Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury

Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

Targeting cholesterol trafficking to mitigate axonal degeneration in hereditary spastic paraplegia

Axonal degeneration underlies many debilitating diseases including hereditary spastic paraplegia(HSP),a genetically and clinically diverse group of disorders characterized by spasticity and weakness of the lower extremities.HSP is one significant cause of chronic neurodisability due to the lack of effective treatments and a wide range of onset ages from early childhood to 70 years.

Astrocyte syncytium:from neonatal genesis to aging degeneration

Modern neuroscience began from all reaching and fierce conflict between“neuronismo and reticulismo”——between neuronal and reticular theories of the organization of the nervous system;the conflict culminated in December of 1906 in Stockholm where Santiago Ramon y Cajal(the proponent of the neuronal doctrine)and Camillo Golgi(who advocated the syncytial reticular organization of neural networks)delivered their Noble prize lectures(Verkhratsky,2009).

Going straight for the gut:gut-brain axis pathology and treatment of Parkinson's disease

This perspective focuses on the recent literature regarding the role of the gut-brain axis(GBA) in fecal microbiota transplantation(FMT) and stem cell therapy(SCT) in Parkinson's disease(PD).PD is the second most common neurodegenerative disease in the United States,yet therapies remain limited.Current research suggests that the GBA may play a role in the pathogenesis of PD.GBAbased FMT as well as SCT offer promising new avenues for PD treatment.Pro bing the interactions between FMT and SCT with the GBA may reveal novel therapeutics for PD.

HCSP-Net:A Novel Model of Age-Related Macular Degeneration Classification Based on Color Fundus Photography

Age-related macular degeneration(AMD)ranks third among the most common causes of blindness.As the most conventional and direct method for identifying AMD,color fundus photography has become prominent owing to its consistency,ease of use,and good quality in extensive clinical practice.In this study,a convolutional neural network(CSPDarknet53)was combined with a transformer to construct a new hybrid model,HCSP-Net.This hybrid model was employed to tri-classify color fundus photography into the normal macula(NM),dry macular degeneration(DMD),and wet macular degeneration(WMD)based on clinical classification manifestations,thus identifying and resolving AMD as early as possible with color fundus photography.To further enhance the performance of this model,grouped convolution was introduced in this study without significantly increasing the number of parameters.HCSP-Net was validated using an independent test set.The average precision of HCSPNet in the diagnosis of AMD was 99.2%,the recall rate was 98.2%,the F1-Score was 98.7%,the PPV(positive predictive value)was 99.2%,and the NPV(negative predictive value)was 99.6%.Moreover,a knowledge distillation approach was also adopted to develop a lightweight student network(SCSP-Net).The experimental results revealed a noteworthy enhancement in the accuracy of SCSP-Net,rising from 94%to 97%,while remarkably reducing the parameter count to a quarter of HCSP-Net.This attribute positions SCSP-Net as a highly suitable candidate for the deployment of resource-constrained devices,which may provide ophthalmologists with an efficient tool for diagnosing AMD.

Biomaterial engineering strategies for modeling the Bruch's membrane in age-related macular degeneration

Age-related macular degeneration,a multifactorial inflammatory degenerative retinal disease,ranks as the leading cause of blindness in the elderly.Strikingly,there is a scarcity of curative therapies,especially for the atrophic advanced form of age-related macular degeneration,likely due to the lack of models able to fully recapitulate the native structure of the outer blood retinal barrier,the prime to rget tissue of age-related macular degeneration.Standard in vitro systems rely on 2D monocultures unable to adequately reproduce the structure and function of the outer blood retinal barrier,integrated by the dynamic interaction of the retinal pigment epithelium,the Bruch's membrane,and the underlying choriocapillaris.The Bruch's membrane provides structu ral and mechanical support and regulates the molecular trafficking in the outer blood retinal barrier,and therefo re adequate Bruch's membrane-mimics are key for the development of physiologically relevant models of the outer blood retinal barrie r.In the last years,advances in the field of biomaterial engineering have provided novel approaches to mimic the Bruch's membrane from a variety of materials.This review provides a discussion of the integrated properties and function of outer blood retinal barrier components in healt hy and age-related macular degeneration status to understand the requirements to adequately fabricate Bruch's membrane biomimetic systems.Then,we discuss novel materials and techniques to fabricate Bruch's membrane-like scaffolds for age-related macular degeneration in vitro modeling,discussing their advantages and challenges with a special focus on the potential of Bruch's membrane-like mimics based on decellularized tissue.

