index, sex, and self-reported race, as well as clinical information, such as pre-operative intraocular pressure (IOP), maximum IOP, and number of pre-operative glaucoma medications, was obtained by reviewing the medical record. Main Outcome Measures: Levels of AH NfL. Results: In a model controlling for age and body mass index (BMI), NfL was significantly elevated in AH from glaucoma patients (mean: 429 pg/mL; standard deviation [SD]: 1136 pg/mL) compared to AH from patients without glaucoma (mean: 3.1 pg/mL; SD: 1.9 pg/mg): P = 0.002. Higher AH NfL was associated with higher maximum IOP (R = 0.44, P = 0.005), higher pre-operative IOP (R = 0.46, P = 0.003), and more pre-operative glaucoma medications (Rs = 0.61, P < 0.001). There was no association between AH NfL and Humphrey visual field mean deviation (R = -0.20, P = 0.220), retinal nerve fiber layer thickness as measured with optical coherence tomography (R = 0.07, P = 0.694), or glaucoma stage (Rs = 0.015, P = 0.935). Conclusion: Our findings suggest that AH NfL may have clinical utility as a marker of glaucomatous neurodegeneration.

Physiological and evolutionary contexts of a new symbiotic species from the nitrogen-recycling gut community of turtle ants.

While genome sequencing has expanded our knowledge of symbiosis, role assignment within multi-species microbiomes remains challenging due to genomic redundancy and the uncertainties of in vivo impacts. We address such questions, here, for a specialized nitrogen (N) recycling microbiome of turtle ants, describing a new genus and species of gut symbiont-Ischyrobacter davidsoniae (Betaproteobacteria: Burkholderiales: Alcaligenaceae)-and its in vivo physiological context. A re-analysis of amplicon sequencing data, with precisely assigned Ischyrobacter reads, revealed a seemingly ubiquitous distribution across the turtle ant genus Cephalotes, suggesting ≥50 million years since domestication. Through new genome sequencing, we also show that divergent I. davidsoniae lineages are conserved in their uricolytic and urea-generating capacities. With phylogenetically refined definitions of Ischyrobacter and separately domesticated Burkholderiales symbionts, our FISH microscopy revealed a distinct niche for I. davidsoniae, with dense populations at the anterior ileum. Being positioned at the site of host N-waste delivery, in vivo metatranscriptomics and metabolomics further implicate I. davidsoniae within a symbiont-autonomous N-recycling pathway. While encoding much of this pathway, I. davidsoniae expressed only a subset of the requisite steps in mature adult workers, including the penultimate step deriving urea from allantoate. The remaining steps were expressed by other specialized gut symbionts. Collectively, this assemblage converts inosine, made from midgut symbionts, into urea and ammonia in the hindgut. With urea supporting host amino acid budgets and cuticle synthesis, and with the ancient nature of other active N-recyclers discovered here, I. davidsoniae emerges as a central player in a conserved and impactful, multipartite symbiosis.

ENDOGENOUS ENDOPHTHALMITIS DUE TO STREPTOCOCCUS ANGINOSUS IN A HEALTHY, YOUNG WOMAN.

PURPOSE: The purpose of this study was to present a case of indolent endogenous endophthalmitis in a young, seemingly healthy woman. METHODS: This study is a retrospective case report. RESULTS: A 25-year-old woman with no significant medical history presented with vision loss in the left eye over the course of 1 month. Examination showed vitritis and a white-yellow lesion overlying the macula and optic nerve in the left eye. Initial laboratory testing for infectious and inflammatory causes was unrevealing. A diagnostic vitrectomy was performed, and the patient was found to have presumed endogenous endophthalmitis due to Streptococcus anginosus, an extremely uncommon bacterium. Subsequent workup did not reveal evidence of bacteremia, endocarditis, or orbital infection. This case is unique because, unlike the three previously reported cases of S. anginosus endophthalmitis, this patient was seemingly healthy, never had an elevated white blood cell count, never had documented bacteremia, had a normal echocardiogram, and had normal orbital findings on magnetic resonance imaging and computed tomography scans. Further questioning revealed a remote history of facial cellulitis and possible sinusitis treated with oral antibiotics, which are the presumed etiology. CONCLUSION: Streptococcus anginosus endophthalmitis can occur in young, seemingly healthy patients. Endogenous endophthalmitis should be considered in the differential diagnosis even without systemic comorbidities or other risk factors. Detailed questioning about medical history and thorough review of systems, including nonocular symptoms, are essential.

A bio-instructive parylene-based conformal coating suppresses thrombosis and intimal hyperplasia of implantable vascular devices.

Implantable vascular devices are widely used in clinical treatments for various vascular diseases. However, current approved clinical implantable vascular devices generally have high failure rates primarily due to their surface lacking inherent functional endothelium. Here, inspired by the pathological mechanisms of vascular device failure and physiological functions of native endothelium, we developed a new generation of bioactive parylene (poly(p-xylylene))-based conformal coating to address these challenges of the vascular devices. This coating used a polyethylene glycol (PEG) linker to introduce an endothelial progenitor cell (EPC) specific binding ligand LXW7 (cGRGDdvc) onto the vascular devices for preventing platelet adhesion and selectively capturing endogenous EPCs. Also, we confirmed the long-term stability and function of this coating in human serum. Using two vascular disease-related large animal models, a porcine carotid artery interposition model and a porcine carotid artery-jugular vein arteriovenous graft model, we demonstrated that this coating enabled rapid generation of self-renewable "living" endothelium on the blood contacting surface of the expanded polytetrafluoroethylene (ePTFE) grafts after implantation. We expect this easy-to-apply conformal coating will present a promising avenue to engineer surface properties of "off-the-shelf" implantable vascular devices for long-lasting performance in the clinical settings.

Lysine Ubiquitylation Drives Rhodopsin Protein Turnover.

Rhodopsin is a G-protein-coupled receptor that is specifically and abundantly expressed in rod photoreceptors. Over 150 rhodopsin mutations cause autosomal dominant retinitis pigmentosa (adRP). The most common mutation in the United States is the conversion of proline to histidine at position 23 (P23H) in the N-terminal domain of rhodopsin. We previously found that P23H rhodopsin was misfolded, ubiquitinylated, and rapidly degraded. Here, we investigated the role of lysine residues on P23H rhodopsin ubiquitinylation and turnover. We transfected HEK293 cells with a P23H human rhodopsin construct where all 11 lysine residues were mutated to arginine (K-null P23H). We found that the K-null P23H rhodopsin was significantly less ubiquitylated than intact P23H rhodopsin. We found that K-null P23H protein turnover was significantly slower compared to P23H rhodopsin through cycloheximide chase analysis. Finally, we also generated a wild-type rhodopsin construct where all lysines were converted to arginine and found significantly reduced ubiquitylation. Our findings identify ubiquitinylation of lysine residues as an important posttranslational modification involved in P23H rhodopsin protein degradation.