Environmental filtering (EF) and dispersal filtering (DF) are widely known to shape plant community assembly. Particularly in arid and semi-arid mountainous regions, however, it remains unclear whether EF or DF dominate in the community assembly of different life forms or how they interact along elevational gradients. This research aims to reveal how different ecological processes influence herbaceous and woody community assembly and how they respond to various environmental drivers and elevational gradients. Here we integrated taxonomic diversity (TD), phylogenetic diversity (PD), and ecological drivers across an elevational gradient of 1,420 m in the Helan Mountain Nature Reserve, in typical arid and semi-arid areas of China. This study showed that the TD and PD of herbaceous communities significantly increase linearly with changing elevation gradients, while woody ‘TD’ showed a unimodal pattern, and there was little relationship between woody ‘PD’ and elevation. Herbaceous species exhibited significant phylogenetic clustering at low elevations, where they were influenced by climate, aspect, and tree cover. However, woody species exhibited random patterns across elevations. Herbaceous and woody species’ taxonomic and phylogenetic beta diversity is governed primarily by spatial turnover rather than nestedness. Spatial turnover is caused primarily by EF and DF’s combined influence, but their relative importance differs between herbaceous and woody communities. Therefore, we conclude that the responses of herbaceous and woody plants along elevation gradients in the Helan Mountains are decoupled due to their different adaptation strategies to climate factors in the drylands. These findings are important for understanding the assembly mechanisms driving plant communities in dryland under the context of dramatic increases in drought driven by climate warming. Mountains are hotspots of biodiversity, covering 24% of the total geographical area and supporting about 50% of the planet’s biodiversity  They proElevation-diversity relationships have been popular in ecology, biogeography, and biodiversity conservation in recent decades . PreviouTheories of community assemblages, including niche-based processes and stochastic processes , consideDrylands are defined as places with an aridity index of less than 0.65. They encompass over 45% of the planet’s land surface and inhabit over 38% of the Earth’s population . The dryThis study investigated herbaceous and woody communities along elevational gradients in the Helan Mountains of arid and semi-arid regions in Northwest China. Here we integrate taxonomic and phylogenetic diversity and environmental drivers  How do the TD and PD of herbaceous and woody communities vary with changing elevation gradients in the Helan Mountains?(2) Which factors in the environment impact the TD and PD of herbaceous and woody communities in this area?(3) How and to what extent do EF and DF affect the spatial turnover of herbaceous and woody species in this region?Picea crassifolia, Pinus tabuliformis, and Ajania fruticulose), shrubs, and grasses are the main land cover types across this region. However, due to the long lifespan and limited distribution of trees, it is difficult to detect tree distribution patterns with changing elevation gradients. Specifically, an interspersed distribution of continuous woody  and grassland dominates in this area. Considering accessibility, we identified 23 study sites with the peak growing season of 2021, from 1,169 m to 2,589 m in the Helan Mountains. At each site, we established a permanent plot (20 m × 20 m) (2 (5 m × 5 m for woody) and 1 m2 (1 m × 1 m for herbaceous) were sampled  , and its × 20 m) . Within  sampled . Each 1 Flora of China (http://www.iplant.cn/) and field observations to understand how different species responded to elevational gradients. To compare the TD and PD of herbaceous and woody communities, species-level phylogenetic trees based on the mega-tree approach were constructed using the “V.PhyloMaker” package  and 76 herbaceous species according to the  package . The pac package . We then package . To dise package , we conv package . Positiv package . Their a package . In addi package , in whicTemperature, precipitation, and their extremes will remarkably influence species’ ecological and evolutionary processes . ConsequWe analyzed the relationship between TD, SESmpd, SESmntd and elevation using simple linear and quadratic regression models  into three parts . The nonlinear model was remarkable for woody communities with relatively low richness at the ends of the elevation range and peak richness in the 1500 ~ 1600 m range (The TD (species richness) and PD (SESmpd and SESmntd) of herbaceous communities significantly increased linearly along the elevational gradient , but it did not depend on the spatial distances when considering the environmental influences . Phylogenetic turnover displayed a similar trend, but it was reduced in prominence when considering spatial influences  or environmental effects . For woody communities, the taxonomic turnover was related to environmental  but it was not associated significantly with spatial distance . Phylogenetic turnover was significantly correlated with the environment  and spatial distance .Environmental and spatial variables explained 33% to 77% of the variation in species turnover Figure 6The species richness of the woody community peaked at mid-elevation areas and declined toward both sides of elevation gradients . The autUnlike woody richness, herbaceous richness showed an increasing tendency along elevational gradients. A study in a subtropical forest supported the pattern that plant species richness increased with elevation . They suIn addition, this study found that both the SESmpd and SESmntd of herbaceous communities significantly increased linearly along the elevational gradient. Still, there is no clear pattern in the phylogenetic structure of woody communities. This difference can be traced to disparities in the responses of various plant functional groups toward climate change, topographic heterogeneity, soil nutrients, and disturbances along the altitudinal gradient in mountainous areas . In the Although the taxonomic and phylogenetic patterns of elevation distribution of herbaceous and woody plants were not consistent, our study indicated Figure 3Here we found a comparatively high taxonomic and phylogenetic species turnover of herbaceous and woody communities in the Helan Mountains flora Figure 5This study found that independent contributions of spatial and environmental factors differentially influenced taxonomic and phylogenetic turnovers of herbaceous and woody species Figure 6As a crucial dimension of biodiversity, beta diversity could offer important evidence to predict ecosystem functioning and improve protected priorities . FurtherIn summary, this study integrates TD, PD, and environmental drivers to evaluate herbaceous and woody species’ general patterns and assembly mechanisms along elevation gradients in arid and semi-arid regions. Our study demonstrated that the responses of herbaceous and woody plants along elevation gradients in the Helan Mountains are decoupled mostly due to the inconsistent influence of biotics and abiotics on them. The TD and PD of herbaceous communities substantially increase linearly along an elevational gradient, while a nonlinear model was remarkable for woody communities with relatively low richness at the ends of the elevation range and peaked richness at mid-altitudes. In addition, there was no relationship between woody PD and elevation. We found TD and PD were mainly dominated by species turnover with fewer contributions from nestedness. The turnover process is primarily caused by a combination of environmental and spatial variables. We also showed that environmental and dispersal filtering jointly shapes the plant community assemblages along elevational gradients in arid and semi-arid areas. These findings highlight that conservationists and policymakers should focus on the different adaptation strategies of herbaceous and woody plants to the drought that continues to increase with global warming.The original contributions presented in the study are included in the article/Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Resources, Data curation, Visualization, Writing - original draft, Writing - review, and editing were performed by JZ. Methodology, Software, Validation, Formal analysis, Investigation, Writing - review, and editing was performed by MA. Investigation, Writing - review, and editing were performed by XH and DD. Validation, Writing - review, and editing were performed by SZ. Investigation, Formal analysis, Data curation was performed by XN. Investigation, Resources, Writing - review and editing, Supervision, Project administration, Funding acquisition were performed by CL. All authors contributed to the article and approved the submitted version.This work was supported by Ningxia Key Research and Development Project ; Ningxia Natural Science Foundation Project (No. 2020AAC03107); Chongqing Municipality Key Forestry Research Project (No. 2021-9); Chongqing Municipality Housing and Urban Construction Committee (No. Chengkezi 2019-1-4-2); Forestry Extension Project of China Central Finance (No. Yulinketui 2020-2); Science Foundation of College of Life Sciences of Southwest University (No. 20212005406201).We are grateful to Mr. Zhu Qiang and Mr. Wang Jifei for their technical and field support during data collection. Finally, we want to express our profound gratitude to Mr. Yan Lingbing for his immeasurable support.