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Age-associated deterioration of physiological functions occur at heterogeneous rates across individual organs. A granular evaluation of systemic metabolic mediators of aging in a healthy human cohort (n = 225) identified prominent increases in circulating uremic toxins that were recapitulated in mice, on which we further characterized the aging phenome across five peripheral organs. Our multi-omics analyses connected systemic aging profiles primarily to kidney metabolism, uncovering a metabolic association between localized glucosylceramide (GluCer) accretion and renal functional decline. Elevated GluCers were also associated with higher risk of deaths in an independent cohort of aged individuals (n = 271). We report GluCer-mTOR signaling commencing at late middle-age that disrupts mitophagy and undermines mitochondrial respiration in kidney. Conserved between human and mice, GluCer-mediated renal dysfunction is female-biased and modulated by intracellular purines. Our work provides molecular basis for the sexually disparate effects of mTOR inhibition on mammalian lifespan, possibly ascribed to the evolutionary cost of female reproduction.
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PURPOSE: Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance. METHODS: A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis. RESULTS: We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8+ T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8+ T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8+ T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers. CONCLUSION: The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.
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BACKGROUND: Sleep deprivation (SD) is a growing global health problem with many deleterious effects, such as cognitive impairment. Microglia activation-induced neuroinflammation may be an essential factor in this. Propofol has been shown to clear sleep debt after SD in rats. This study aims to evaluate the effects of propofol-induced sleep on ameliorating sleep quality impairment and cognitive decline after 48 h SD. METHODS: Almost 8-12-week-old rats were placed in the SD system for 48 h of natural sleep or continuous SD. Afterwards, rats received propofol (20 mg·kg-1·h-1, 6 h) via the tail or slept naturally. The Morris water maze (MWM) and Y-maze test assessed spatial learning and memory abilities. Rat EEG/EMG monitored sleep. The expression of brain and muscle Arnt-like protein 1 (BMAL1), brain-derived neurotrophic factor (BDNF) in the hippocampus and BMAL1 in the hypothalamus were assessed by western blot. Enzyme-linked immunosorbent assay detected IL-6, IL-1ß, arginase 1 (Arg1), and IL-10 levels in the hippocampus. Immunofluorescence was used to determine microglia expression as well as morphological changes. RESULTS: Compared to the control group, the sleep-deprived rats showed poor cognitive performance on both the MWM test and the Y-maze test, accompanied by disturbances in sleep structure, including increased total sleep time, and increased time spent and delta power in non-rapid eye movement sleep. In addition, SD induces abnormal expression of the circadian rhythm protein BMAL1, activates microglia, and causes neuroinflammation and nerve damage. Propofol reversed these changes and saved sleep and cognitive impairment. Furthermore, propofol treatment significantly reduced hippocampal IL-1ß and IL-6 levels, increased BDNF, Arg1, and IL-10 levels, and switched microglia surface markers from the inflammatory M1 type to the anti-inflammatory M2 type. CONCLUSION: Propofol reduces SD-induced cognitive impairment and circadian rhythm disruption, possibly by lowering neuronal inflammation and switching the microglia phenotype from an M1 to an M2 activated state, thus exerting neuroprotective effects.
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Fatores de Transcrição ARNTL , Disfunção Cognitiva , Aprendizagem em Labirinto , Microglia , Propofol , Ratos Sprague-Dawley , Privação do Sono , Animais , Privação do Sono/complicações , Microglia/efeitos dos fármacos , Microglia/metabolismo , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/biossíntese , Masculino , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Ratos , Propofol/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Sono/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismoRESUMO
Objective: To determine the impacts to research the impacts of pain's Specialized Pain Management Nursing Care in the perioperative period on pain symptoms and life quality of patients experiencing minimally invasive surgery for spinal injury. Method: Eighty patients with a spinal injury who underwent minimally invasive surgery in the Department of Orthopedics of Baoding No.1 Hospital from January 2018 to December 2021 were retrospectively analyzed. They were split into two groups following different nursing methods (n=40 each group). Specialized Pain Management Nursing Care were given to patients in the observation group. Those in the control group were given treated with routine care. Their pain score and nursing effect were compared, after which their quality of life, daily living ability and complication rate compared and analyzed. Results: The pain degree in the control group was considerably more than that in the observation group in the 1st postoperative period. The pain degree, which decreased in both groups, slumped more significantly in the observation group on the 2nd and 3rd postoperative days. The postoperative hospital stays and pain duration in the observation group were shorter than those in the control group (P<0.05), and the nursing effect was significantly better than that in the control group (P<0.05). After postoperative nursing intervention. Conclusion: Minimally invasive surgery integrated with the Specialized Pain Management Nursing Care can remarkably ameliorate pain after spinal injury surgery, reducing complications' incidence, and improving the life quality for patients.
