Photoreceptor degeneration is a leading cause of untreatable sight loss. Previously, we showed that human pluripotent stem cell-derived cone photoreceptors (hCones) can rescue retinal function in the Rd1 mouse model of rod-cone dystrophy. However, retinal degenerations display markedly different severities and concomitant remodeling of the remaining retina; for photoreceptor replacement therapy to be broadly effective, it must work for a variety of disease phenotypes. Here, we sought to rescue the Aipl1-/- model of Leber congenital amaurosis, a particularly fast, severe condition. After transplantation of hCones, host cone bipolar cells underwent extensive remodeling and formed nascent synaptic-like connections. Electrophysiological recordings showed robust rescue of light-evoked activity across visually relevant photopic intensities, and treated mice exhibited visually evoked optokinetic head-tracking behavior. Thus, human cone photoreceptor replacement therapy is feasible even in very severe cases of retinal dystrophy, offering promise as a disease-agnostic therapy in Leber congenital amaurosis (LCA) and in other advanced retinal degenerations.

BACKGROUND:Retinal dystrophy caused by genetic deficiency of AIPL1 causes severe and rapidly progressive impairment of sight from birth. We sought to evaluate whether early intervention by gene supplementation therapy was safe and could improve outcomes in children with this condition. METHODS:This non-randomised, single-arm, clinical study conducted in the UK involved four children aged 1·0-2·8 years with severe retinal dystrophy associated with biallelic disease-causing sequence variants in AIPL1. We designed a recombinant adeno-associated viral vector comprising the human AIPL1 coding sequence driven by a human rhodopsin kinase promoter region (rAAV8.hRKp.AIPL1). The product was manufactured under a Specials Licence from the Medicines and Health products Regulatory Authority (UK) and made available to affected children with local ethics approval. We administered the product to one eye of each child by subretinal injection. The children were prescribed oral prednisolone to protect against harm from inflammation. Outcome measures included visual acuity (as assessed with a novel touchscreen test), functional vision (assessed by observing and recording the children's visual behaviour and their ability to perform simple vision-guided tasks), visual evoked potentials (assessed by recording cortical electrophysiological responses to full-screen black-and-white flickering stimuli), and retinal structure (assessed with handheld optical coherence tomography [OCT] and widefield fundus imaging). To identify adverse effects, including inflammation and retinal detachment, we conducted ocular examinations using slit-lamp biomicroscopy and dilated fundoscopy. Safety was further assessed by testing of visual acuity, ophthalmoscopy, handheld OCT and widefield fundus imaging. FINDINGS:Patients were selected for treatment between July 12, 2019, and March 16, 2020. Before intervention, the children's binocular visual acuities were limited to perception of light. At a mean of 3·5 years (range 3·0-4·1) after intervention, the visual acuities of the children's treated eyes had improved to a mean of 0·9 logarithm of the minimal angle of the minimum angle of resolution ([logMAR] range 0·8-1·0); visual acuities before intervention were equivalent to 2·7 logMAR. In contrast, the visual acuities of the children's untreated eyes became unmeasurable at the final follow-up. In the two children able to comply with testing, an objective test of visual acuity confirmed improvements in visual function, and measurement of visual evoked potentials showed enhanced activity of the visual cortex, specific to the treated eyes. In three of the children, structural lamination of the outer retina was better preserved in the treated eye than in the untreated eye, and, for all four children, retinal thickness appeared better preserved in the treated eye than in the untreated eye. The treated eye of one child developed cystoid macular oedema. No other safety concerns were identified. INTERPRETATION:Our findings indicate that young children with AIPL1-related retinal dystrophy benefited substantially from subretinal administration of rAAV8.hRKp.AIPL1, with improved visual acuity and functional vision and evidence of some protection against progressive retinal degeneration, without serious adverse effects. FUNDING:UK National Institute for Health Research and Moorfields Eye Charity.

