Cell replacement with stem cell-derived retinal ganglion cells from different protocols

Glaucoma,characterized by a degenerative loss of retinal ganglion cells,is the second leading cause of blindness worldwide.There is currently no cure for vision loss in glaucoma because retinal ganglion cells do not regenerate and are not replaced after injury.Human stem cell-derived retinal ganglion cell transplant is a potential therapeutic strategy for retinal ganglion cell degenerative diseases.In this review,we first discuss a 2D protocol for retinal ganglion cell differentiation from human stem cell culture,including a rapid protocol that can generate retinal ganglion cells in less than two weeks and focus on their transplantation outcomes.Next,we discuss using 3D retinal organoids for retinal ganglion cell transplantation,comparing cell suspensions and clusters.This review provides insight into current knowledge on human stem cell-derived retinal ganglion cell differentiation and transplantation,with an impact on the field of regenerative medicine and especially retinal ganglion cell degenerative diseases such as glaucoma and other optic neuropathies.

用于重建物理和虚拟抓取的可重构数据手套

In this work,we present a reconfigurable data glove design to capture different modes of human hand-object interactions,which are critical in training embodied artificial intelligence(AI)agents for fine manipulation tasks.To achieve various downstream tasks with distinct features,our reconfigurable data glove operates in three modes sharing a unified backbone design that reconstructs hand gestures in real time.In the tactile-sensing mode,the glove system aggregates manipulation force via customized force sensors made from a soft and thin piezoresistive material;this design minimizes interference during complex hand movements.The virtual reality(VR)mode enables real-time interaction in a physically plausible fashion:A caging-based approach is devised to determine stable grasps by detecting collision events.Leveraging a state-of-the-art finite element method,the simulation mode collects data on fine-grained four-dimensionalmanipulation events comprising hand and object motions in three-dimensional space and how the object's physical properties(e.g.,stress and energy)change in accordance with manipulation over time.Notably,the glove system presented here is the first to use high-fidelity simulation to investigate the unobservable physical and causal factors behind manipulation actions.In a series of experiments,we characterize our data glove in terms of individual sensors and the overall system.More specifically,we evaluate the system's three modes by①recording hand gestures and associated forces,②improving manipulation fluency in VR,and③producing realistic simulation effects of various tool uses,respectively.Based on these three modes,our reconfigurable data glove collects and reconstructs fine-grained human grasp data in both physical and virtual environments,thereby opening up new avenues for the learning of manipulation skills for embodied AI agents.

Photobiomodulation for the treatment of retinal diseases: a review

Photobiomodulation（PBM）,also known as low level laser therapy,has recently risen to the attention of the ophthalmology community as a promising new approach to treat a variety of retinal conditions including agerelated macular degeneration,retinopathy of prematurity,diabetic retinopathy,Leber’s hereditary optic neuropathy,amblyopia,methanol-induced retinal damage,and possibly others.This review evaluates the existing research pertaining to PBM applications in the retina,with a focus on the mechanisms of action and clinical outcomes.All available literature until April 2015 was reviewed using Pub Med and the following keywords：＂photobiomodulation AND retina＂,＂low level light therapy AND retina＂,＂low level laser therapy AND retina＂,and＂FR/NIR therapy AND retina＂.In addition,the relevant references listed within the papers identified through Pub Med were incorporated.The literature supports the conclusion that the low-cost and noninvasive nature of PBM,coupled with the first promising clinical reports and the numerous preclinical-studies in animal models,make PBM well-poised to become an important player in the treatment of a wide range of retinal disorders.Nevertheless,large-scale clinical trials will be necessary to establish the PBM therapeutic ranges for the various retinal diseases,as well as to gain a deeper understanding of its mechanisms of action.

Use of sensory substitution devices as a model system for investigating cross-modal neuroplasticity in humans

Blindness provides an unparalleled opportunity to study plasticity of the nervous system in humans.Seminal work in this area examined the often dramatic modifications to the visual cortex that result when visual input is completely absent from birth or very early in life（Kupers and Ptito,2014）.More recent studies explored what happens to the visual pathways in the context of acquired blindness.This is particularly relevant as the majority of diseases that cause vision loss occur in the elderly.

Dark,Beyond Deep:A Paradigm Shift to Cognitive AI with Humanlike Common Sense

Recent progress in deep learning is essentially based on a“big data for small tasks”paradigm,under which massive amounts of data are used to train a classifier for a single narrow task.In this paper,we call for a shift that flips this paradigm upside down.Specifically,we propose a“small data for big tasks”paradigm,wherein a single artificial intelligence(AI)system is challenged to develop“common sense,”enabling it to solve a wide range of tasks with little training data.We illustrate the potential power of this new paradigm by reviewing models of common sense that synthesize recent breakthroughs in both machine and human vision.We identify functionality,physics,intent,causality,and utility(FPICU)as the five core domains of cognitive AI with humanlike common sense.When taken as a unified concept,FPICU is concerned with the questions of“why”and“how,”beyond the dominant“what”and“where”framework for understanding vision.They are invisible in terms of pixels but nevertheless drive the creation,maintenance,and development of visual scenes.We therefore coin them the“dark matter”of vision.Just as our universe cannot be understood by merely studying observable matter,we argue that vision cannot be understood without studying FPICU.We demonstrate the power of this perspective to develop cognitive AI systems with humanlike common sense by showing how to observe and apply FPICU with little training data to solve a wide range of challenging tasks,including tool use,planning,utility inference,and social learning.In summary,we argue that the next generation of AI must embrace“dark”humanlike common sense for solving novel tasks.