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Understanding the targets and interactions of long non-coding RNAs (lncRNAs) related to the retinoic acid-inducible gene-I (RIG-I) signaling pathway is essential for developing interventions, which would enable directing the host inflammatory response regulation toward protective immunity. In the RIG-I signaling pathway, lncRNAs are involved in the important processes of ubiquitination, phosphorylation, and glycolysis, thus promoting the transport of the interferon regulatory factors 3 and 7 (IRF3 and IRF7) and the nuclear factor kappa B (NF-κB) into the nucleus, and activating recruitment of type I interferons (IFN-I) and inflammatory factors to the antiviral action site. In addition, the RIG-I signaling pathway has recently been reported to contain the targets of coronavirus disease-19 (COVID-19)-related lncRNAs. The molecules in the RIG-I signaling pathway are directly regulated by the lncRNA–microRNAs (miRNAs)–messenger RNA (mRNA) axis. Therefore, targeting this axis has become a novel strategy for the diagnosis and treatment of cancer. In this paper, the studies on the regulation of the RIG-I signaling pathway by lncRNAs during viral infections and cancer are comprehensively analyzed. The aim is to provide a solid foundation of information for conducting further detailed studies on lncRNAs and RIG-I in the future and also contribute to clinical drug development. The innate immune system serves as the first line of defense against viral infection and is equipped with patterns recognition receptors (PRRs) . The inf. Upon viral infection, CARD in RIG-I is exposed, allowing itself to interact with tripartite motif-containing protein 25 (TRIM25) and mitochondrial antiviral signaling gene (MAVS) (.PRRs in the innate immune system are broadly classified according to the homology of the protein domain in toll-like receptors (TLRs) , RIG-I-le (MAVS) . CARDs oe (MAVS) . Furthere (MAVS) . After be (MAVS) . Subseque (MAVS) . The rele (MAVS)  without a protein-coding capacity. However, lncRNAs may have the splicing products of RNA polymerase II or III, 5’-capped, and 3’-polyadenylation . ResearcThe present review aimed to summarize the relevant studies in the literature, which have explored how lncRNAs modulate the RIG-I signaling pathway by creating feedback or feedforward regulatory loops. Understanding host-virus and host-tumor interactions would help to develop efficient therapeutic strategies for infection control and maintenance of immune homeostasis, thus providing a foundation for future clinical research on medication and drug development.RIG-I reportedly recognizes viral RNAs during a viral infection, leading to the induction of downstream signaling pathways . Therefovia GA-rich motifs, which are located on the incomplete pairing strand of long stem structure. This process was reported to occur during the late phase of vesicular stomatitis virus (VSV) infection and stabilize the intramolecular interaction between the CARDs and helicase domains. Furthermore, both 5’ppp-lnc-Lsm3b and 5’-OH-lnc-Lsm3b were reported to effectively suppress double-stranded RNA (dsRNA)-induced ATPase activity of RIG-I  reportedly activated the zeste enhancer homolog 2 (EZH2)-mediated enhancement of RIG-I . AnotherMAVS transmits signals from RLRs after infection with RNA virus . A studyn by E3 ligase TRIM25 stabilizes the 2CARD and RD regions into a signaling-active, oligomeric, “lock-washer” conformation, in which the ubiquitin chains are bound to the outer rim of the 2CARD tetramer  during viral infection. This binding of lncRNA-GM and GSTM1 blocks the interaction of GSTM1 with the kinase TBK1, thereby reducing the GSTM1-mediated S-glutathionylation, enhancing TBK1 activity, and promoting the production of the downstream mediators of antiviral response. After virus infection, lncRNA-GM levels rapidly decrease, leading to the promotion of GSTM1-mediated S-glutathionylation of the Cys637 residue in TBK1. This generates an inactive form of TBK1 that is incapable of inducing IRF3 phosphorylation and transcription activity. Consequently, the RIG-I downstream signaling pathway is attenuated while the replication and escape of viruses are promoted . The gluA multi-function lncRNA named RIG-I-dependent IAV-upregulated noncoding RNA (RDUR) reportedly enhances host antiviral immunity by positively regulating the phosphorylation of IRF3. On the other hand, virus-induced expression of RDUR prevents the host from a critical inflammation reaction, possibly through negative feedback control of both IκBα phosphorylation and NF-κB p65 phosphorylation . Nuclearvia the RIG-I-dependent signaling pathway involving NF-κB. However, it remains to be explored whether IRF3 and IRF7 are involved in the regulation of the lncRNA ISR in the RIG-I-dependent signaling  during early human development. However, whether lncRHOXF1 directly activates IFN-β and/or ISGs needs further study . LncRNAsvia HIF-1α signaling and promotion of aerobic glycolysis -stimulator of interferon genes (STING) pathway. This was revealed by using cancer immunotherapy based on targeting nucleic acid receptors /miR-545 axis in hepatocellular carcinoma (HCC) cells . The ove.The RIG-I–lncRNA–tumor signaling axis is also regulated by IFN signaling. It has been reported that lncRNA AFAP1-AS1 is upregulated the most significantly in lung cancer and is also associated with poor prognosis . ConsistWe found only two studies that reported the regulation of the RIG-I signaling pathway by lncRNAs during antitumor immunity. Anyway, with antitumor innate immune responses, several intriguing and crucial aspects remain to be investigated, and the results of such an investigation would further expand the understanding of the mechanism underlying the interaction between RIG-I and lncRNAs. The most recent studies have reported effective combination therapy techniques for metastatic and low-immunogenicity tumors . Future The increasing number of studies on the recognition of PRRs and their ligands in recent years have greatly improved our understanding of the RIG-I signaling pathway machinery and provided novel insights into the treatment of immune-related diseases . With thIn general, lncRNAs have been reported to modulate the host immune response by regulating the expression of RIG-I and MAVS, the production of IFNs and inflammatory factors, the transcription of antiviral ISGs, and a series of post-translational modifications, such as polyubiquitination, glycolysis, and phosphorylation. The sources of lncRNAs, which are associated with the regulation of the RIG-I signaling pathway, are listed in A better understanding of the mechanisms observed for SARS-CoV-2-infected cells and the mediators involved in immune responses to this virus is a prerequisite for the development of diagnostic markers and therapeutic strategies targeting COVID-19. In this regard, a detailed exploration of the new targets of SARS-CoV-2-associated lncRNAs that are capable of binding to RIG-I would be the current challenge. It is worth noting that glycolysis could be a breakthrough.Drug resistance is a well-recognized challenge encountered in the clinical treatment of various malignant tumors. In this sense, RIG-I participates in the innate immune response and is also involved in the regulation of apoptosis, which has been related to the occurrence and development of various tumors . The lncThis article provides a summary of research on the regulation of RIG-I by lncRNAs, which would be of assistance to scholars involved in this field. Future studies would further expand the repertoire of lncRNAs involved in the RIG-I regulatory circuit, thus providing critical information for potential therapeutic purposes. The identification of novel molecular targets for lncRNAs is imperative for the development of effective therapeutic methods to improve the prognosis of patients.JL conceived the idea, analysis of literature, and writing of the manuscript; QJ, FC, and DC performed manuscript preparation contributed collection; TG and YYH helped perform constructive discussions; JZ, YQH, and TS contributed to the conception of the review. All authors contributed to the article and approved the submitted version.This work was funded by the Program of the Guizhou Science and Technology Department, China (No. QKHPTRC[2018]5772-035); the Program of the Health Commission of Guizhou Province, China (No. GZWKJ-2021-533); the National Nature Science Foundation of China (NSFC) ; Collaborative Innovation Center of Chinese Ministry of Education (2020-39); Guizhou University Dendrobium nobile industry development key technology engineering research center (No. QKJ-2022-048), Guizhou Provincial Department of Education "four new" and "four modernizations" science and technology research project (No. QJJ-2022-006).