High-purity aluminum (Al) Litz wires have become increasingly attractive as conductors in cryogenic electrical machines (CEMs) and “passives” such as chokes and transformers for power electronics due to their light weight, high thermal conductivity, and potential to reduce both DC and AC (eddy) losses at cryo-temperatures. However, these losses are interrelated: a decrease in one results in an increase in the other with changing cryo-temperatures. Thus, defining optimal operating conditions as a function of Al Litz wire parameters is essential to minimize overall losses, a domain yet unexplored. This study investigated the DC and AC losses of two bespoke Al Litz coils at diverse cryo-temperatures and frequencies based on numerical modeling and experiments, elucidating the prerequisite for achieving minimal loss. New analytical equations were formulated to calculate the minimum total loss and minimum-loss resistivities. The minimum-loss resistivities were used to quantify optimal operating temperatures and residual-resistance ratio (RRR) values for distinct Al Litz wire diameters. The research reveals that relentlessly pursuing ultra-low temperatures or high-purity conductors does not consistently contribute to a high efficiency in CEMs. This work enhances comprehension of electromagnetic losses in Litz wires and serves as a pivotal reference for cryogenic electric component design.

"Hyperconducting" motors can be a viable solution to meet the challenging power density and efficiency requirements for aircraft electric propulsion. They exploit the extremely high electric conductivity of readily-available materials such as copper or aluminum at cryogenic temperatures such as those enabled by liquid H2, which is one of the envisaged primary energy sources in future electric aircraft. Unlike High-Temperature Superconductors, hyperconducting aluminum does not suffer from quench and can offer some residual transient power capability in the case of loss of cryo-coolant. This paper presents an analytic modelling framework for estimating dimensional and per-unit cryo-losses as a sum of DC and AC winding losses, cryo-efficiency, and volumetric torque density in terms of the motor main dimensions, electric and magnetic loadings, and surface current density. Crucially, the analysis shows that product the "surface current density × resistivity" can be optimized in order to minimize total winding losses in a hyperconducting motor. An analytic correlation for the optimal surface current density is derived and can be used to inform the design of a hyperconducting motor. Finally, the paper discusses the application of the developed analytical framework to the electromagnetic design of a hyperconducting motor demonstrator rated to 80 kW at 6,000 rpm, and includes preliminary coil test results at 25 K.

Cryogenic electric machines (CEMs) offer significant potential for highly power-dense and ultra-efficient net-zero aircraft. Aluminum (Al) displays superior conductivity to copper (Cu) at cryo-temperatures, making Al Litz wires an attractive option for CEM windings to minimize DC and eddy losses. However, accurately quantifying Al Litz wire losses remains challenging, particularly considering their unknown electromagnetic behavior at different cryo-temperatures and frequencies when embedded in iron cores. To address this, a specialized test setup was developed to measure the losses of two customized Al Litz coils, alongside a Cu Litz coil, under varying cryo-temperatures (25 to 77 K) and frequencies (50 to 1000 Hz). A numerical model was also developed using COMSOL, incorporating a temperature-dependent electrical conductivity and a homogenization model for Litz wires with rectangular cross-sections. The model was incorporated into an analytic design procedure to maximize the test-rig loss ratio within the tight space and maximum heat rejection constraints of the cryostat, to allow accurate loss separation. The experimental data aligns closely with the numerical simulations, enabling a comprehensive analysis of the loss characteristics of Al Litz wires. This study provides a detailed design methodology and serves as a valuable resource for developing CEMs for zero-emission electric aircraft.