Influence of Sox protein SUMOylation on neural development and regeneration

SRY-related HMG-box(Sox) transcription factors are known to regulate central nervous system development and are involved in several neurological diseases.Post-translational modification of Sox proteins is known to alter their functions in the central nervous system.Among the different types of post-translational modification,small ubiquitin-like modifier(SUMO) modification of Sox proteins has been shown to modify their transcriptional activity.Here,we review the mechanisms of three Sox proteins in neuronal development and disease,along with their transcriptional changes under SUMOylation.Across three species,lysine is the conserved residue for SUMOylation.In Drosophila,SUMOylation of Sox N plays a repressive role in transcriptional activity,which impairs central nervous system development.However,de SUMOylation of Sox E and Sox11 plays neuroprotective roles,which promote neural crest precursor formation in Xenopus and retinal ganglion cell differentiation as well as axon regeneration in the rodent.We further discuss a potential translational therapy by SUMO site modification using AAV gene transduction and Clustered regularly interspaced short palindromic repeats-Cas9 technology.Understanding the underlying mechanisms of Sox SUMOylation,especially in the rodent system,may provide a therapeutic strategy to address issues associated with neuronal development and neurodegeneration.

Compartmentalization of local cAMP signaling in neuronal growth and survival

Intracellular signal transduction controlling neuronal development and survival is conveyed by second messengers that are often differentially regulated over space and time.The highly polarized morphology of neurons is conferred by a network of regulatory signaling pathways that determine axon guidance and dendrite formation.Among these,cyclic adenosine monophosphate(cAMP)is a second messenger that is critical for numerous neuronal functions and known to activate and integrate a variety of downstream pathways.In the central nervous system(CNS),cAMP-dependent signaling is involved in growth cone motility,neuronal metabolism,axon extension in vitro,neuroprotection,and survival in vivo.The complexity of cAMP-dependent neuronal physiology and function raises fundamental questions about the mechanisms determining the specificity by which cAMP can regulate these processes.

Agreement in identification of glaucomatous progression between the optic disc photography and Heidelberg Retina Tomography in young glaucomatous patients

AIM:To evaluate concordance between the clinical assessment of glaucomatous progression of the optic disc photography and progression identified by Heidelberg Retina Tomograph(HRT)in patients with suspected primary juvenile open angle glaucoma(JOAG).METHODS:Optic disc photographs and corresponding HRTⅡseries were reviewed.Optic disc changes between first and final photographs were noted as well as progression identified by HRT topographic change analysis(TCA)and rim area regression line(RARL)Agreement between progression indentified by photography and HRT methods was assessed.Progression,determined from optic disc photographs by consensus assessment was used as the reference standard.RESULTS:A total of 31 patients(59 eyes)with suspected JOAG were studied.Agreement for progression/no progression between TCA and photography was obtained in 4 progressing eyes and 38stable eyes(71.19%,k=0.11).Agreement for progression/no progression between RARL and photography was detected in 5 progressing eyes and in 34 stable eyes(66.10%,k=0.15).The number of HRT per patient was statistically higher in the progressing group(P=0.034).CONCLUSION:Agreement for detection of longitudinal changes between photography and HRT analysis was poor.One way to improve the chance of discovery of the progression could be increasing the number of HRT examinations.

Identification and validation of key biomarkers and potential therapeutic targets for primary open-angle glaucoma

Primary open-angle glaucoma(POAG)is a prevalent cause of blindness worldwide,resulting in degeneration of retinal ganglion cells and permanent damage to the optic nerve.However,the underlying pathogenetic mechanisms of POAG are currently indistinct,and there has been no effective nonsurgical treatment regimen.The objective of this study is to identify novel biomarkers and potential therapeutic targets for POAG.The mRNA expression microarray datasets GSE27276 and GSE138125,as well as the single-cell high-throughput RNA sequencing(sc RNA-seq)dataset GSE148371 were utilized to screen POAGrelated differentially expressed genes(DEGs).Functional enrichment analyses,protein-protein interaction(PPI)analysis,and weighted gene co-expression network analysis(WGCNA)of the DEGs were performed.Subsequently,the hub genes were validated at a single-cell level,where trabecular cells were annotated,and the mRNA expression levels of target genes in different cell clusters were analyzed.Immunofluorescence and quantitative real-time PCR(q PCR)were performed for further validation.DEGs analysis identified 43 downregulated and 32 upregulated genes in POAG,which were mainly enriched in immune-related pathways,oxidative stress,and endoplasmic reticulum(ER)stress.PPI networks showed that FN1 and DUSP1 were the central hub nodes,while GPX3 and VAV3 were screened out as hub genes through WGCNA and subsequently validated by q PCR.Finally,FN1,GPX3,and VAV3 were determined to be pivotal core genes via single-cell validation.The relevant biomarkers involved in the pathogenesis of POAG,may serve as potential therapeutic targets.Further studies are necessary to unveil the mechanisms underlying the expression variations of these genes in POAG.