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The questionnaire survey was conducted, the somatology indexes were measured, and the PSG, insulin, glycolipid metabolism parameters, and serum inflammatory factors were detected. Body weight, body mass index, waist circumference, and Epworth sleepiness scale (ESS) score were all significantly increased in the OSAHS + CHD group compared with those in the OSAHS group (p < 0.05). The microarousal index (MAI), apnea hypopnea index (AHI), cumulative percentage of time spent at oxygen saturation below 90% (CT90%), oxygen desaturation index (ODI), lowest oxygen saturation (LSaO2), total apnea time (TAT), and mean oxygen saturation (MSaO2) had statistically significant differences between the OSAHS + CHD group and the OSAHS group (p < 0.05). According to the Spearman correlation analysis of AHI, LSaO2, MSaO2, CT90%, ODI, and MAI with HOMA-IR in both groups, MAI, AHI, CT90%, and ODI were positively correlated with HOMA-IR (r > 0), while LSaO2 and MSaO2 were negatively correlated with HOMA-IR (r < 0). Compared with the OSAHS group, the OSAHS + CHD group had an obviously increased level of triglyceride (TG) (p < 0.05), and obviously increased levels of serum inflammatory factors C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) (p < 0.05). The occurrence of OSAHS complicated with CHD is related to inflammatory factors, glycolipid metabolism, obesity rate, and HOMA-IR.The aim of this study is to explore the association between obstructive sleep apnea hypopnea syndrome (OSAHS) complicated with coronary heart disease (CHD) and inflammatory factors, glycolipid metabolism, obesity, and insulin resistance. A total of 400 patients diagnosed with OSAHS who underwent polysomnography (PSG) monitoring in the Sleep Diagnosis and Treatment Center of Beijing Luhe Hospital from March 2015 to September 2018 were selected and divided into the OSAHS group ( Obstructive sleep apnea hypopnea syndrome (OSAHS), whose morbidity rate is annually increasing, is mainly manifested as sleep structure disorder, drowsiness, breath blockage, apnea, snoring, etc. , which in = 114) and the OSAHS + CHD group (n = 286) according to disease condition.A total of 400 patients diagnosed with OSAHS who underwent PSG monitoring in the Sleep Diagnosis and Treatment Center of Beijing Luhe Hospital from March 2015 to September 2018 were selected and divided into the OSAHS group  score ≥9 points]; those with an apnea hypopnea index (AHI) ≥ 5 times/h according to PSG; those with upper airway stenosis and obstruction shown in the examination; those diagnosed with OSAHS; and those with an ESS score <9 points but AHI ≥5 times/h. According to the international common visual diameter method, the degree of vascular stenosis = /vessel diameter near the heart of the stenosis segment × 100%, and coronary angiography showed that the stenosis degree of the inner diameter of the main branches was more than 50%, which could also be diagnosed as OSAHS complicated with CHD. Exclusion criteria were as follows: patients with upper airway resistance syndrome, simple snoring, or narcolepsy; those with a clear history of diabetes earlier than OSAHS; those with IR caused by other factors, such as pancreatic exocrine disease or endocrine diseases; and those with severe malformations of the mouth, nose, or neck.The main contents of questionnaire survey are as follows:Basic information: gender and age.Past medical history: with or without a history of upper respiratory diseases , cardiovascular/cerebrovascular diseases, hypertension, and diabetes.Personal history: with or without a history of smoking and alcoholism.Family history: with or without a family history of OSAHS, heart disease, and diabetes.ESS score: The daytime sleepiness was scored in all subjects according to the ESS  was measured using a weighing scale and recorded.Waist circumference: the circumference (cm) of the plane at the midpoint between the inferior margin of rib and the crista iliaca.Height: The patients kept their body upright and their heels were placed together, and then the height (cm) was measured and recorded.2 (kg/m2).Body mass index (BMI) = weight/heightWaist-to-height ratio (WHtR) = waist circumference (cm)/height (cm).via PSG from 9:00 p.m. to 8:00 a.m. the next day. The following indexes were recorded and analyzed: cumulative percentage of time spent at oxygen saturation below 90% (CT90%), oxygen desaturation index (ODI), microarousal index (MAI), AHI, lowest oxygen saturation (LSaO2), mean oxygen saturation (MSaO2), longest apnea time (LAT), and total apnea time (TAT).In the daytime, the patients did not sleep without eating food containing stimulants and sedatives that affected sleep. The sleep process (more than 7 h overnight) was monitored After fasting for more than 8 h overnight, the peripheral venous blood (elbow venous blood samples) was drawn in the morning to detect FPG and FINS through hexokinase assay and chemiluminescence assay. The IR level was evaluated using homeostasis model assessment of IR (HOMA-IR): HOMA-IR = FINS (mIU/ml) × FPG (mmol/L)/22.5.After fasting for more than 8 h overnight, the peripheral venous blood (elbow venous blood samples) was drawn in the morning to routinely detect FPG, total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL).via enzyme-linked immunosorbent assay (ELISA) according to the instructions, and the results were averaged.After fasting overnight, 3–4 ml of venous blood was drawn from patients and centrifuged at 3,000 rpm for 15 min. Then, the supernatant was taken using a micropipettor and stored at −80°C. The levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ) in both groups were determined repeatedly 3 times t-test. p < 0.05 suggested that the difference was statistically significant.SPSS 20.0 software was used for statistical analysis. The differences in inflammatory factors, glycolipid metabolism, obesity rate, and HOMA-IR were compared between the two groups using p < 0.05), while other indexes had no statistically significant differences between the two groups (p > 0.05)   , while LSaO2 and MSaO2 were negatively correlated with HOMA-IR (r < 0) (HOMA-IR was the highest (4.65 ± 0.71) in the OSAHS + CHD group and the lowest (1.24 ± 0.25) in the OSAHS group (p > 0.05). Compared with the OSAHS group, the OSAHS + CHD group had an obviously increased level of TG, showing a statistically significant difference (p < 0.05)  . MAI, TAT, AHI, CT90%, ODI, LSaO2, and MSaO2 had obvious differences between the OSAHS + CHD group and the OSAHS group (p < 0.05). There were no obvious differences in the FPG, TC, HDL, and LDL between the OSAHS + CHD group and the OSAHS group (p > 0.05). Compared with the OSAHS group, the OSAHS + CHD group had an obviously increased level of TG, and there was a statistically significant difference (p < 0.05). To sum up, OSAHS has a significant correlation with obesity. OSAHS patients have such symptoms as daytime sleepiness, greasy food preference, and fat accumulation, which will aggravate the obesity of patients. The number of obesity patients with OSAHS + CHD is remarkably larger than those with OSAHS. Therefore, increasing the amount of exercise and reducing the intake of excessive high-calorie food can effectively improve the symptoms of OSAHS. In this study, among the glycolipid metabolism parameters, only TG had obvious changes in OSAHS + CHD compared with OSAHS, but no remarkable changes were observed in other parameters. Such a result is consistent with the conclusion made by Qing who used the SAS score and 4 different kinds of questionnaires as the screening tools for OSAHS such that the excessive fat accumulation in the thorax due to obesity leads to a decline in chest wall compliance and an increase in respiratory muscle resistance, which are most apparent in a supine position, and hypoxemia occurs in severe cases, forming a vicious cycle . According to the Spearman correlation analysis of AHI, LSaO2, MSaO2, CT90%, ODI, and MAI with HOMA-IR in both groups, AHI, CT90%, ODI, and MAI were positively correlated with HOMA-IR (r > 0), while LSaO2 and MSaO2 were negatively correlated with HOMA-IR (r < 0). Moreover, compared with the OSAHS group, the OSAHS + CHD group had obviously increased levels of serum inflammatory factors CRP, TNF-α, IL-6, and IFN-γ, displaying statistically significant differences (p < 0.05). Hotamisligil et al. studied and found that IR is closely related to plasma pro-inflammatory factors, and the enhanced IR corresponds to the increased secretion of pro-inflammatory cytokines. Due to the increase in respiratory resistance, the patient experiences hypoxia, and a large number of inflammatory cytokines are expressed, thereby increasing the concentration of inflammatory factors in plasma. Such a result is consistent with the conclusion made by Cai et al. in their study on respiratory resistance in OSAHS patients that there is an inseparable relationship between OSAHS and IR, heart disease, and inflammatory factors, which demonstrates that detection of IR, heart disease, and inflammatory factors in patients may have an important significance for the prevention and treatment of OSAHS (In this study, HOMA-IR was the highest in the OSAHS + CHD group and the lowest in the OSAHS group (of OSAHS .In conclusion, glycolipid metabolism, obesity rate, HOMA-IR, and inflammatory factors are all significantly increased in OSAHS + CHD compared with OSAHS.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The study was approved by the ethics committee of Beijing Luhe Hospital, and written informed consents were signed by the patients and/or guardians. The patients/participants provided their written informed consent to participate in this study.YW wrote the manuscript. YW and HZ were responsible for questionnaire survey and measurement of somatology indexes. YT and RY performed ELISA. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