Abstract Cancer modeling systems can be advantageous in enabling personalized medicine through rapid testing of therapeutic responsiveness. However, modeling systems often fail in these efforts due to 1) inadequately replicating unique patient genetics, 2) inadequately modeling the patient tumor microenvironment (TME), and 3) lack of internal validation references when isolated from clinical drug response data. We have developed a patient-derived models of cancer (PDMC) program for pancreatic cancer that addresses these challenges. By integrating patient cancer modeling and tissue engineering efforts with clinical trial protocols that perform serial tissue biopsies and analyses during treatment, we can make direct assessments of how different modeling systems replicate actual patient outcomes. Clinical trial protocols include tissue biopsies pre- and post- treatment using targeted therapeutics including MEK and PARP inhibitors. The modeling program, meanwhile, includes collecting metadata from pre- and post- treatment biopsies, the banking of patient tissues, cell line and xenograft generation from each biopsy, multiomic comparisons of models to patient tissue, comparisons of therapeutic responsiveness in models, and ultimately tissue re-engineering through bioprinting of tumor cells along with TME components. Whole exome sequencing is used to confirm that genetic alterations are preserved in each model, and we have established models representing a range of human PDAC genomic profiles. This includes common KRAS and TP53 mutations, as well as rare BRCA mutations and KRAS-wild-type tumors with BRAF mutations. Many cancer-associated fibroblast (CAF) lines have also been established through this program. Including patient derived cell lines, CAD lines, endothelial cells, and PBMCs into 3D bioprinted tumors allows us to better model the TME. Assays performed upon bioprinted tissues can then be directly compared to the same assays performed on the patient tumor to assess similarities as well as further obstacles. Ongoing efforts include building a resource of precise and validated PDMCs for diverse pancreatic cancers, and establishing a path forward for improved cancer modeling for the actualization of personalized medicine in PDAC treatment. Citation Format: Alexander C. Smith, John Muschler, Mike Munks, Rosalie C. Sears, Jonathan Brody. Enhancing models of pancreatic cancer: Integrating patient-derived models with tissue engineering to investigate clinical responses to therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B060.

PURPOSE:To assess the safety and efficacy of AAV5-hRKp.RPGR in participants with retinitis pigmentosa GTPase regulator (RPGR)-associated X-linked retinitis pigmentosa (XLRP). DESIGN:Open-label, phase 1/2 dose escalation/expansion study (ClinicalTrials.gov Identifier: NCT03252847). METHODS:Males (≥5 years old) with XLRP-RPGR were evaluated. In the dose escalation phase, subretinal AAV5-hRKp.RPGR (low: 1.0 × 1011 vg/ml; intermediate: 2.0 × 1011 vg/ml; high: 4.0 × 1011 vg/ml) was administered to the poorer-seeing eye (n = 10). Dose confirmation (intermediate dose) was carried out in 3 pediatric participants. In the dose expansion phase, 36 participants were randomized 1:1:1 to immediate (low or intermediate dose) or deferred (control) treatment. The primary outcome was safety. Secondary efficacy outcomes included static perimetry, microperimetry, vision-guided mobility, best corrected visual acuity, and contrast sensitivity. Safety and efficacy outcomes were assessed for 52 weeks for immediate treatment participants and 26 weeks for control participants. RESULTS:AAV5-hRKp.RPGR was safe and well tolerated, with no reported dose-limiting events. Most adverse events (AEs) were transient and related to the surgical procedure, resolving without intervention. Two serious AEs were reported with immediate treatment (retinal detachment, uveitis). A third serious AE (increased intraocular pressure) was reported outside the reporting period. All ocular inflammation-related AEs responded to corticosteroids. Treatment with AAV5-hRKp.RPGR resulted in improvements in retinal sensitivity and functional vision compared with the deferred group at Week 26; similar trends were observed at Week 52. CONCLUSIONS:AAV5-hRKp.RPGR demonstrated an anticipated and manageable AE profile through 52 weeks. Safety and efficacy findings support investigation in a phase 3 trial.

In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express μ-opioid receptors (μORs). Disrupting μOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids.

The human macula is a specialized, M/L cone-rich region of the eye, critical for high acuity vision, but little is known about the pathways regulating its development. Transcriptional regulation by Retinoic Acid (RA) is essential for many aspects of human eye development. Here, we report a striking biphasic expression of the RA-catabolizing enzyme, CYP26A1, in early human macular development between post-conception weeks 6-17. Early inhibition of RA signaling in human retinal organoids (hROs) prompts early cell cycle exit, and an increase in cone photoreceptors, while late inhibition alters cone subtype specification. Conversely, FGF8, which is negatively regulated by RA and vital for High Acuity Area specification in chick, is not expressed in the nascent human macula and had no effect on hRO photoreceptor fate. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * CMZ : Ciliary marginal zone CS : Carnegie Stage CYP26 : cytochrome P450 family 26 d : Day FGF : Fibroblast growth factor GCL : Ganglion cell layer HAA : High acuity area hROs : Human stem cell derived retinal organoids INL : Inner nuclear layer LE : Lens epithelium mROs : Mouse stem cell derived retinal organoids NBL : Neuroblastic Layer ONH : Optic Nerve Head ONL : Outer nuclear layer PCW : Post-conception weeks PM : Presumptive Macula RA : Retinoic Acid RAR : Retinoic Acid Receptor RARE : Retinoic Acid Response Element RFZ : Rod-free zone RGC : Retinal ganglion cells RPCs : Retinal Progenitor Cells RXR : Retinoid X receptor [1]: pending:yes