Taurine: a promising nutraceutic in the prevention of retinal degeneration

Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.

Using MsfNet to Predict the ISUP Grade of Renal Clear Cell Carcinoma in Digital Pathology Images

Clear cell renal cell carcinoma(ccRCC)represents the most frequent form of renal cell carcinoma(RCC),and accurate International Society of Urological Pathology(ISUP)grading is crucial for prognosis and treatment selection.This study presents a new deep network called Multi-scale Fusion Network(MsfNet),which aims to enhance the automatic ISUP grade of ccRCC with digital histopathology pathology images.The MsfNet overcomes the limitations of traditional ResNet50 by multi-scale information fusion and dynamic allocation of channel quantity.The model was trained and tested using 90 Hematoxylin and Eosin(H&E)stained whole slide images(WSIs),which were all cropped into 320×320-pixel patches at 40×magnification.MsfNet achieved a micro-averaged area under the curve(AUC)of 0.9807,a macro-averaged AUC of 0.9778 on the test dataset.The Gradient-weighted Class Activation Mapping(Grad-CAM)visually demonstrated MsfNet’s ability to distinguish and highlight abnormal areas more effectively than ResNet50.The t-Distributed Stochastic Neighbor Embedding(t-SNE)plot indicates our model can efficiently extract critical features from images,reducing the impact of noise and redundant information.The results suggest that MsfNet offers an accurate ISUP grade of ccRCC in digital images,emphasizing the potential of AI-assisted histopathological systems in clinical practice.

Using choroidal thickness to detect myopic macular degeneration

AIM:To explore the usage of choroidal thickness measured by swept-source optical coherence tomography(SS-OCT)to detect myopic macular degeneration(MMD)in high myopic participants.METHODS:Participants with bilateral high myopia(≤−6 diopters)were recruited from a subset of the Guangzhou Zhongshan Ophthalmic Center-Brien Holden Vision Institute High Myopia Cohort Study.SS-OCT was performed to determine the choroidal thickness,and myopic maculopathy was graded by the International Meta-Analysis for Pathologic Myopia(META-PM)Classification.Presence of MMD was defined as META-PM category 2 or above.RESULTS:A total of 568 right eyes were included for analysis.Eyes with MMD(n=106,18.7%)were found to have older age,longer axial lengths(AL),higher myopic spherical equivalents(SE),and reduced choroidal thickness in each Early Treatment Diabetic Retinopathy Study(ETDRS)grid sector(P<0.001).The area under the receiver operating characteristic(ROC)curves(AUC)for subfoveal choroidal thickness(0.907)was greater than that of the model,including age,AL,and SE at 0.6249,0.8208,and 0.8205,respectively.The choroidal thickness of the inner and outer nasal sectors was the most accurate indicator of MMD(AUC of 0.928 and 0.923,respectively).An outer nasal sector choroidal thickness of less than 74μm demonstrated the highest odds of predicting MMD(OR=33.8).CONCLUSION:Choroidal thickness detects the presence of MMD with high agreement,particularly of the inner and outer nasal sectors of the posterior pole,which appears to be a biometric parameter more precise than age,AL,or SE.

Regulatory factors of Nrf2 in age-related macular degeneration pathogenesis

Age-related macular degeneration(AMD)is a complicated disease that causes irreversible visual impairment.Increasing evidences pointed retinal pigment epithelia(RPE)cells as the decisive cell involved in the progress of AMD,and the function of anti-oxidant capacity of PRE plays a fundamental physiological role.Nuclear factor erythroid 2 related factor 2(Nrf2)is a significant transcription factor in the cellular anti-oxidant system as it regulates the expression of multiple anti-oxidative genes.Its functions of protecting RPE cells against oxidative stress(OS)and ensuing physiological changes,including inflammation,mitochondrial damage and autophagy dysregulation,have already been elucidated.Understanding the roles of upstream regulators of Nrf2 could provide further insight to the OS-mediated AMD pathogenesis.For the first time,this review summarized the reported upstream regulators of Nrf2 in AMD pathogenesis,including proteins and miRNAs,and their underlying molecular mechanisms,which may help to find potential targets via regulating the Nrf2 pathway in the future research and further discuss the existing Nrf2 regulators proved to be beneficial in preventing AMD.