AGO2), the only protein with catalytic activity in the human Argonaute family, is considered as a key component of RNA interference (RNAi) pathway. Here we performed a yeast two-hybrid screen using the human Argonaute 2 PIWI domain as bait to screen for new AGO2-interacting proteins and explored the specific mechanism through a series of molecular biology and biochemistry experiments.Argonaute 2  as a novel AGO2 binding partner. Biochemical and bioinformatic analysis demonstrates that this interaction is performed in an RNA-independent manner and the N-terminal coiled-coil motif of PSMC3 is required. Depletion of PSMC3 impairs the activity of the targeted cleavage mediated by small RNAs. Further studies showed that depletion of PSMC3 decreased AGO2 protein amount, whereas PSMC3 overexpression increased the expression of AGO2 at a post-translational level. Cycloheximide treatment indicated that PSMC3 depletion resulted in a decrease in cytoplasmic AGO2 amount due to an increase in AGO2 protein turnover. The absence of PSMC3 promoted ubiquitination of AGO2, resulting in its degradation by the 26S proteasome. Mechanistically, PSMC3 assists in the interaction of AGO2 with the deubiquitylase USP14(ubiquitin specific peptidase 14) and facilitates USP14-mediated deubiquitination of AGO2. As a result, AGO2 is stabilized, which then promotes RNAi.We identified PSMC3 plays an essential role in regulating the stability of AGO2 and thus in maintaining effective RNAi.Our findings demonstrate that The online version contains supplementary material available at 10.1186/s11658-022-00411-y. AGO1, AGO2, AGO3, and AGO4), which are ubiquitously expressed and associated with miRNAs and siRNAs physically interacts with AGO2 and catalyzes proline hydroxylation of the AGO2 protein. Depletion of C-P4H(I) subunits reduced the stability of AGO2 resulting in impairment of small-RNA-programmed siRISC activity, but miRISC activity was not altered upon C-P4H(I) knockdown[AGO2 and all AGOs can be involved in translational repression, we speculate that this result may be due to the compensatory effect of other AGO proteins. For PSMC3 affecting the protein levels of cytoplasmic AGO2 rather than nuclear AGO2, we found that USP14 was not localized in the nucleus through the Uniprot database (https://www.uniprot.org/), and our results confirmed this (Additional file However, there are still many unanswered questions. Regarding the fact that knockdown. Since tPSMC3 plays an important role in assisting USP14 to deubiquitinate AGO2, which in turn maintains the stability of AGO2 to ensure effective RNAi.Our findings demonstrate that Additional file 1: FigureS1. PSMC3 interacts with AGO2. Figure S2. PSMC3 is required for mRNA cleavage rather than translational repression. Figure S3. Depletion of PSMC3 by siRNAs. FigureS4. PSMC3 is essential to maintain AGO2 protein levels. Figure S5.Determination of the AGO2 ubiquitination sites. Figure S6. PSMC3 and AGO2 both interact with USP14. Figure S7. Proteasome inhibition abrogates the effect of PSMC3 depletion on siRISC activities. Figure S8. USP14 protein is localized in cytoplasm.


Strongyloides stercoralis infection with low therapeutic response.Individuals infected with the human T-lymphotropic virus type 1 (HTLV-1) may present severe and disseminated forms of S. stercoralis infection and the seroprevalence of IgG anti-S. stercoralis antibodies in individuals infected with HTLV-1 attending the Reference Center for HTLV-1 (CHTLV) in Salvador, Bahia, Brazil.To investigate the S. stercoralis was performed using the Hoffman, Pons and Janer, agar plate culture, and Baermann-Morais methods. The IgG anti-S. stercoralis detection was performed using an in house enzyme-linked immunosorbent assay (ELISA). The HTLV-1 infection was diagnosed using a commercial ELISA and confirmed by Western blot.We conducted a cross-sectional study in 178 HTLV-1-infected individuals treated at the HTLV specialized center between January, 2014, and December, 2018. The parasitological diagnosis of S. stercoralis infection was 3.4% (6/178). Individuals infected with S. stercoralis from rural areas  also showed S. stercoralis hyperinfection . The frequency of circulating anti-S. stercoralis IgG antibodies was 20.8% (37/178). The frequency of S. stercoralis infection. Considering the high susceptibility and unfavorable outcome of the infection in these individuals, the serological diagnosis for S. stercoralis should be considered when providing treatment. HTLV-1-infected people living in precarious sanitary conditions are more prone to develop severe forms of  Strongyloides mostly distributed throughout tropical and subtropical regions -Strongyloides stercoralis, the most common agent of this disease, is classified according to its prevalence: sporadic (<1%), endemic (1-5%), or hyperendemic (> 5%) . Hyperendemic areas are located mainly in the tropics, especially in the developing countries of Asia, Sub-Saharan Africa, and Latin America (notably Brazil and Colombia) ,S. stercoralis infection between 1990 and 2009 was approximately 5.5%, which means the country is hyperendemic , the prevalence of infection ranges from 4.6% to 6.6% ,Strongyloidiasis, a neglected tropical disease that affects around 370 million people worldwide, is caused by soil-transmitted helminths of the genus S. stercoralis infection can be characterized as chronic or asymptomatic. However, immunosuppressed individuals, such as those infected with human T-lymphotropic virus type 1 (HTLV-1), have a greater susceptibility to infection, which can progress to life-threatening forms of strongyloidiasis -,In the general population, ,S. stercoralis in patients infected with HTLV-1 from Japan ,S. stercoralis infection varies according to the geographic region with greater occurrence in the North and Northeast regions ,,Five to ten million people are infected with HTLV-1 worldwide ,,The HTLV-1 transmission may occur in three ways: a) through sexual contact with a 60% efficiency when transmitted from man to woman and 4% from female to male; b) via the blood when sharing syringes or contaminated needles, or by blood transfusion, and c) vertically from mother to child, especially through breastfeeding S. stercoralis infection and the seroprevalence of IgG anti-S. stercoralis antibodies in individuals infected with HTLV-1 attending the Reference Center for HTLV-1 (CHTLV) in Salvador, Bahia, Brazil.The present study aimed to investigate the prevalence of The present cross-sectional study was conducted in 178 HTLV-1-infected individuals seen and treated at the Integrated Multidisciplinary Center for HTLV (CHTLV) of the Bahiana School of Medicine and Public Health (EBMSP), in Salvador, Bahia, from January 2014 to December 2018.S. stercoralis were performed at the Faculty of Pharmacy of the Federal University of Bahia, Salvador, Brazil.CHTLV is a public outpatient clinical center that provides interdisciplinary care and services including general medical treatment, laboratory diagnosis, psychological counseling, and physical therapy. All individuals with associated comorbidities, such as immunosuppression due to the chronic use of glucocorticosteroids, HIV infection, or chronic alcohol abuse, were excluded from the study. The parasitological and immunological diagnoses of g. Sera were frozen at −20°C until use.A questionnaire was drawn up to collect socio-demographic data and information on individuals’ residential sanitary conditions. Fresh stool samples were obtained from all enrolled subjects and submitted to parasitological examination as described below. Blood samples were collected in tubes containing polymer gel for serum separation and then centrifuged for 10 minutes at 1,620We screened serum samples for HTLV-1 antibodies at the CHTLV by microparticle CLIA chemiluminescence  and confirmed by Western blot following the manufacturer’s instructions .,S. stercoralis IgG was performed by ELISA Fresh stool samples from each subject were examined by three different parasitological methods: Hoffman, Pons and Janer The parasite load was quantified by counting the number of larvae under microscopy (10 x objective lens) found in approximately 1 g of