An examination of the mechanisms driving the therapeutic effects of an AAV expressing a soluble variant of VEGF receptor-1.

In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1ß and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions.

Prognostic Significance of 18F-FDG PET/CT Radiomics in Patients With Resectable Pancreatic Ductal Adenocarcinoma Undergoing Curative Surgery.

PURPOSE: This study aimed to investigate the prognostic significance of PET/CT radiomics to predict overall survival (OS) in patients with resectable pancreatic ductal adenocarcinoma (PDAC). METHODS: We enrolled 627 patients with resectable PDAC who underwent preoperative 18F-FDG PET/CT and subsequent curative surgery. Radiomics analysis of the PET/CT images for the primary tumor was performed using the Chang-Gung Image Texture Analysis toolbox. Radiomics features were subjected to least absolute shrinkage and selection operator (LASSO) regression to select the most valuable imaging features of OS. The prognostic significance was evaluated by Cox proportional hazards regression analysis. Conventional PET parameters and LASSO score were assessed as predictive factors for OS by time-dependent receiver operating characteristic curve analysis. RESULTS: During a mean follow-up of 28.8 months, 378 patients (60.3%) died. In the multivariable Cox regression analysis, tumor differentiation, resection margin status, tumor stage, and LASSO score were independent prognostic factors for OS (HR, 1.753, 1.669, 2.655, and 2.946; all P < 0.001, respectively). The time-dependent receiver operating characteristic curve analysis showed that the LASSO score had better predictive performance for OS than conventional PET parameters. CONCLUSION: The LASSO score using the 18F-FDG PET/CT radiomics of the primary tumor was the independent prognostic factor for predicting OS in patients with resectable PDAC and may be helpful in determining therapeutic and follow-up plans for these patients.

Comparison of Keratometry and Total Corneal Power, as measured by a swept-source OCT-based optical biometer, for IOL power calculation in Asian eyes.

PURPOSE: To investigate whether standard keratometry (K) or total corneal power (TCP) lead to more accurate refractive outcomes for intraocular lens (IOL) power calculation. SETTING: Public hospital. DESIGN: Retrospective evaluation of a diagnostic test instrument. METHODS: Preoperatively all patients underwent optical biometry with the Anterion (Heidelberg), a swept-source optical coherence tomographer providing both K and TCP. The same IOL model was implanted in all cases. The whole sample was divided into a training dataset, used to optimize the formula constants, and a testing dataset, used to investigate the spherical equivalent prediction error (SEQ-PE) of 8 IOL power formulas. Trueness, precision and accuracy were evaluated by means of the robust two-sample t-test. Cochran's Q test was performed to assess whether the percentage of eyes with an SEQ-PE within each threshold was significantly different; in such an event, the McNemar test was then applied. RESULTS: Both the training and testing datasets included 317 eyes. No significant differences were detected for trueness, due to constant optimization. Precision and accuracy were better when K was entered, although a statistically significant difference was observed only with the EVO (precision: p = 0.02 and accuracy: p = 0.03) and Haigis formula (p <0.01 for both precision and accuracy). No significant differences were observed for the percentage of eyes with an absolute SEQ-PE within any threshold. CONCLUSIONS: With most formulas, IOL power calculation is not more accurate when TCP is used instead of K.

Prodigiosin regulates cancer metabolism through interaction with GLUT1.

In contrast to normal cells, cancer cells predominantly utilise glycolysis for ATP generation under aerobic conditions, facilitating proliferation and metastasis. Targeting glycolysis is effective for cancer treatment. Prodigiosin (PDG) is a natural compound with various bioactivities, including anticancer effects. However, the precise action mechanisms and molecular targets of PDG, which has demonstrated efficacy in regulating glucose metabolism in cancer cells, remain elusive. Here, we aimed to investigate the anti-cancer activity of PDG and mechanism in cancer metabolism. PDG regulated cancer metabolism by suppressing intracellular ATP production rate and levels. It inhibited glycolysis and mitochondrial oxidative phosphorylation, impeding ATP production dependent on both glycolysis and mitochondrial respiration. Moreover, it inhibited cellular glucose uptake by directly interacting with glucose transporter 1 without affecting its mRNA or protein levels in HCT116 cells. We provide insights into the anti-cancer effects of PDG mediated via cancer metabolism regulation, suggesting its therapeutic potential for cancer.