Visualizing Wallerian degeneration in the corticospinal tract after sensorimotor cortex ischemia in mice

Stroke can cause Wallerian degeneration in regions outside of the brain,particularly in the corticospinal tract.To investigate the fate of major glial cells and axons within affected areas of the corticospinal tract following stroke,we induced photochemical infarction of the sensorimotor cortex leading to Wallerian degeneration along the full extent of the corticospinal tract.We first used a routine,sensitive marker of axonal injury,amyloid precursor protein,to examine Wallerian degeneration of the corticospinal tract.An antibody to amyloid precursor protein mapped exclusively to proximal axonal segments within the ischemic cortex,with no positive signal in distal parts of the corticospinal tract,at all time points.To improve visualization of Wallerian degeneration,we next utilized an orthograde virus that expresses green fluorescent protein to label the corticospinal tract and then quantitatively evaluated green fluorescent protein-expressing axons.Using this approach,we found that axonal degeneration began on day 3 post-stroke and was almost complete by 7 days after stroke.In addition,microglia mobilized and activated early,from day 7 after stroke,but did not maintain a phagocytic state over time.Meanwhile,astrocytes showed relatively delayed mobilization and a moderate response to Wallerian degeneration.Moreover,no anterograde degeneration of spinal anterior horn cells was observed in response to Wallerian degeneration of the corticospinal tract.In conclusion,our data provide evidence for dynamic,pathogenic spatiotemporal changes in major cellular components of the corticospinal tract during Wallerian degeneration.

RDH12-associated retinal degeneration caused by a homozygous pathogenic variant of 146C>T and literature review

AIM:To describe the clinical,electrophysiological,and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant.METHODS:The patient underwent a complete ophthalmologic examination including best-corrected visual acuity,anterior segment and dilated fundus,visual field,spectral-domain optical coherence tomography(OCT)and electroretinogram(ERG).The retinal disease panel genes were sequenced through chip capture high-throughput sequencing and Sanger sequencing was used to confirm the result.Then we reviewed the characteristics of the patients reported with the same variant.RESULTS:A 30-year male presented with severe early retinal degeneration who complained night blindness,decreased visual acuity,vitreous floaters and amaurosis fugax.The best corrected vision was 0.04 OD and 0.12 OS,respectively.The fundus photo and OCT showed bilateral macular atrophy but larger areas of macular atrophy in the left eye.Autofluorescence shows bilateral symmetrical hypo-autofluorescence.ERG revealed that the amplitudes of a-and b-wave were severely decreased.Multifocal ERG showed decreased amplitudes in the local macular area.A homozygous missense variant c.146C>T(chr14:68191267)was found.The clinical characteristics of a total of 13 patients reported with the same pathologic variant varied.CONCLUSION:An unusual patient with a homozygous pathogenic variant in the c.146C>T of RDH12 which causes late-onset and asymmetric retinal degeneration are reported.The clinical manifestations of the patient with multimodal retinal imaging and functional examinations have enriched our understanding of this disease.

A Multi-Task Deep Learning Framework for Simultaneous Detection of Thoracic Pathology through Image Classification

Thoracic diseases pose significant risks to an individual's chest health and are among the most perilous medical diseases. They can impact either one or both lungs, which leads to a severe impairment of a person’s ability to breathe normally. Some notable examples of such diseases encompass pneumonia, lung cancer, coronavirus disease 2019 (COVID-19), tuberculosis, and chronic obstructive pulmonary disease (COPD). Consequently, early and precise detection of these diseases is paramount during the diagnostic process. Traditionally, the primary methods employed for the detection involve the use of X-ray imaging or computed tomography (CT) scans. Nevertheless, due to the scarcity of proficient radiologists and the inherent similarities between these diseases, the accuracy of detection can be compromised, leading to imprecise or erroneous results. To address this challenge, scientists have turned to computer-based solutions, aiming for swift and accurate diagnoses. The primary objective of this study is to develop two machine learning models, utilizing single-task and multi-task learning frameworks, to enhance classification accuracy. Within the multi-task learning architecture, two principal approaches exist soft parameter sharing and hard parameter sharing. Consequently, this research adopts a multi-task deep learning approach that leverages CNNs to achieve improved classification performance for the specified tasks. These tasks, focusing on pneumonia and COVID-19, are processed and learned simultaneously within a multi-task model. To assess the effectiveness of the trained model, it is rigorously validated using three different real-world datasets for training and testing.