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Elderly individuals undergoing surgical procedures are often confronted with the peril of experiencing postoperative cognitive dysfunction (POCD). Prior research has demonstrated the exacerbating effect of sevoflurane anesthesia on neuroinflammation, which can further deteriorate the condition of POCD in elderly patients. Intermittent fasting (IF) restricts food consumption to a specific time window and has been demonstrated to ameliorate cognitive dysfunction induced by neuropathic inflammation. We subjected 18-month-old male mice to 16â¯hours of fasting and 8â¯hours of unrestricted eating over a 24-hour period for 0, 1, 2, and 4 weeks, followed by abdominal exploration under sevoflurane anesthesia. In this study, we aim to explore the potential impact of IF on postoperative cognitive function in aged mice undergoing sevoflurane surgery through the preoperative implementation of IF measures. The findings indicate two weeks of IF leads to a significant enhancement of learning and memory capabilities in mice following surgery. The cognitive performance, as determined by the novel object recognition and Morris water maze tests, as well as the synaptic plasticity, as measured by in vivo electrophysiological recordings, has demonstrated marked improvements. Furthermore, the administration of IF markedly enhances the expression of synaptic-associated proteins in hippocampal neurons, concomitant with a decreasing expression of pro-inflammatory factors and a reduced density of microglial cells within the hippocampal brain region. To summarize, the results of this study indicate that IF may mitigate inflammation in the hippocampal area of the brain. Furthermore, IF appears to provide a safeguard against cognitive impairment and synaptic plasticity impairment brought on by sevoflurane anesthesia.
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Purpose: During the period of COVID-19 pandemic, the social restrictions and isolation exerted a significant impact on the sleep quality of Chinese college students. This study aims to delve into the influence of physical activity on the sleep quality of college students as well as the mediating roles of stress and smartphone addiction. Materials and Methods: A cohort of 274 eligible college students (146 males and 128 females) were selected for the investigation. The International Physical Activity Questionnaire Short Form, Stress Perception Scale, Smartphone Addiction Scale, and Pittsburgh Sleep Quality Index were employed to assess the levels of physical activity, stress, smartphone addiction, and sleep quality among college students. For data analysis, descriptive statistics, correlation analysis, and chained mediation effect tests were performed sequentially. Results: The findings revealed: (1) a significant negative correlation between physical activity and stress, smartphone addiction, and sleep quality among college students (r = -0.216, p < 0.001; r = -0.224, p < 0.001; r = -0.259, p < 0.001); (2) independent mediating roles of stress and smartphone addiction in the relationship between physical activity and sleep quality; and (3) chained mediating effects of stress and smartphone addiction in the association between physical activity and sleep quality. Conclusion: This study deepens our comprehension of how physical activity augments the quality of slumber, concurrently emphasizing that mitigating stress levels and alleviating smartphone addiction constitute effective strategies for preventing sleep issues among college students.
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PIKfyve is an endosomal lipid kinase that synthesizes phosphatidylinositol 3,5-biphosphate from phosphatidylinositol 3-phsphate. Inhibition of PIKfyve activity leads to lysosomal enlargement and cytoplasmic vacuolation, attributed to impaired lysosomal fission processes and homeostasis. However, the precise molecular mechanisms underlying these effects remain a topic of debate. In this study, we present findings from PIKfyve-deficient zebrafish embryos, revealing enlarged macrophages with giant vacuoles reminiscent of lysosomal storage disorders. Treatment with mTOR inhibitors or effective knockout of mTOR partially reverses these abnormalities and extend the lifespan of mutant larvae. Further in vivo and in vitro mechanistic investigations provide evidence that PIKfyve activity is essential for mTOR shutdown during early zebrafish development and in cells cultured under serum-deprived conditions. These findings underscore the critical role of PIKfyve activity in regulating mTOR signaling and suggest potential therapeutic applications of PIKfyve inhibitors for the treatment of lysosomal storage disorders.