Effect duration of lumbar sympathetic ganglion neurolysis in patients with complex regional pain syndrome: a prospective observational study.

Lumbar sympathetic ganglion neurolysis (LSGN) has been used for long-term pain relief in patients with complex regional pain syndrome (CRPS). However, the actual effect duration of LSGN has not been accurately measured. This prospective observational study measured the effect duration of LSGN in CRPS patients and investigated the relationship between temperature change and pain relief. After performing LSGN, the skin temperatures of both the maximum pain site and the plantar area in the affected and unaffected limbs were measured by infrared thermography, and pain intensity was assessed before and at 2 weeks, 1 month, and 3 months. The median time to return to baseline temperature was calculated using survival analysis. The skin temperature increased significantly at all-time points relative to baseline in both regions (maximum pain site: 1.4 °C ± 1.0 °C, plantar region: 1.28 °C ± 0.8 °C, all P < 0.001). The median time to return to baseline temperature was 12 weeks (95% confidence interval [CI] 7.7-16.3) at the maximum pain site and 12 weeks (95% CI 9.4-14.6) at the plantar area. Pain intensity decreased significantly relative to baseline, at all-time points after LSGN. In conclusion, the median duration of the LSGN is estimated to be 12 weeks.

Analysis of patient health questionnaire-9 (PHQ-9) based depression prevalence according to a discordance between quantitative urinary cotinine levels and self-report of second-hand smoke exposure among adults: A cross-sectional study.

Background: Second-hand smoke (SHS) exposure appears to be more common among individuals with depression. However, self-report of SHS exposure is an inaccurate classification compared to confirming SHS exposure using urinary cotinine (UC). Additionally, the dose-response relationship between depression and UC is controversial. Methods: The severe stress rate and depression prevalence was estimated among 14530 Korean participants aged ≥19 years using data patient health questionnaire-9 (PHQ-9) and on UC from the Korean National Health and Nutrition Examination Survey. Measured UCs were divided into four categories: UC- (≤0.3 µg/L), UC± (0.4 µg/L-0.9 µg/L), UC+ (1.0 µg/L-11.9 µg/L), and UC++ (≥12.0 µg/L). Results: About 55.0 % participants were female and participants' mean age was 51.1 years. Non-smokers were 80.3 %. Among non-smokers, non-SHS exposure participants (SR-) and SHS exposure participants (SR+) were 83.0 % and 17.0 %, respectively. When UC- was used as the reference subgroup, the UC++ subgroup showed a higher depression prevalence, whereas the UC ± subgroup showed a lower prevalence. In the same UC categories, the depression prevalence and severe stress rate were higher among females than among males. Furthermore, the SR + subgroup had a higher severe stress rate than the SR- subgroup. Conclusions: Our study showed a paradoxical reduction in the depression prevalence and severe stress rate in the UC ± subgroup compared to the UC- subgroup. Additionally, the dose-response relationship between the SHS exposure biomarker and the depression prevalence was not linear. Our study indicates that an emotional stress-based model may be more appropriate for explaining the relationship between depression and SHS exposure.

Relation between change of effective lens position and toric IOL rotation after toric IOL implantation.

OBJECTIVE: To evaluate the relationship between change of effective lens position (ELP) and toric intraocular lens (IOL) rotation in patients with increasing postoperative refractive astigmatism after successful toric IOL implantation. METHODS: The subjects include 61 people (61 eyes) with increasing residual astigmatism >0.5 D 3 months after successful toric IOL implantation. Clinical measurements included preoperative, 1-week, and 1-, 2-, and 3-month postoperative visual acuity; refraction; keratometer; anterior and posterior corneal astigmatism; ELP by Scheimpflug camera imaging; and IOL axis by slit-lamp biomicroscopic photograph with pupil dilation. RESULTS: Residual astigmatism in postoperative month 3 (0.81 ± 0.50 D) is higher than that at postoperative week 1 (0.41 ± 0.38 D; p < 0.05). ELP decreased by 264.44 ± 163.25 µm, and the IOL rotated by 2.91 ± 1.44 degrees from week 1 to month 3 (p < 0.05). The ELP change had a positive correlation with IOL rotation (R2 = 0.383; p = 0.006), and the postoperative refractive astigmatic change had a positive correlation with ELP change (R2 = 0.272; p = 0.027) and IOL rotation (R2 = 0.272; p = 0.0001) from week 1 to month 3. CONCLUSION: ELP change can influence toric IOL rotation and increase residual astigmatism after toric IOL implantation.