Abstract Oncogenic Kras drives cancer progression through cooperation with multiple cellular factors, many of which are yet to be determined. The β1 integrins, a family of extracellular matrix receptors, are strong candidates; they are implicated in many aspects of cancer progression including cell growth and survival signaling, cell migration and metastasis. Additionally, multiple studies have identified β1 integrins within the interactome of oncogenic Kras. We are investigating the potential cooperation if β1 integrins in Kras-mediated oncogenesis using genetic perturbations within the tamoxifen-inducible and conditional Ptf1a-CreERTM; LSL- KrasG12D (p48-KCER) model of pancreatic cancer. Conditional deletion of the β1 integrins from the adult pancreas produced minimal tissue abnormalities; there were no obvious tissue defects at 6 months post induction, although there was some evidence of pancreatitis at 1 year post induction. However, deletion of the β1 integrins within the KCER model of pancreatic cancer (KCER-Δβ1) resulted in a profound suppression of pancreatic disease progression. There was no detectable neoplasias at 3 months post-induction and minimally detectable neoplasias at 6 months post-induction, compared to prominent neoplasia development and stromal expansion in the control KCER mice at these time-points. Moderate stromal expansion was observed in KCER-Δβ1 mice at 6 months post-induction despite the lack of neoplasia development. To investigate the mechanisms of this integrin-KRAS cooperation, we conditionally deleted the expression of two canonical integrin signaling molecules, the integrin-linked kinase (ILK) and the focal adhesion kinase (FAK). Neither the ILK knockout (KCER-ΔILK) nor the FAK knockout (KCER-ΔFAK) phenocopied the KCER-Δβ1 mice, as both developed neoplasias and stromal expansion at 3 months post-induction and beyond. To explore the role of integrin activation, we next deleted expression of the integrin-cytoskeleton linker molecule Talin-1 in the KCER model. Surprisingly, even though Talin-1 is key to integrin activation, the KCER-ΔTalin-1 mice also failed to phenocopy the KCER-Δβ1, showing ample neoplasia development at 3 and 6 months post-induction, and trending towards faster disease progression at later stages. These combined results demonstrate crucial cooperation between oncogenic Kras and β1 integrins to drive pancreatic cancer progression, and point to non-canonical β1 integrin functions in mediating this cooperation. Citation Format: John L. Muschler, Ge Huang, Alexander C. Smith, Rosalie C. Sears. Oncogenic KRAS relies on β1 integrin expression to drive pancreatic neoplasia and PDAC development [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B098.

BACKGROUND: Language in nonmedical data sets is known to transmit human-like biases when used in natural language processing (NLP) algorithms that can reinforce disparities. It is unclear if NLP algorithms of medical notes could lead to similar transmissions of biases. RESEARCH QUESTION: Can we identify implicit bias in clinical notes, and are biases stable across time and geography? STUDY DESIGN AND METHODS: To determine whether different racial and ethnic descriptors are similar contextually to stigmatizing language in ICU notes and whether these relationships are stable across time and geography, we identi fi ed notes on critically ill adults admitted to the University of California, San Francisco (UCSF), from 2012 through 2022 and to Beth Israel Deaconess Hospital (BIDMC) from 2001 through 2012. Because word meaning is derived largely from context, we trained unsupervised word-embedding algorithms to measure the similarity (cosine similarity) quantitatively of the context between a racial or ethnic descriptor (eg, African-American ) and a stigmatizing target word (eg, nonco-operative ) or group of words ( violence , passivity , noncompliance , nonadherence ). RESULTS: In UCSF notes, Black descriptors were less likely to be similar contextually to violent words compared with White descriptors. Contrastingly, in BIDMC notes, Black descriptors were more likely to be similar contextually to violent words compared with White descriptors. The UCSF data set also showed that Black descriptors were more similar contextually to passivity and noncompliance words compared with Latinx descriptors. INTERPRETATION: Implicit bias is identifiable in ICU notes. Racial and ethnic group descriptors carry different contextual relationships to stigmatizing words, depending on when and where notes were written. Because NLP models seem able to transmit implicit bias from training data, use of NLP algorithms in clinical prediction could reinforce disparities. Active debiasing strategies may be necessary to achieve algorithmic fairness when using language models in clinical research.