feces using the Baermann-Moraes method. The number of larvae was categorized as “non-quantified” when the parasite was not detected using the Baermann-Moraes method, 1-10, 11-50, 51-100, 101-500, and higher than 500 larvae/g of feces.Strongyloides stercoralis third-stage infective larvae (L3) were obtained from the stool of hyperinfested patients. The larvae were cultured in animal charcoal at 28° C for five days and recovered using Rugai’s method g for 30 min at 4 °C, after which the supernatant was collected and analyzed for protein content by the Lowry, et al. S. stercoralis antigen in 0.06 mol/L carbonate-bicarbonate buffer, pH 9.6, then incubated overnight at 4 °C and washed 3 times in PBS containing 0.05% Tween-20 (PBS-T). All plates were then blocked with 100 μL PBS-T containing 8% w/v skim milk (PBS-T-Milk) for 1 hour at 37 °C. After the blocking, the wells were washed as described previously. Serum samples diluted at 1:100 in PBS-T-Milk were incubated at 37°C in duplicate in a volume of 100 μL per well for 1 hour. After washing, 100 μL of 1:4000 anti-human IgG conjugated to horseradish peroxidase  was added to each plate and incubated under identical conditions. Reactions were visualized by adding substrate, 100 μL of 0.051 mol/L citrate-phosphate buffer (pH 5.0) containing 0.0037 mol/L p-phenylenediamine, and 0.04% hydrogen peroxide followed by a 20 minute incubation period in the absence of light after which 20 μL of 8N sulfuric acid were added to stop the reaction. Absorbance was measured at 450-630 nm on a microplate reader .The wells of microtiter plates (Corning Inc. Costar polystyrene EIA/RIA plates) were coated with 100 μL of 10 μg/mL ,As the sampling plan was not probabilistic, inferential statistics  were not used due to the skewed estimate of the standard error S.stercoralis ELISA were determined by the receiver operating characteristic curve (ROC) using a total of 81 HTLV-negative sera from 34 samples of individuals infected with S. stercoralis (positive controls), 24 without parasitic infections, and 23 who had intestinal parasites other than S. stercoralis (negative controls).The cut-off, sensitivity, and specificity for the IgG- anti-S. stercoralis and other parasites received prompt treatment.This project was approved by the Research Ethics Committee, Faculty of Pharmacy, Federal University of Bahia, under number 2616338. All individuals who agreed to participate in the study signed the Informed Consent Form. Patients diagnosed with The mean age of HTLV-1 individuals was 45.60±17.26 years. The majority  were females from Salvador and the outlying metropolitan area . Most people  had a low level of formal education varying from no formal education to incomplete high school and came from low-income families  receiving between half and a full monthly minimum wage. Regarding their residential sanitary conditions and hygiene habits, most had access to piped water , sewage system and/or septic tank  and lived in areas with paved streets ; 16.3% (29/178) of individuals had a habit of walking barefoot .S. stercoralis. From these, 83.3% (5/6) were males, 50% (3/6) lived in rural areas of the state of Bahia, and 66.7% (4/6) reported walking barefoot regularly . The pathogenic protozoa Giardia duodenalis was found in 2.8% (5/178) of individuals. Other non-pathogenic protozoa were more prevalent, such as Endolimax nana  and Entamoeba coli   with 15.2% (27/178) of monoparasitism and 7.9% (14/178) of polyparasitism. The most frequent helminths were  11/178) .S. stercoralis was diagnosed in 3.4% (6/178) of the study population. When participants were separated into groups 1 (urban areas) and 2 , the infection rate was 1.9% (3/161) and 17.6% (3/17), respectively. The total frequency of other parasites in individuals in the rural areas was 88.2% (15/17) while in individuals from urban areas, the parasitic frequency was 16.1% (26/161). The most frequent pathogenic helminths in individuals from rural areas were Ascaris lumbricoides 52.9% (9/17), Trichuris trichiura 47.1% (8/17), Enterobius vermicularis 29.4% (5/17) while in urban areas S. stercoralis, hookworms, and Ascaris lumbricoides had a low frequency of 1.9% (3/161 each). Helminth eggs including E. vermicularis were diagnosed using the Hoffman and Pons and Janer parasitological methods. The pathogenic protozoa G. duodenalis was found in 29.4% (5/17) of individuals from rural areas and none in urban areas  sensitivity and 97.87% (23/24) specificity. S. stercoralis IgG antibodies were detected in 20.8% (37/178) of HTLV-1 individuals  in association with HTLV-1 ,We found a frequency of 3.4% Although they came from low-income families, most HTLV-1 subjects lived in the city of Salvador or in other urban areas of cities in the state of Bahia where basic urban amenities are available: treated potable water supply, sewage system connection, regular rubbish disposal, and paved streets and sidewalks. In contrast, the individuals living in rural areas were from poor families with very low incomes.S. stercoralis, other geohelminths such as A. lumbricoides, T. trichiura, and hookworm were found in the parasitological examination of HTLV-1 patients. These geohelminths were more frequently found in individuals living in rural areas. Several studies have shown that precarious living conditions such as lack of access to basic sanitation, health services, and schooling are the main determinants in the acquisition of intestinal parasitic infections, which continue to represent a major threat to public health in rural areas, as well as in peripheral regions next to urban zones ,,Besides anti-S. stercoralis antibodies was 20.8%, which was much higher than the prevalence of larvae in feces. Souza, et al. S. stercoralis antibodies contrasting with 1.3% of positive parasitological diagnosis in individuals with lupus erythematosus. Conversely, frequencies of specific antibodies and S. stercoralis larvae in feces were very similar in alcoholic individuals, 22.0% and 23.5%, respectively, with a high agreement between the diagnostic methods S. stercoralis infections by individuals living in endemic areas due to precarious hygiene habits and/or sanitary conditions.The frequency of specific S. stercoralis were considered hyperinfected with one presenting all parasite evolutionary forms in feces. Factors linked to genetics and host immune response can trigger the infection and determine the severity of strongyloidiasis in individuals with HTLV. HTLV-1 coinfection induces a strong activation of the immune system. The exacerbated production of IFN-γ and TNF-α induced by HTLV-1 infection may negatively modulate the Th2-type cellular response and, consequently, decrease the levels of the main immune mediators involved in the defense against S. stercoralis such as IL-4, IL-5, and IL-13, and IgE -S. stercoralis hyperinfection showed no alterations except for a significant increase in IL-17 levels following strongyloidiasis treatment Strongyloides in coinfected patients, although a larger number of individuals should be studied to evaluate the immunomodulation in HTLV-1 and S. stercoralis coinfection by IL-17.Three individuals with a parasitological diagnosis of S. stercoralis infection. Considering the high susceptibility and unfavorable outcome of the infection in these individuals, early diagnosis using parasitological and immunological methods and prompt treatment are critical for the successful management of strongyloidiasis in HTLV-1 carriers, especially those living in rural areas. Additionally, public policies are necessary to improve access to health services and basic sanitation for individuals at high risk of developing severe strongyloidiasis, such as HTLV-1-patients.In conclusion, our study suggests that HTLV-1-infected people living in poverty with precarious sanitary conditions are more predisposed to develop severe forms of