Atomic Layer Deposition of Zirconia on Titanium Implants Improves Osseointegration in Rabbit Bones.

Purpose: Atomic layer deposition (ALD) is a method that can deposit zirconia uniformly on an atomic basis. The effect of deposited zirconia on titanium implants using ALD was evaluated in vivo. Methods: Machined titanium implants (MTIs) were used as the Control. MTIs treated by sandblasting with large grit and acid etching (SA) and MTIs deposited with zirconia using ALD are referred to as Groups S and Z, respectively. Twelve implants were prepared for each group. Six rabbits were used as experimental animals. To evaluate the osteogenesis and osteocyte aspects around the implants, radiological and histological analyses were performed. The bone-to-implant contact (BIC) ratio was measured and statistically analyzed to evaluate the osseointegration capabilities. Results: In the micro-CT analysis, more radiopaque bone tissues were observed around the implants in Groups S and Z. Histological observation found that Groups S and Z had more and denser mature bone tissues around the implants in the cortical bone area. Many new and mature bone tissues were also observed in the medullary cavity area. For the BIC ratio, Groups S and Z were significantly higher than the Control in the cortical bone area (P < 0.017), but there was no significant difference between Groups S and Z. Conclusion: MTIs deposited with zirconia using ALD (Group Z) radiologically and histologically showed more mature bone formation and activated osteocytes compared with MTIs (Control). Group Z also had a significantly higher BIC ratio than the Control. Within the limitations of this study, depositing zirconia on the surface of MTIs using ALD can improve osseointegration in vivo.

Stilbenoid derivatives as potent inhibitors of HIF-1α-centric cancer metabolism under hypoxia.

Hypoxia-inducible factor (HIF)-1α is a crucial transcription factor associated with cancer metabolism and is regarded as a potent anticancer therapeutic strategy within the hypoxic microenvironment of cancer. In this study, stilbenoid derivatives were designed, synthesized, and assessed for their capacity to inhibit HIF-1α-associated cancer metabolism and evaluated for inhibition of cancer cell viability and HIF activation. Through the structure-activity relationship studies, compound 28e was identified as the most potent derivative. Specifically, under the hypoxic condition, 28e reduced the accumulation of HIF-1α protein and the expression of its target genes related to glucose metabolism without affecting the expression of HIF-1α mRNA. Furthermore, 28e inhibited glucose uptake, glycolytic metabolism, and mitochondrial respiration, decreasing cellular ATP production under hypoxic conditions. In addition, 28e displayed significant anti-tumor effects and effectively suppressed the accumulation of HIF-1α protein in tumor tissue in vivo xenograft model. These findings suggest that our stilbenoid derivatives exert their anticancer effects by targeting HIF-1α-centered cancer metabolism under hypoxic conditions.

Seasonal variation in peripheral vestibular disorders based on Korean population data.