This paper investigates a novel flux-trapping technique in Type II High-Temperature Superconducting (HTS) rotor coils. This method can be implemented in superconducting electrical machines to take advantage of in situ magnetisation by using the stator coils to energise the rotor HTS coils. This study investigates the feasibility of energizing a rotor HTS coil using a stator winding. The methodology includes modelling and test-rig development and aims to improve practical HTS system implementation for aerospace propulsion applications. Experimental results show that the design is feasible by observing a slow decay of the magnetic field in the air-gap after the external current source has been turned off. The rate of decay of the magnetic field in the airgap is dependent on the resistance of the HTS joint.

Abstract Disruptive medical events such as pneumonia and hip fracture occur more frequently among older adults with dementia than those without dementia. It is not well-understood whether these events increase the risk of mortality to a greater extent for people with dementia (PWD) compared to people without dementia (PWoD). Using data from the Health and Retirement Study linked to Medicare claims, we estimated the impact of hip fracture and pneumonia on risk of mortality among 700 PWD and 12,438 PWoD using a Cox proportional hazards model. PWD had a higher risk of mortality both in the case of hip fracture (HR 1.64, 95% CI 1.31, 1.96) and pneumonia (HR 1.21 95% CI 1.09, 1.34) compared to PWoD who experienced those events. This study provides evidence that dementia may increase mortality after a disruptive medical event and suggests that the clinical course of dementia may not always be slow and gradual.

The retina encompasses a network of neurons, glia and epithelial and vascular endothelia cells, all coordinating visual function. Traditionally, molecular information exchange in this tissue was thought to be orchestrated by synapses and gap junctions. Recent findings have revealed that many cell types are able to package and share molecular information via extracellular vesicles (EVs) and the technological advancements in visualisation and tracking of these delicate nanostructures has shown that the role of EVs in cell communication is pleiotropic. EVs are released under physiological conditions by many cells but they are also released during various disease stages, potentially reflecting the health status of the cells in their cargo. Little is known about the physiological role of EV release in the retina. However, administration of exogenous EVs in vivo after injury suggest a neurotrophic role, whilst photoreceptor transplantation in early stages of retina degeneration, EVs may facilitate interactions between photoreceptors and Müller glia cells. In this review, we consider some of the proposed roles for EVs in retinal physiology and discuss current evidence regarding their potential impact on ocular therapies via gene or cell replacement strategies and direct intraocular administration in the diseased eye.

Retinitis pigmentosa (RP) is a disease characterised by photoreceptor cell death. It can be initiated by mutations in a number of different genes, primarily affecting rods, which will die first, resulting in loss of night vision. The secondary death of cones then leads to loss of visual acuity and blindness. We set out to investigate whether increased mitochondrial reactive oxygen species (ROS) formation, plays a role in this sequential photoreceptor degeneration. To do this we measured mitochondrial H2O2 production within mouse eyes in vivo using the mass spectrometric probe MitoB. We found higher levels of mitochondrial ROS that preceded photoreceptor loss in four mouse models of RP: Pde6brd1/rd1; Prhp2rds/rds; RPGR-/-; Cln6nclf. In contrast, there was no increase in mitochondrial ROS in loss of function models of vision loss (GNAT-/-, OGC), or where vision loss was not due to photoreceptor death (Cln3). Upregulation of Nrf2 transcriptional activity with dimethylfumarate (DMF) lowered mitochondrial ROS in RPGR-/- mice. These findings have important implications for the mechanism and treatment of RP.