Subretinal fibrosis secondary to neovascular age-related macular degeneration:mechanisms and potential therapeutic targets

Subretinal fibrosis is the end-stage sequelae of neovascular age-related macular degeneration.It causes local damage to photoreceptors,retinal pigment epithelium,and choroidal vessels,which leads to permanent central vision loss of patients with neovascular age-related macular degeneration.The pathogenesis of subretinal fibrosis is complex,and the underlying mechanisms are largely unknown.Therefore,there are no effective treatment options.A thorough understanding of the pathogenesis of subretinal fibrosis and its related mechanisms is important to elucidate its complications and explore potential treatments.The current article reviews several aspects of subretinal fibrosis,including the current understanding on the relationship between neovascular age-related macular degeneration and subretinal fibrosis;multimodal imaging techniques for subretinal fibrosis;animal models for studying subretinal fibrosis;cellular and non-cellular constituents of subretinal fibrosis;pathophysiological mechanisms involved in subretinal fibrosis,such as aging,infiltration of macrophages,different sources of mesenchymal transition to myofibroblast,and activation of complement system and immune cells;and several key molecules and signaling pathways participating in the pathogenesis of subretinal fibrosis,such as vascular endothelial growth factor,connective tissue growth factor,fibroblast growth factor 2,platelet-derived growth factor and platelet-derived growth factor receptor-β,transforming growth factor-βsignaling pathway,Wnt signaling pathway,and the axis of heat shock protein 70-Toll-like receptors 2/4-interleukin-10.This review will improve the understanding of the pathogenesis of subretinal fibrosis,allow the discovery of molecular targets,and explore potential treatments for the management of subretinal fibrosis.

Circular RNA expression and the competitive endogenous RNA network in pathological,age-related macular degeneration events:A cross-platform normalization study

Age-related macular degeneration(AMD)causes irreversible blindness in people aged over 50 worldwide.The dysfunction of the retinal pigment epithelium is the primary cause of atrophic AMD.In the current study,we used the ComBat and Training Distribution Matching method to integrate data obtained from the Gene Expression Omnibus database.We analyzed the integrated sequencing data by the Gene Set Enrichment Analysis.Peroxisome and tumor necrosis factor-α(TNF-α)signaling and nuclear factor kappa B(NF-κB)were among the top 10 pathways,and thus we selected them to construct AMD cell models to identify differentially expressed circular RNAs(circRNAs).We then constructed a competing endogenous RNA network,which is related to differentially expressed circRNAs.This network included seven circRNAs,15 microRNAs,and 82 mRNAs.The Kyoto Encyclopedia of Genes and Genomes analysis of mRNAs in this network showed that the hypoxia-inducible factor-1(HIF-1)signaling pathway was a common downstream event.The results of the current study may provide insights into the pathological processes of atrophic AMD.

Lipolysaccharide-Induced Neuroinflammation Is Associated with Alzheimer-Like Amyloidogenic Axonal Pathology and Dendritic Degeneration in Rats