Objectives: Comprehensive studies in which the seasonal variation in peripheral vestibular disorders was evaluated using data from an entire population are insufficient. The seasonal variation in peripheral vestibular disorders based on data from the entire Korean population was investigated in the present study. Methods: Retrospective data from the National Health Insurance Service of Korea from 2008 to 2020 was analyzed. Benign paroxysmal positional vertigo (BPPV), vestibular neuritis (VN), and Meniere's disease (MD) were defined based on diagnostic, treatment, or audiovestibular test codes. The seasonal incidence for each peripheral vestibular disorder was calculated among all study subjects. Results: For the entire study cohort, the incidence of BPPV was significantly higher in spring (odds ratio [OR] = 1.031, 95% confidence interval [CI] = 1.026-1.037), autumn (OR = 1.024, 95% CI = 1.019-1.029), and winter (OR = 1.051, 95% CI = 1.046-1.056) than in summer. The incidence of VN was significantly lower in winter (OR = 0.917, 95% CI = 0.907-0.927) than in summer. The incidence of MD was significantly higher in spring (OR = 1.027, 95% CI = 1.015-1.039) and autumn (OR = 1.029, 95% CI = 1.017-1.041) and significantly lower in winter (OR = 0.919, 95% CI = 0.908-0.931) than in summer. Differences were also observed in seasonal variation based on sex and age. Conclusions: Significant seasonal variation occurred in peripheral vestibular disorders including BPPV, VN, and MD based on the entire Korean population data. Furthermore, seasonal variation showed differences based on sex and age. Level of Evidence: 4.

A comparative analysis of the physical fitness profile of Korean women's national amateur boxers by weight category.

The purpose of this study was to examine the differences in specific physical fitness of the national amateur women's boxer. The Korean women's national amateur boxers were classified into the lightweight category (LWC, n=21) and middleweight category (MWC, n=13), and body composition (percentage body fat and body mass index) and specific physical fitness (maximal muscle strength, anaerobic power, isokinetic muscle strength, cardiopulmonary endurance) were measured. The Mann-Whitney U-test was conducted to determine the differences in the body composition and specific physical fitness in women's boxers. The percentage body fat (P=0.004) and body mass index (P<0.001) were significantly higher in the LWC compared to MWC. In addition, LWC showed significantly higher isokinetic muscle strength (P<0.001), upper anaerobic mean power (P=0.002), maximal muscle strength (P=0.003), and maximal heart rate at anaerobic threshold (P=0.029), maximal oxygen consumption (P<0.001) and the 20-m shuttle-run exercise (P=0.004) compared to MWC. In conclusion, the body fat percentage and body mass index levels among body composition were significantly higher in the MWC than in the LWC, and the constant muscle strength, maximum muscle strength, and cardiopulmonary endurance levels were significantly higher in the LWC than in the MWC. The results of this study are expected to provide useful data for planning future strategies for efficient and scientific training programs for each weight category.

Methanotrophs mediated biogas valorization: Sustainable route to polyhydroxybutyrate production.

This study explores the ability of methanotrophs to convert biogas into biopolymers, addressing H2S as a limitation in the utilization of biogas as a carbon source for bioconversion. Transcriptomic analysis was conducted to understand the growth and changes in the expression patterns of Type I and II methanotrophs under varying H2S concentrations. Results suggested that Type II methanotrophs can possess a native H2S utilization pathway. Both Type I and II methanotrophs were evaluated for their growth and polyhydroxybutyrate (PHB) production from biogas. Methylocystis sp. MJC1 and Methylocystis sp. OK1 exhibited a maximum biomass production of 4.0 and 4.5 gDCW/L, respectively, in fed-batch culture, aligning with the transcriptome data. Furthermore, Methylocystis sp. MJC1 produced 2.9 g PHB/L from biogas through gas fermentation. These findings underscore biogas-based biotechnology as an innovative solution for environmental and industrial challenges with further optimization and productivity enhancement research expected to broaden the potential in this field.

Surgical Outcomes of Low-Flow Bypass Surgery in Intracranial Atherosclerotic Steno-Occlusive Diseases.