The electrical submersible pump (ESP) is a key artificial lift enabler within the oil industry. Since their launch in late 1920s, induction motors have been the main motor technology used in ESPs. Recent advancements in technology have opened opportunities for the development of higher performance and more efficient topologies for electrical machines. This paper aims to provide a review of different motor technologies in the well oil and water fluid lifting industry. The analysis in this paper is constructed around a comparison between several electrical machine technologies when exposed to the harsh downhole environment. The dimensions of each machine are similar and provide a fair comparison. The advantages and drawbacks of each motor are presented in respect to key mechanical or electrical considerations. Solutions are recommended when there is evidence from previous work, and several questions are raised for the feasibility of certain topologies in respect to the new challenges. Results show why the induction machine (IM) was selected by ESP providers in late 1920s and why it still has value nearly 100 years later. Permanent magnet machines (PMMs) offer higher power density levels in a smaller package. Synchronous reluctance motors (SyncR) offer a more robust and cheaper alternative, but the design is relatively new and further analysis is still required. Advancements in switched reluctance machines (SRMs) allows for the development of a motor with IM torque capabilities. Both SRM and BLDC (brushless DC) require pulse width modulation (PWM) square-pulse drives, which may prove to be a challenge when driven over a long cable. This paper emphasises the importance of a proper analysis of each motor technology in respect to a particular application. The design of electrical machines should be tailored around the specification of each environment to provide a more robust and efficient system. Although some literature is available on the comparison of PMM and IM in the artificial lift (AL) industry, it seems to promote PMMs with little attempt to suggest improvements for traditional IM topologies, which still offer many benefits in terms of ease of manufacture, robustness and capability to operate in extreme environments such as with high temperatures. This paper discusses several other technologies that have not previously been considered. The aim of the paper is to provide a holistic view of the possible problems each technology will face in the downhole environment and inform future work on possible design improvements for the most promising technologies. In addition, the paper will provide a comparative assessment of the different motor technologies in terms of their strength and weaknesses, and also issues that should be addressed for ESP applications.

Abstract Litz wires operating in a cryogenic environment can potentially improve both the efficiency and power density of electrical machines and passive components. However, due to the low resistivity and high magnetic fields, eddy‐current losses may become significant in cryogenically cooled windings, especially in airgap winding arrangements or in the case of significant slot leakage fields, unless the litz wire parameters are carefully chosen. A framework for litz wire loss performance optimization and experimental characterisation at cryogenic temperatures is provided. An optimum operating temperature for minimum loss is derived based on analytical expressions, which highlights the role of litz wire parameters, current density and external field. The proximity loss model, used to calculate the optimum operating temperature, is validated experimentally. Two test rigs with different magnetic cores were designed and built. Copper and aluminium litz wires with a strand diameter down to 0.1 mm were tested in a liquid nitrogen bath with a uniform harmonic external magnetic field up to 0.5 T peak and a frequency up to 1 kHz. Measurements show good agreement with the theoretical results and confirm that the proposed model can be confidently used during the preliminary design of cryogenic windings.

CreTrp1 mice are widely used for conditional retinal pigment epithelium (RPE) gene function studies. Like other Cre/LoxP models, phenotypes in CreTrp1 mice can be affected by Cre-mediated cellular toxicity, leading to RPE dysfunction, altered morphology and atrophy, activation of innate immunity, and consequent impairment of photoreceptor function. These effects are common among the age-related alterations of RPE that feature in early/intermediate forms of age-related macular degeneration. This article characterizes Cre-mediated pathology in the CreTrp1 line to elucidate the impact of RPE degeneration on both developmental and pathologic choroidal neovascularization. Nonredundant roles of the two major components of the hypoxia-inducible factor (HIF) family of transcription regulators, HIF1α and HIF2α, were identified. Genetic ablation of Hif1a protected against Cre-induced degeneration of RPE and choroid, whereas ablation of Hif2a exacerbated this degeneration. Furthermore, HIF1α deficiency protected CreTrp1 mice against laser-induced choroidal neovascularization, whereas HIF2α deficiency exacerbated the phenotype. Cre-mediated degeneration of the RPE in CreTrp1 mice offers an opportunity to investigate the impact of hypoxia signaling in the context of RPE degeneration. These findings indicate that HIF1α promotes Cre recombinase-mediated RPE degeneration and laser-induced choroidal neovascularization, whereas HIF2α is protective.