HTLV-1 is a retrovirus which causes diverse diseases in 10% of its infected population, significantly worsening their quality of life and mortality rate. Even though it is globally distributed and is endemic in many countries (including Peru), it is still highly neglected. It spreads through vertical, sexual and parenteral transmission. As no effective treatment against this virus exist, prevention is required to contain it. The World Health Organization published a technical report on the matter in 2021, with the collaboration of international HTLV-1 experts. However, neither the impact of sexual transmission (cause of the majority of adult cases and infection in non-endemic areas) nor its prevention were considered. Evidence is presented, which shows the magnitude of sexual transmission, its risk factors and preventive measures; hoping it will encourage health workers to help eradicate this infection. T-cell lymphotropic virus 1 (HTLV-1) was the first human oncogenic retrovirus to be discovered 40 years ago (T-cell leukemia/lymphoma (ATL) and tropical spastic paraparesis or HTLV-1 associated myelopathy (TSP/HAM) (Human TSP/HAM) .According to outdated 9-yeard-old information, it affects more than 10 million people . But thi2 = 95.51%) , and Central Australia . In Peru 95.51%) . A studyThe prevalence of HTLV-1 is higher in women, who are more susceptible to TSP/HAM . In contSexual transmission of HTLV-1 has been observed to be more efficient from male to female . Similarp < 0.001)  , meaningThis infection mechanism could be the most important within epidemiologically closed communities, such as the indigenous populations of Brazil; where there is an increase in the prevalence of HTLV-1 with age and a similar transmission from male to female and female to male .In Salvador, epicenter of HTLV-1 in Brazil, a higher prevalence of the virus was seen in patients with a history of sexually transmitted infections (STIs) and older age, predominantly women, and there was an absence of infection in children under 13 years of age ; all theExtensive evidence suggests the importance of sexual transmission of HTLV-1. A cohort study of Japanese blood donors aged 16–69 years found a higher incidence in women (50–59 years) than in men (60–69 years) in endemic and non-endemic areas . Howeverp = 0.01) (Due to the similarity between the human immunodeficiency virus (HIV) and HTLV-1 transmission, multiple studies were done on HIV risk groups to define the groups susceptible to HTVL-1: female sex workers (FSW), men who have sex with men (MSM), STI patients and injecting drug users . HTLV-1  = 0.01) .Before the appearance of current antiretroviral therapy (ART) against HIV, HTLV-1 was an influencing factor in the outcome of infected patients. A publication from the pre-ART era, described a not significant higher mortality and a shorter survival time in those with CDC (Centers for Disease Control and Prevention) stage IV (acquired immunodeficiency syndrome or AIDS) with dual infection of HIV and HTLV-1/2 . HIV-1 iFortunately, there has been a decrease in co-infection of these retroviruses, as observed in Pará, Brazil, where the prevalence of dual infection with HTLV-1/2 and HIV-1 has decreased from 8% in the 1990's to 1.4% in 2020 . Sex witHolmes mentions, in his book on sexually transmitted diseases , that anVarious studies performed in Peru highlight the magnitude of the sexual transmission of HTLV-1 and the need for prevention; since its prevalence is higher in FSW than in the general population. In a study of cervical secretions of seropositive FSW, virus shedding in genital tract secretions was associated with mucopurulent cervicitis  and gross and visible vaginal secretions  . No signp < 0.0001). In addition, a significant association between the virus and duration of prostitution  was found (p < 0.0001) and HBV markers (p < 0.0001). Independent associations between the virus and having been a FSW in Callao , older age  and positive RPR/FTA  were observed , homosexual orientation (p < 0.012), receptive role (p < 0.021), considering themselves a sex worker (p < 0.012), the number of male partners (p < 0.047), syphilis (p < 0.004) and HSV-2 (p < 0.000) (p < 0.000), having only male sexual partners (p < 0.030), being receptive (p < 0.007), anorectal abnormalities (p < 0.002), syphilis (p < 0.000) and HSV-2 (p < 0.000). Once the multivariate regression analysis was done, HTLV-1 was found to be associated with syphilis , HSV-2 , coinfection with HIV , coinfection with HTLV-2  and older age   . Meanwhip < 0.01), parallel to a significant decrease in HTLV-1 prevalence from 14.5% in 1993 to 3.1% in 2010 (p < 0.01) (p < 0.05) (p < 0.02) were also significantly associated with HTLV- 1  . A study < 0.05) . Time wo < 0.05)  and a hi HTLV- 1 . Similar HTLV- 1 .Another study in clandestine sex workers in Lima documented the decrease of infection rate of HTLV-1 from 10.3% to 1.7% thanks to the use of condoms with all sexual partners instead of occasionally  . Likewisp < 0.04), having had more than four sexual partners , more than four pregnancies , age ≥38 years  and <7 years of studies  (p < 0.05) in one of the regions evaluated   were defvaluated ; reaffirGenital ulcers, sexual relations with prostitutes in the case of men, not using a condom, and a large number of sexual partners are also risk factors in the general population , 27–29. The low relevance given to the sexual transmission of HTLV-1 worldwide led HTLV experts from the Global Virus Network to write an open letter to the World Health Organization (WHO) in 2018 , 34, wheConsequently, supported by the Australian and Japanese governments, the WHO organized a meeting in Japan, where it where it convened international experts on HTLV-1 (including from Peru) to consolidate current knowledge about the virus and how to prevent it . In MarcThis article presents evidence that shows that HTLV-1 infection is more frequent in high-risk populations and that sexual transmission is greater from men to women. Likewise, the presence of other sexual infections and bacterial vaginosis favor this type of transmission, not to mention that it is consistent with time practicing as sexual workers . Condom use can reduce this transmission and is an inexpensive measure available to all. Nonetheless, HTLV-1 is not mentioned in the STI Treatment Guidelines of 2021 of the Center for Disease Control, be it for prevention, screening or treatment.HTLV-1 screening is usually performed in blood and organ donors and diagnosis is reserved for those with a positive result or symptoms and risk factors which require molecular confirmation. The absence of commercially available tests of such nature and of (reliable) register systems for infected patients make the mapping of the actual dissemination of HTLV-1 difficult . This ocIdeally, sexual partners of seropositive patients should be screened for infection and referred for counseling and follow up if they have a positive result, but the lack of knowledge of this virus among the population and health professionals restricts this procedure . AlthougThis review highlights the lack of information on the sexual transmission of HTLV-1, the risk different sexual practices pose to the infection, and its prevention. This should be of great interest, because no appropriate treatment for the disease it causes exist and the creation of a vaccine is not yet affordable. The authors hope the information presented helps to encourage health workers and institutions responsible for the care of the population to further investigate and participate in HTLV-1 sexual transmission prevention, promoting simple and cheap methods such as adequate counseling on sexual and reproductive health and the use of condoms. It may take a long time to introduce national measures, but the awareness of health professionals can help spread prevention initiatives among local institutions and speed up the creation of adequate country and worldwide programs.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.All authors participated in the conception, design, data recollection and writing of this article. The supervisor gave the final approval of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that is endemic in a number of regions across the world. There are an estimated 5–10 million people infected worldwide. Japan is currently the only country with a national antenatal screening programme in place. HTLV-1 is primarily transmitted sexually in adulthood, however it can be transmitted from mother-to-child perinatally. This can occur transplacentally, during the birth process or via breastmilk. If HTLV-1 is transmitted perinatally then the lifetime risk of adult T cell leukemia/lymphoma rises from 5 to 20%, therefore prevention of mother-to-child transmission of HTLV-1 is a public health priority. There are reliable immunological and molecular tests available for HTLV-1 diagnosis during pregnancy and screening should be considered on a country by country basis. Further research on best management is needed particularly for pregnancies in women with high HTLV-1 viral load. A first step would be to establish an international registry of cases and to monitor outcomes for neonates and mothers. We have summarized key risk factors for mother-to-child transmission of HTLV-1 and subsequently propose a pragmatic guideline for management of mothers and infants in pregnancy and the perinatal period to reduce the risk of transmission. This is clinically relevant in order to reduce mother-to-child transmission of HTLV-1 and it's complications. Human T cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that was first identified in 1979 , 3. It iIt has been estimated that there are 20,000-30,000 HTLV-1 seropositive people living in England and Wales . HoweverThe majority of HTLV-1 infections are acquired via sexual transmission in adult life. Sexual transmission between serodiscordant heterosexual couples has been estimated at rates from 0.9 to 2.5 per 100 person-years . HTLV-1 Ex vivo observations revealed that HTLV-1 transmission is through cell-to-cell transfer from infected to uninfected T lymphocytes. HTLV-1 integrates into the host cell DNA, mostly CD4+ T-lymphocytes, where it persists with a single copy per genome/cell . In. InEx viome/cell  and cardome/cell  . In the proposed management algorithm we suggest antibody testing is performed in all infants of HTLV-1 positive