BACKGROUND AND OBJECTIVES: The role of bypass surgery in intracranial atherosclerotic steno-occlusive diseases (ICADs) remains controversial. We aimed to analyze the surgical outcomes of bypass surgery in patients with the ICADs in a single tertiary institution. METHODS: Among 1018 cases of low-flow bypass surgery between 2003 and 2022, 215 patients with the ICAD refractory to medical treatment were finally enrolled in this study. Clinical and radiological outcomes were retrospectively evaluated, with survival analyses. RESULTS: All strokes, cerebral infarctions, and intracranial hemorrhages occurred in 12.1% (n = 26), 9.8% (n = 21), and 2.3% (n = 5), respectively, during the clinical follow-up of 54.6 ± 47.6 months (range, 0.6-237.8 months). Among all stroke events, 84.6% (n = 22) occurred within 30 postoperative days. The 2-year and 5-year cumulative risks of all strokes were 12.1% each. The mean modified Rankin Scale scores were 1.6 ± 1.1 (range, 0-5) preoperatively and 0.8 ± 1.2 (range, 0-6) at last (P < .01). The patency of direct bypass was 99.1% (n = 213) just before discharge and 96.3% (n = 184 of 191 patients with available tests) at the last angiographic follow-up of 27.0 ± 27.3 months (range, 2.3-97.3 months). All the patients with available data (n = 190) showed hemodynamic improvement on acetazolamide-challenged single-photon emission computed tomography with 99mTc-hexamethylpropyleneamine oxime during the follow-up of 38.6 ± 36.7 months (range, 2.3-158.6 months). CONCLUSION: Low-flow bypass surgery showed acceptable treatment outcomes in the prevention of recurrent stroke.

Risk factors for middle ear cholesteatoma surgery based on Korean population data.

BACKGROUND: Studies of risk factors for middle ear cholesteatoma surgery using population-based data are lacking. OBJECTIVES: To investigate the risk factors for cholesteatoma surgery in adults based on population data from Korea. MATERIALS AND METHODS: For this retrospective study, we used Korean National Health Insurance Service National Sample Cohort data. Patients who were 20 years or older and underwent mastoidectomy from 2006 through 2015 under the diagnostic codes of cholesteatoma were defined as patients with middle ear cholesteatoma surgery. The control group was comprised of the remaining database sample in 2006. Sociodemographic factors in 2006 and histories of medical diseases, allergic diseases, and chronic sinusitis from 2003 through 2005 were compared between cholesteatoma surgery and control groups. RESULTS: A total of 459 patients underwent cholesteatoma surgery. In multivariate Cox regression analysis, age 40-59 years and residence in metropolitan cities and small- and medium-sized cities and counties were significant risk factors for cholesteatoma surgery whereas allergic rhinitis, asthma, atopic dermatitis, and chronic sinusitis were not significant risk factors for middle ear cholesteatoma surgery. CONCLUSIONS AND SIGNIFICANCE: The present study found no evidence of associations between allergic diseases or chronic sinusitis and cholesteatoma surgery in adults.

Inhibition of Neuron-Restrictive Silencing Factor (REST/NRSF) Chromatin Binding Attenuates Epileptogenesis.

The mechanisms by which brain insults lead to subsequent epilepsy remain unclear. Insults including trauma, stroke, infections, and long seizures (status epilepticus, SE) increase the nuclear expression and chromatin binding of the neuron-restrictive silencing factor/RE-1 silencing transcription factor (NRSF/REST). REST/NRSF orchestrates major disruption of the expression of key neuronal genes, including ion channels and neurotransmitter receptors, potentially contributing to epileptogenesis. Accordingly, transient interference with REST/NRSF chromatin binding after an epilepsy-provoking SE suppressed spontaneous seizures for the 12 d duration of a prior study. However, whether the onset of epileptogenesis was suppressed or only delayed has remained unresolved. The current experiments determined if transient interference with REST/NRSF chromatin binding prevented epileptogenesis enduringly or, alternatively, slowed epilepsy onset. Epileptogenesis was elicited in adult male rats via systemic kainic acid-induced SE (KA-SE). We then determined if decoy, NRSF-binding-motif oligodeoxynucleotides (NRSE-ODNs), given twice following KA-SE (1) prevented REST/NRSF binding to chromatin, using chromatin immunoprecipitation, or (2) prevented the onset of spontaneous seizures, measured with chronic digital video-electroencephalogram. Blocking NRSF function transiently after KA-SE significantly lengthened the latent period to a first spontaneous seizure. Whereas this intervention did not influence the duration and severity of spontaneous seizures, total seizure number and seizure burden were lower in the NRSE-ODN compared with scrambled-ODN cohorts. Transient interference with REST/NRSF function after KA-SE delays and moderately attenuates insult-related hippocampal epilepsy, but does not abolish it. Thus, the anticonvulsant and antiepileptogenic actions of NRSF are but one of the multifactorial mechanisms generating epilepsy in the adult brain.