Efficacy of initial dose botulinum toxin A injection in acute concomitant esotropia with different clinical characteristics

To the Editor:Acute concomitant esotropia(ACE)is an acquired esotropia with a sudden appearance and no pathologic changes on cerebral imaging.There are various treatments for ACE,including extraocular muscle surgery,botulinum toxin A(BTA)injection,prisms,and divergence training.[1]BTA had been used in the treatment of ACE since it was approved by Food and Drug Administration(FDA,USA)in 1989.[2]Some researchers have confirmed that its effect is stable and has unique advantages in the treatment of ACE.

Laboratory evaluation of higher-order aberrations and light scattering in explanted opacified intraocular lenses

Background:Intraocular lens(IOL)calcification is a serious condition that can only be treated by removing the clouded lens.Since explantation bears the risk of complications,it is often deferred until the patient finds the symptoms intolerable.Usually,as the IOL opacifies,visual acuity is minimally affected early on.In this study,we assessed the impact of IOL opacification on optical quality.Methods:We analyzed ten opacified explanted IOLs(Oculentis GmbH).Wavefront aberrations were obtained with a SHSOphthalmic device(Optocraft GmbH),which features a Hartmann-Shack sensor.The root mean square(RMS)of higher-order aberrations(HOAs)was compared.The effect of calcification on image quality was assessed through the Strehl ratio(SR).We detected light scattering with a C-Quant(Oculus GmbH)and expressed it as a straylight parameter.Results:At 2 mm,3mm and 4 mm,the mean RMS(±standard deviation)was 0.033μm(±0.026μm),0.044μm(±0.027),and 0.087μm(±0.049),respectively.The mean SR value was 0.81±0.15 at 3 mm,with four IOLs showing a nearly diffraction-limited performance,but in two explants,opacification precluded reliable measurements.Increased straylight was found in all opacified IOLs with a mean value of 150.2±56.3 deg^(2)/sr at 3 mm.Conclusions:We demonstrated that IOL opacification induces HOAs.However,the RMS remained low,which resulted only in a slight reduction of the SR-derived optical quality.On the other hand,we found a severe straylight elevation in the opacified lenses,which may result in dysphotopsia,such as glare,and subjective complaints,despite good visual acuity.

Influence of fractures in different inferior orbital wall locations on ocular motility disorders

Orbital floor fractures affect eye movement,but the underlying mechanism remains unclear.Therefore,the present retrospective study aimed to clinically characterize fractures in different inferior.

Questions about NgAgo

Dear Editor： Gao et al. published data in Nature Biotechnology （Nat Biotechnol. 2016 May 2） showing that DNA-guided genome editing using the Natronobacterium gregoryi Argonaute （NgAgo） protein targeted 47 mammalian genomic loci with a 100% success rate and an efficiency of 21.3%-41.3% at various targets. This report led us to test NgAgo＇s utility in various cells and organisms such as mouse and zebrafish for gene editing.

Erratum to： Questions about NgAgo

In the original publication of this article the Figure 1E legend has been incorrectly published.

Single-cell transcriptomic Atlas of aging macaque ocular outflow tissues

The progressive degradation in the trabecular meshwork(TM)is related to age-related ocular diseases like primary open-angle glaucoma.However,the molecular basis and biological significance of the aging process in TM have not been fully elucidated.Here,we established a dynamic single-cell transcriptomic landscape of aged macaque TM,wherein we classified the outflow tissue into 12 cell subtypes and identified mitochondrial dysfunction as a prominent feature of TM aging.Furthermore,we divided TM cells into 13 clusters and performed an in-depth analysis on cluster O,which had the highest aging score and the most significant changes in cell proportions between the two groups.Ultimately,we found that the APOE gene was an important differentially expressed gene in cluster O during the aging process,highlighting the close relationship between cell migration and extracellular matrix regulation,and TM function.Our work further demonstrated that silencing the APOE gene could increase migration and reduce apoptosis by releasing the inhibition on the PI3K-AKT pathway and downregulating the expression of extracellular matrix components,thereby increasing the aqueous outflow rate and maintaining intraocular pressure within the normal range.Our work provides valuable insights for future clinical diagnosis and treatment of glaucoma.