mothers at 18 months of age. This is because by 18 months maternal antibody will have waned and the results are likely to be representative of the child's own antibody response  testing is undertaken by contacting the National Center for Human Retrovirology  was associated with a significant increase in the risk of transmission. Transmission risk went from 6.4% when the PVL was <1 to 36.1% when the PVL was 1% or greater. In addition, the same study (10 but increased significantly when ≥2.0 log10. Symptomatic patients (e.g. those with HAM / ATL) have been shown to have a greatly increased PVL when compared with asymptomatic carriers  has been found to be an independent risk factor for increased transmission to the infant . Hisada me study  showed tcarriers .We, therefore, recommend stratifying pregnant women who are not symptomatic due to HTLV-1 infection, into low risk (PVL < 1%) and high risk (PVL ≥ 1%) based on their PVL. Women who are symptomatic with ATL should always be considered high-risk, but those with other symptomatic conditions  may be stratified according to their PVL.Strongyloides stercoralis  cesarean section may reduce the risk .As in management of HIV-1, antiretroviral medications could be used to reduce HTLV-1 transmission rates in high-risk infants. However, there are few data regarding the use of antiretrovirals for peri-exposure prophylaxis for neonates. We have published a case series  of four in vitro data suggest their use may be beneficial  treatment for HTLV-1 infection in pregnancy or for prevention of MTCT of HTLV-1 that we are aware of, although limited neficial . Severaldovudine . Zidovuddovudine  ZDV withdovudine  and is odovudine . Both ZDdovudine . While sdovudine –53 of analf-life , it is ialf-life . Of notealf-life .Drawing together the available evidence on HTLV-1 transmission, and our experience of managing women and their infants, and bearing in mind the potential role of cesarean section, maternal and neonatal antiretroviral therapy, and avoidance of breastfeeding in preventing mother-to-child transmission of HIV, a similar retrovirus, we propose the following perinatal algorithm  for manahttp://www.htlv.eu/) for advice in the management of pregnant women with HTLV-1 infection.The algorithm is based on assessment of transmission risk according to clinical disease and PVL: women with no symptoms and PVL < 1%, follow the green path with normal pregnancy, birth and postnatal care, avoiding breast feeding if feasible; women with ATL (whatever the PVL), follow the red path with antiretroviral treatment, elective cesarean section, avoidance of breast feeding and PEP for the infant; women with no symptoms / mild symptoms and PVL >1% follow the yellow path and should be considered for antiretroviral treatment, elective cesarean section, avoidance of breast feeding and PEP for the infant. Clinicians are welcome to contact the National Center for Human Retrovirology (Data on prevention of mother-to-child transmission of HTLV-1 have been available since the 1980s and are robust, all demonstrating the effectiveness of avoidance of breast-feeding or at least limiting to less than 3 months duration. Mother-to-child transmission is associated with a high risk of subsequent HTLV-1 associated disease especially adult T-cell leukemia. Data on reducing the risk of peripartum transmission are limited, therefore, we propose a pragmatic perinatal algorithm to aid management of these cases, highlighting transmission risks, perinatal diagnostics, and antiretroviral and obstetric interventions. However, further study on best management for the prevention of mother-to-child transmission of HTLV-1 is needed, especially for high-risk pregnancies. A first step would be to establish an international registry of cases and to monitor outcomes for neonates and mothers.RB: writing—original draft and writing-review and editing. SD: conceptualisation, writing—original draft, and writing—review and editing. MB, HL, LC, GC, DK, LP, and GT: conceptualisation and writing—review and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This isolated form is associated with an 80–90% risk of progression to an NDD, such as PD or DLB, within 10 years of first diagnosis.3 iRBD commonly presents in males >50 years and is estimated to occur in 2% of the general population.4 Thus, identifying iRBD provides a rare opportunity to modify future risk of neurodegeneration and there are anticipated opportunities for patients with iRBD to enrol in neuroprotective drug trials to prevent progression to an overt NDD.It is important to recognise potential RBD because it is also strongly associated with neurodegenerative disease (NDD): RBD affects approximately 50% of people with Parkinson’s disease (PD), 80% of people with dementia with Lewy bodies (DLB), and almost 100% of people with multiple system atrophy (MSA).4When we sleep, we pass through four distinct stages. During the stage of sleep most associated with dreaming, REM sleep, the eyes move around quickly but all other skeletal muscle tone is lost (atonia) and thus limbs become floppy; this effectively causes paralysis of our bodies during dreaming. However, in RBD the brainstem system that produces atonia is faulty, possibly damaged by early pathology, and people can therefore physically act out their dreams.1 Unfortunately, it can be challenging for clinicians to disentangle such symptoms from other sleep disorders that have similar symptoms, and therefore RBD is generally under-recognised , or falling out of bed. More commonly, presentation to a GP is initiated by a bed partner who notices kicking and punching movements during sleep.cognised .15) and referring patients on to a neurologist or sleep specialist for further assessment. The International RBD Study Group state that an overnight sleep study (video polysomnography [vPSG]) in a sleep laboratory is mandatory for the identification of RBD.6 A neurologist may also assess cognitive and motor symptoms to determine any current evidence of a recognisable NDD. In the absence of an overt NDD, diagnosis of iRBD can lead to treatment , as well as opportunities for risk modification and clinical trial recruitment that hold potential to slow or even stop progression to NDD ?’7 An answer of ‘yes’ should prompt a referral for further investigations. The diagnostic accuracy of this question is 94% sensitivity/87% specificity  when compared with the gold standard of vPSG;7 however, this should be used only as an initial screening for onward referral. It is also important to recognise that people without bed partners are far more likely to respond ‘no’ to this question, and a history suggestive of RBD should still prompt referral.A validated single screening question for ‘probable’ RBD is: 8 A dose reduction or drug switch of antidepressant drug class should be considered when investigating symptoms of iRBD.Keeping in mind that some people with RBD will already have an NDD, it is important to consider general safety, especially around driving. Visual hallucinations should be directly asked about  and, if present, the patient should be told to stop driving and inform their relevant driving authority. Prolonged antidepressant use may occasionally trigger iRBD, particularly in those taking selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, and tricyclic antidepressants.8 Sleeping environment modifications are also helpful to minimise risk to people with RBD and their bed partners, including sleeping in a separate room, using pillow barricades, removing potentially dangerous items from the room, or sleeping on a mattress on the floor.1Two recommended medications to be given at night are clonazepam and melatonin. A recent review found that clonazepam (given at doses ranging from 0.125 to 3 mg) improved symptoms in about two-thirds of patients, but should be used cautiously in older adults, as it can cause morning drowsiness, confusion, and falls. Melatonin is considered a safer option with fewer side effects and, when given at doses ranging from 2 to 6 mg, has been found to improve symptoms in a third of RBD cases.before degeneration of the brain. In 2020, the Lancet Commission provided strong evidence that 40% of all dementia cases are attributable to 12 modifiable risk factors, such as excessive alcohol consumption, hypertension, and smoking,9 but currently it is unclear whether the trajectory of iRBD can be changed.This is the central question of numerous research studies, including clinical drug trials, as there is a rare opportunity for intervention up to 10 years While there remains uncertainty around iRBD and its association with different types of NDD, it is clear that iRBD is a prodrome of neurodegeneration. This means there is an opportunity for dementia risk reduction through managing potentially modifiable dementia risk factors. GPs therefore play a vital role in recognising potential iRBD and applying preventive medicine approaches with the aim of trying to alter iRBD trajectories. Furthermore, GPs will play a similarly vital role in timely referral to specialist settings when cognitive impairment and/or parkinsonism emerge.