Structural Optimization of BODIPY Derivatives: Achieving Stable and Long-Lived Green Emission in Hyperfluorescent OLEDs.

Boron dipyrromethene (BODIPY) derivatives are widely studied as terminal emitters in organic light-emitting diodes (OLED) due to their narrow emission and high photoluminescence quantum yield (PLQY). However, the strategy for precisely tuning their emission toward a high color purity is still challenging. Herein, we developed a new design strategy to regulate the emission of BODIPY derivatives by modifying the electronic and steric dominance using functionalities, such as nitrile, pentafluorophenyl, diethyl, and monobenzyl. These rational modifications yielded a series of four novel green BODIPY emitters, namely, tPN-BODIPY, tPPP-BODIPY, tPBn-BODIPY, and tPEN-BODIPY, each benefited with a tuned emissions range of 517 to 542 nm with a narrow fwhm of 25 nm and high photoluminescence quantum yield up to 96%. Among these synthesized BODIPYs, an unsymmetrical tPBn-BODIPY was chosen as a final dopant (FD) to explore its application in OLED devices. The fabricated TADF sensitized fluorescence-OLED (TSF-OLED) exhibits a narrow band pure green emission at 531 nm with corresponding CIE coordinates of (x, y) = (0.27, 0.68) and a maximum external quantum efficiency (EQE) of 20%. Furthermore, the TSF-OLED displayed an exceptionally prolonged device operational lifetime (LT90) of 210 h at an initial luminescence of 3000 cd m-2.

Natural course of hemodynamically stable hemispheres contralateral to operated hemispheres in adult patients with ischemic moyamoya diseases.

The necessity of bilateral bypass in adult moyamoya disease (MMD) remains unclear despite its recommendation for pediatric and hemorrhagic cases. We aimed to investigate the natural course of hemodynamically stable unoperated hemispheres after bypass surgery for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD. Among 288 patients, the mean age at the first operation of the unstable hemispheres was 40.8 ± 12.2 years. The mean follow-up period was 62.9 ± 46.5 months. 45 patients (15.6%) experienced stroke events in the unoperated hemisphere, consisting of hemorrhagic stroke in 8 (2.8%) and ischemic stroke in 37 (12.8%), including progressive transient ischemic attack in 25 (8.7%) and infarction in 12 (4.2%). Among them, 39 patients (13.5%) underwent bypass surgery. The annual risk of total stroke is 3.0%/patient-year, with 2.5% for ischemic stroke and 0.5% for hemorrhagic stroke. The 5- and 10-year cumulative risks of ischemic stroke were 13.4% and 18.3%, respectively, and those of hemorrhagic stroke were each 3.2%. The natural course of hemodynamically stable hemispheres contralateral to the operated ones appeared fairly good. Additional bypass surgery on the unoperated hemispheres should be considered for symptomatic and hemodynamically unstable hemispheres in adult patients with ischemic MMD during the follow-up.

Gossamer: Scaling Image Processing and Reconstruction to Whole Brains.

Neuronal reconstruction-a process that transforms image volumes into 3D geometries and skeletons of cells- bottlenecks the study of brain function, connectomics and pathology. Domain scientists need exact and complete segmentations to study subtle topological differences. Existing methods are diskbound, dense-access, coupled, single-threaded, algorithmically unscalable and require manual cropping of small windows and proofreading of skeletons due to low topological accuracy. Designing a data-intensive parallel solution suited to a neurons' shape, topology and far-ranging connectivity is particularly challenging due to I/O and load-balance, yet by abstracting these vision tasks into strategically ordered specializations of search, we progressively lower memory by 4 orders of magnitude. This enables 1 mouse brain to be fully processed in-memory on a single server, at 67× the scale with 870× less memory while having 78% higher automated yield than APP2, the previous state of the art in performant reconstruction.