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Doenças por Armazenamento dos Lisossomos , Lisossomos , Fosfatidilinositol 3-Quinases , Transdução de Sinais , Serina-Treonina Quinases TOR , Peixe-Zebra , Animais , Humanos , Doenças por Armazenamento dos Lisossomos/metabolismo , Doenças por Armazenamento dos Lisossomos/patologia , Doenças por Armazenamento dos Lisossomos/genética , Lisossomos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/antagonistas & inibidoresRESUMO
Recently a new family of partially coherent fields incorporating generalized inseparable cross-coupled phases named generalized higher-order twisted partially coherent beams (GHTPCBs) have been introduced. The twist factor u is a key parameter that not only quantifies the strength of the generalized cross-coupled phase for a given order, but also determines the amount of the concomitant orbital angular momentum (OAM). In this paper, we propose a simple and reliable method to measure the factor u using a two-pinhole mask. Without need of complicated optical system, it only requires to capture the far-field diffraction intensity distribution of the GHTPCB passing through the mask. By analyzing the Fourier spectrum of the intensity distribution, the value of twist factor can be derived nearly in real time. The influence of the separation distance between two pinholes and the pinholes' diameter and position on the measurement accuracy are thoroughly studied both in theory and experiment. The experimental results agree well with the theoretical results. Our methodology can also be extended to measure the sole factor of similar position dependent phases such as the topological charge of a vortex phase.
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Urban expansion often occurs at the expense of cropland loss, posing challenges to sustainable urban growth and food security. However, detailed investigations into urban expansion and cropland loss remain limited, particularly in regions with varying levels of urbanization. Here, we take Guangdong Province, China, as a case study to exemplify how urban expansion affects cropland using remotely sensed land use products. We adopted geospatial analysis, correlation indicators, and landscape metrics to uncover their spatial relationships at 10-m spatial resolutions. Results showed that urban areas increased by 6335 km2 while cropland decreased by 3780 km2 from 2017 to 2022. Notably, 41 % of newly expanded urban areas were from croplands, and 45 % of lost croplands were converted to urban areas. Western Guangdong experienced the largest extent of urban expansion and cropland loss, emerging as a hotspot region in recent years. Additionally, our analysis observed the increasing compactness of urban areas and the growing fragmentation of cropland landscapes over time. These findings shed light on the intricate dynamics between urban expansion and cropland loss in rapidly urbanizing regions, which provide valuable insights for sustainable urban development, agricultural practice, and land management in the future.
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Recent advances have revealed that the role of the immune system is prominent in the antitumor response. In the present study, it is aimed to provide an expression profile of tumor-infiltrating lymphocytes (TILs), including mature B cells, plasma cells, and their clinical relevance in neuroblastoma. The expression of CD20 and CD138 was analyzed in the Cangelosi786 dataset (n = 769) as a training dataset and in our cohort (n = 120) as a validation cohort. CD20 high expression was positively associated with favorable overall survival (OS) and event-free survival (EFS) (OS: P < 0.001; EFS: P < 0.001) in the training dataset, whereas CD138 high expression was associated with poor OS and EFS (OS: P < 0.001; EFS: P < 0.001) in both the training and validation datasets. Accordingly, a combined pattern of CD20 and CD138 expression was developed, whereby neuroblastoma patients with CD20highCD138low expression had a consistently favorable OS and EFS compared with those with CD20lowCD138high expression in both the training and validation cohorts (P < 0.0001 and P < 0.01, respectively). Examination of potential molecular functions revealed that signaling pathways, including cytokineâcytokine receptor interactions, chemokine, and the NF-kappa B signaling pathways, were involved. Differentially expressed genes, such as BMP7, IL7R, BIRC3, CCR7, CXCR5, CCL21, and CCL19, predominantly play important roles in predicting the survival of neuroblastoma patients. Our study proposes that a new combination of CD20 and CD138 signatures is associated with neuroblastoma patient survival. The related signaling pathways reflect the close associations among the number of TILs, cytokine abundance and patient outcomes and provide therapeutic insights into neuroblastoma.
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Single-cell RNA sequencing (scRNA-seq) is a potent advancement for analyzing gene expression at the individual cell level, allowing for the identification of cellular heterogeneity and subpopulations. However, it suffers from technical limitations that result in sparse and heterogeneous data. Here, we propose scVSC, an unsupervised clustering algorithm built on deep representation neural networks. The method incorporates the variational inference into the subspace model, which imposes regularization constraints on the latent space and further prevents overfitting. In a series of experiments across multiple datasets, scVSC outperforms existing state-of-the-art unsupervised and semi-supervised clustering tools regarding clustering accuracy and running efficiency. Moreover, the study indicates that scVSC could visually reveal the state of trajectory differentiation, accurately identify differentially expressed genes, and further discover biologically critical pathways.