Chronic neuroinflammation is thought to play an etiological role in Alzheimer’s disease (AD) which is characterized pathologically by amyloid and tau formation, as well as neuritic dystrophy and synaptic degeneration. The causal relationship between these pathological events is a topic of ongoing research and discussion. Recent data from transgenic AD models point to a tight spatio-temporal link between neuritic and amyloid pathology, with the obligatory enzyme for β-amyloid (Aβ) production, namely β-secretase-1 (BACE1), being overexpressed in axon terminals undergoing dystrophic change. However, the axonal pathology inherent with BACE1 elevation seen in transgenic AD mice may be secondary to increased soluble Aβ in these genetically modified animals. Further, it is unclear whether the inflammation seen in AD is the result of , or the cause of neuritic dystrophy. Here we explored the occurrence of AD-like axonal and dendritic pathology in adult rat brains affected by LPS-induced chronic neuroinflammation. Unilateral intracerebral LPS injection induced prominent inflammatory response in glial cells in the ipsilateral cortex and hippocampal formation. BACE1 protein levels were elevated in the ipsilateral hippocampal lysates in the LPS-treated animals relative to controls. BACE1 immunoreactive dystrophic axons appeared in the LPS-treated ipsilateral cortex and hippocampal formation, colocalizing with increased β-amyloid precursor protein and Aβ antibody (4G8) immunolabeling. Quantitative Golgi studies revealed reduction of dendritic branching points and spine density on cortical layer III and hippocampal CA3 pyramidal neurons in the LPS-treated ipsilateral cerebrum. These findings suggest that Alzheimer-like amyloidogenic axonal pathology and dendritic degeneration occur in wildtype mammalian brain in partnership with neuroinflammation following LPS injection.

Inner blood-retina barrier involvement in dry age-related macular degeneration(AMD) pathology

Age-relatedmaculardegeneration(AMD)isaprogressiveneurodegenerative disease with a global prevalence of 8.7%in people over the age of 45. It is one of the leading causes of central retinal blindness in the industrialized world leading to loss of an individual’s ability to read, drive and see fine details, such as recognition of faces. By 2040, it is estimated that 288 million individuals worldwide will be diagnosed with AMD due to improved life expectancy(Wong et al., 2014).

Dendrite pathology and neurodegeneration:focus on m TOR

Dendrites are exquisitely specialized cellular compart- ments that critically influence how neurons receive and process information. Most synaptic inputs are received onto dendritic shafts, or small protuberances known as dendritic spines, and are then integrated and transmitted to the cell soma. During nervous system development, dendrites are dynamic, expanding and retracting rapidly, in response to intrinsic and environmental cues. Selective elimination of dendritic processes, also known as developmental pruning, ensures precise connectivity and refines neuronal networks.

Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition.The clinical picture is dominated by upper and lower motor neuron degeneration,but extra-motor pathology is increasingly recognized,including cerebellar pathology.Post-mortem and neuroimaging studies primarily focus on the chara cterization of supratentorial disease,des pite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis.Cardinal clinical features of amyotrophic lateral sclerosis,such as dysarthria,dysphagia,cognitive and behavioral deficits,saccade abnormalities,gait impairment,respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology.This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral scle rosis.Structural imaging studies consistently capture cerebellar grey matter volume reductions,diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alte rations and functional imaging studies commonly report increased functional connectivity with supratentorial regions.Increased functional connectivity is commonly interpreted as evidence of neuro plasticity representing compensatory processes despite the lack of post-mortem validation.There is a scarcity of post-mortem studies focusing on cerebellar alte rations,but these detect pTDP-43 in cerebellar nuclei.Ce rebellar pathology is an overloo ked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms,wides p read connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

cGMP signaling:a potential therapeutic target for neurodegeneration in glaucoma?

Neurodegeneration of the central nervous system(CNS)underscores many of humanity’s most debilitating diseases,including Alzheimer’s disease,Parkinson’s disease,and multiple sclerosis.Recently,the nitric oxide-guanylate cyclase-cyclic guanosine monophosphate(NOGC-cGMP)signaling pathway has gained traction as a neuroprotective pathway in the CNS.As an extension of the CNS,the retina is also susceptible to neurodegeneration with age.The most prevalent optic neuropathy is glaucoma,the world’s leading cause of irreversible blindness,predicted to affect more than 112 million people worldwide by 2040(Calkins,2021).In glaucoma,vision loss occurs due to the progressive degeneration of retinal ganglion cells(RGCs),the output neurons of the retina,along with their axons which form the optic nerve(Wareham et al.,2022).Degeneration of RGCs leads to a characteristic pattern of scotopic visual field deficiencies that spread from one retinotopic sector to the next(Elze et al.,2015).Visual deficits are linked to increasing age and the sensitivity of RGCs to intraocular pressure(Calkins,2021).