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Recent advancements in spatial transcriptomics (ST) technologies offer unprecedented opportunities to unveil the spatial heterogeneity of gene expression and cell states within tissues. Despite these capabilities of the ST data, accurately dissecting spatiotemporal structures (e.g., spatial domains, temporal trajectories, and functional interactions) remains challenging. Here, we introduce a computational framework, PearlST (partial differential equation [PDE]-enhanced adversarial graph autoencoder of ST), for accurate inference of spatiotemporal structures from the ST data using PDE-enhanced adversarial graph autoencoder. PearlST employs contrastive learning to extract histological image features, integrates a PDE-based diffusion model to enhance characterization of spatial features at domain boundaries, and learns the latent low-dimensional embeddings via Wasserstein adversarial regularized graph autoencoders. Comparative analyses across multiple ST datasets with varying resolutions demonstrate that PearlST outperforms existing methods in spatial clustering, trajectory inference, and pseudotime analysis. Furthermore, PearlST elucidates functional regulations of the latent features by linking intercellular ligand-receptor interactions to most contributing genes of the low-dimensional embeddings, as illustrated in a human breast cancer dataset. Overall, PearlST proves to be a powerful tool for extracting interpretable latent features and dissecting intricate spatiotemporal structures in ST data across various biological contexts.
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BACKGROUND: Previous study consistently showed that lower serum sodium (SNa) was associated with a greater risk of mortality in hemodialysis (HD) patients. However, few studies have focused on the change in SNa (ΔSNa = post-HD SNa - pre-HD SNa) during an HD session. METHODS: In a retrospective cohort of maintenance HD adults, all-cause mortality and cardio-cerebrovascular event (CCVE) were followed up for a medium of 82 months. Baseline pre-HD SNa and ΔSNa were collected; time-averaged pre-HD SNa and ΔSNa were computed as the mean values within 1-year, 2-year and 3-year intervals after enrollment. Cox proportional hazards models were used to evaluate the relationships of pre-HD and ΔSNa with outcomes. RESULTS: Time-averaged pre-HD SNa were associated with all-cause mortality (2-year pre-HD SNa: HR [95% CI] 0.86 [0.74-0.99], p = 0.042) and CCVE (3-year pre-HD SNa: HR [95% CI] 0.83 [0.72-0.96], p = 0.012) with full adjustment. Time-averaged ΔSNa also demonstrated an association with all-cause mortality (3-year ΔSNa: HR [95% CI] 1.26 [1.03-1.55], p = 0.026) as well as with CCVE (3-year ΔSNa: HR [95% CI] 1.51 [1.21-1.88], p = <0.001) when fully adjusted. Baseline pre-HD SNa and ΔSNa didn't exhibit association with both outcomes. CONCLUSIONS: Lower time-averaged pre-HD SNa and higher time-averaged ΔSNa were associated with a greater risk of all-cause mortality and CCVE in HD patients.
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Falência Renal Crônica , Sódio , Adulto , Humanos , Estudos Retrospectivos , Diálise Renal/efeitos adversos , Modelos de Riscos ProporcionaisRESUMO
Background: Nowadays, it is widely acknowledged that mobile phone addiction is a risky factor for insomnia symptoms, but to date, people know little about the underlying relationship between them among undergraduates during the COVID-19 pandemic. The purpose of the present study was to examine the potential association between mobile phone addiction and insomnia, as well as the mediating role of social anxiety and the moderating role of physical activity. Methods: Using the Mobile Phone Addiction Tendency Scale, Social Phobia Inventory, Physical Activity Rating Scale and Insomnia Severity Index, 301 eligible college students in China were investigated. For data analysis, descriptive analysis, correlation analysis, moderating effect test, moderating effect test were carried out in turn. Results: The findings revealed a favorable correlation between mobile phone addiction, social anxiety and insomnia, as well as between social anxiety and insomnia. But physical activity was negatively correlated with social anxiety and mobile phone addiction, and social anxiety partially mediated the relationship between mobile phone addiction and insomnia. Additionally, physical activity played a significant moderating effect between mobile phone addiction and social anxiety. Conclusion: This study advances the knowledge of how mobile phone addiction raises the likelihood of experiencing insomnia symptoms, and also implies that upping physical activity level could lessen the harmful impacts from mobile phone addiction.
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COVID-19 , Distúrbios do Início e da Manutenção do Sono , Humanos , COVID-19/epidemiologia , Pandemias , Distúrbios do Início e da Manutenção do Sono/epidemiologia , China/epidemiologia , Fatores de Risco , Estudantes , Dependência de TecnologiaRESUMO
Given the highly heterogeneous characteristics of advanced gastric cancer (GC), most patients must receive neoadjuvant therapy or conversion therapy consisting of chemotherapy to decrease tumor grade and improve the likelihood of complete resection. Drug resistance, however, always leads to an aborted conversion therapy and inevitable death. When meet drug resistance, alternative drug regimens will be applied with immunotherapy or targeted therapy, whose clinical efficacy remains limited when new drug resistance or severer liver and kidney toxicity emerge. Photodynamic therapy (PDT), a novel treatment, has demonstrated remarkable therapeutic efficacy in different stages of GC. However, no report has been reported so far on the clinical application of photodynamic therapy in conversion therapy after drug resistance. Here we report a case of middle-aged patient with advanced GC, who experienced failure of conversion therapy consisted of multi-line chemotherapy along with immunotherapy. Ultimate success was achieved through a comprehensive conversion therapy of PDT, chemotherapy, immunotherapy, and targeted therapy. Subsequently, the patient underwent robotic-assisted radical gastrectomy while the surgical specimen showed no tumor cell exists. The patient underwent 3 cycles of systemic adjuvant therapy following surgical intervention. Presently, the patient remains 17 months in a satisfactory state of health.
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Fotoquimioterapia , Fármacos Fotossensibilizantes , Terapia de Salvação , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Pessoa de Meia-Idade , Masculino , Terapia de Salvação/métodos , Gastrectomia , Resistencia a Medicamentos Antineoplásicos , Imunoterapia/métodosRESUMO
[This corrects the article DOI: 10.1016/j.ekir.2022.09.030.].
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Urinary tract infections (UTIs) are a common health issue affecting individuals worldwide. Recurrent urinary tract infections (rUTI) pose a significant clinical challenge, with limited understanding of the underlying mechanisms. Recent research suggests that the urobiome, the microbial community residing in the urinary tract, may play a crucial role in the development and recurrence of urinary tract infections. However, the specific virulence factor genes (VFGs) driven by urobiome contributing to infection recurrence remain poorly understood. Our study aimed to investigate the relationship between urobiome driven VFGs and recurrent urinary tract infections. By analyzing the VFGs composition of the urinary microbiome in patients with rUTI compared to a control group, we found higher alpha diversity in rUTI patients compared with healthy control. And then, we sought to identify specific VFGs features associated with infection recurrence. Specifically, we observed an increased abundance of certain VGFs in the recurrent infection group. We also associated VFGs and clinical data. We then developed a diagnostic model based on the levels of these VFGs using random forest and support vector machine analysis to distinguish healthy control and rUIT, rUTI relapse and rUTI remission. The diagnostic accuracy of the model was assessed using receiver operating characteristic curve analysis, and the area under the ROC curve were 0.83 and 0.75. These findings provide valuable insights into the complex interplay between the VFGs of urobiome and recurrent urinary tract infections, highlighting potential targets for therapeutic interventions to prevent infection recurrence.
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Parvovirus B19 infection can cause chronic pure red cell aplasia in immunosuppressed hosts or acute and transient aplastic crises in immunocompetent hosts. In dialysis patients, only transient aplastic crisis induced by parvovirus B19 infection has been reported. We herein report the first case of an adult dialysis patient who developed chronic pure red cell aplasia associated with parvovirus B19 infection. Repeated pneumonia and heart failure may contribute to an immunocompromised status, making the patient more vulnerable to parvovirus B19 infection. This case expands on the differential diagnosis of chronic anemia in patients undergoing dialysis.
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We demonstrate that the spiral spectrum (also known as orbital angular momentum spectrum) of a Laguerre-Gaussian (LG) beam with topological charge (TC) l is asymmetrically broadened propagating through moderate-to-strong atmospheric turbulence, even the statistics of turbulence is isotropic. This phenomenon is quite different from that predicted in weak turbulence where the spiral spectrum of a disturbed LG beam is symmetric with respect to its TC number l. An explicit analytical expression of the spiral spectrum of the LG beam with l = 1 is derived based on the extend Huygens-Fresnel integral and quadratic approximation, which is used to illustrate the transition scenarios of the spiral spectrum from symmetry to asymmetry in weak-to-strong turbulence. The physical mechanism for the asymmetric spiral spectrum in moderate-to-strong turbulence is thoroughly discussed. Our results are confirmed by the multi-phase screen numerical simulations and are consistent with the experimental results reported in Phys. Rev. A105, 053513 (2022)10.1103/PhysRevA.105.053513 and Opt. Lett.38, 4062 (2013)10.1364/OL.38.004062.