An enzyme-free terahertz uric acid sensor based on a metallic slot array metamaterial was proposed and realized both theoretically and experimentally. The sensing model was verified in simulation and femtosecond laser processing technology was employed to ablate slots in the copper plate to fabricate metamaterials. Analytes were tested with liquid phase deposition on the metamaterial by a terahertz frequency domain spectroscopy system. Gradient concentrations of uric acid, ascorbic acid, and a mixture of them were measured separately with a good linear response. A significant decrease in sensitivity was observed in the ascorbic acid assay compared with the uric acid assay. The test results of the mixture also proved that our device is resistant to ascorbic acid. It is a simple and effective method for monitoring uric acid concentrations and the strategy of eliminating interference while modulating the resonance peak location mentioned here can be rationally projected for the development of other sensors. Hyperuricemia, a metabolic disease like diabetes, is rising owing to modern human dietary changes ,2. It shGreat efforts have been put towards developing methods of monitoring UA academically, including spectrophotometry, mass spectrometry, and chemical sensors based on electrochemical methods, among others. Enzyme-based spectrophotometry is the most widely accepted method for detecting uric acid ,6, and iSpectroscopy detection involving no reaction and biomaterial may be a better solution for uric acid monitoring, and various pieces of research on different spectroscopy have been proposed ,15. As tMetamaterials, artificial materials constructed from periodic cells that are subwavelength in size, provide a new strategy to enhance the wave–matter interaction . ThroughAs for the selectivity accomplishment part, Terahertz spectroscopy may be a practical option. Terahertz (THz) wave is an electromagnetic wave in the frequency range of 0.1–10 THz, which is located between microwave and infrared lights in the electromagnetic spectrum . In addiIn this work, we propose a spectroscopic THz metamaterial UA sensor without any modifications nor any enzyme-like biomaterial. A theoretical model of this UA sensor was developed using a finite element simulation method and the simulation sensitivity was calculated to be 805.5 GHz/RIU. Both the sensitivity and selectivity of the UA sensor were demonstrated in UA detection. The UA was detected with a sensitivity of 0.117 GHz/μM and the limit of detection (LOD) is 9 μM. The AA response was experimentally revealed and analyzed, as the main interference for the UA detection. High immunity to AA interference was demonstrated experimentally in the detection of hybrid solutions. The reliability of the sensing experiments is also verified. The possible principle is also proposed and discussed.Metallic hole array (MHA), a microstructure that penetrates subwavelength size holes in a metal plate, is a branch of metamaterials. MHA’s transmission properties in the visible wavelength band have long been researched. At a specific aperture size, a high transmittance peak can be obtained from MHA, with peaks that exceed predictions from previous small-aperture diffraction theory. This is because of the MHA’s surface plasmon resonance (SPR) mode being excited. This unusual light transmission phenomenon is known as extraordinary of transmission (EOT). According to the central wavelength equation of the EOT peak , an equaAs multi-band optics research advances, researchers have discovered the EOT effect in the terahertz band as well. It is possible to obtain high transmission peaks in the THz band by modifying the size of the microstructure of MHA metamaterials. The simplicity of MHA metamaterials and the absence of dielectrics has made them an important direction of research in the design of terahertz metamaterial structures.Employing copper with low dielectric loss as a substrate, we designed a metallic slot array (MSA) metamaterial by compressing one diameter of a circular hole based on MHA. A significant THz-EOT phenomenon is also observed in the simulation. To achieve THz resonance-enhanced sensing of UA, the resonance peak of the metamaterial needs to be modulated to coincide with the frequency of the characteristic peak of UA. The characteristic terahertz spectrum peak of UA is located at 1.5 THz , while AA comparison and analysis of the surface currents in the slot cell and hole cell is shown in A similar THz photoelectric conversion effect was not found in the hole structure, which proves that the resonant coupling response of the THz wave and the SPP of the slot structure is stronger than that of the hole structure, resulting in a low energy utilization efficiency for incident THz waves. 1) is 140 μm, the slot length (A) is 87 μm, the slot width (B) is 15 μm, and the thickness of the substrate is 50 μm. An MSA metamaterial with a resonance peak just coinciding with the UA characteristic peak is proposed, with the size optimization. The inset of 2 = 0.995). Based on Equation (3), the simulation sensitivity can be calculated as 805.5 GHz/RIU. The results demonstrate the high dielectric environment sensitivity of our proposed MSA metamaterial sensing model.To investigate the formation principle of this resonance peak, the surface current (top) and magnetic field (bottom) of the metamaterial at resonant frequency  and non-resonant frequency  were simulated, as shown in 2) is expanded to 400 μm, the slot length (C) is 280 μm, the slot width (D) is 90 μm, and the thickness is kept constant at 50 μm. The transmittance curve in Finally, an MSA metamaterial with a low-frequency (LF) resonance peak is created by scaling up the period and size of the cell to validate the MSA metamaterial sensing model. Femtosecond laser processing is employed to process the MSA metamaterial UA sensor. A series of sensing tests were performed for UA, AA, and a mixture of UA and AA to verify the usability and anti-interference to AA of this THz UA sensor. The UA and AA powders used in the experiments were purchased from . In normal human serum, UA levels range between 100 and 420 μM, blood UA levels exceeding 420 μM is the diagnostic criteria for hyperuricemia, and the highest concentration is about 600 μM for clinical observation. Detection ranges covering 100 to 650 μM are the standard technical requirement for practical devices.A gradient concentrations of UA solution at 180, 340, 500, and 640 μM were prepared and tested. AA with the same gradient concentrations were also tested to verify the selectivity of this sensor for uric acid. Four other derivatives, dopamine, glucose, purine, and urea at 640 μM, were detected for comparison with the results in UA and AA assays. In addition, mixing 640 μM AA with four gradient concentrations of UA separately, a mixture for testing sensor resistance to AA interference was formulated.Finally, for practical application scenarios, the long-term durability of the device and the humidity environment effect were investigated.All spectral data for this work were performed on the transmission test module of THz-FDS . It mainly consists of two distributed feedback (DFB) lasers, two fiber-coupled InGaAs optical mixers, dual laser-controlled smart electronics, and a four-reflector transmission test optical path, as shown in A resonant peak with 96% transmittance in the 1.35 THz band was found, which can be used for THz resonance-enhanced sensing. Through the next experiments, we demonstrated that the THz MSA metamaterial UA sensor has a high sensing performance and selectivity for UA, which is well suited for future applications in the early monitoring and disease diagnosis of UA.2 of 0.99. Test sensitivity is determined as the frequency shift caused by a unit change in concentration. The sensitivity of the HF sensor in UA detection is 0.164 GHz/μM. In addition, HF sensor’s LOD for UA is calculated, which is 5.5 μM.The LF sensor depositing the same gradient concentration of UA was also characterized. The transmittance curve variation of the LF sensor is shown in To validate the THz resonant coupled sensing enhancement theory, different analytes were deposited onto the sensor for transmission spectroscopy testing. In The resonant peak frequency shifts of different analytes at the same concentration (640 μM) were also measured. The mixture of gradient concentrations UA and 640 μM AA were measured to test the sensor’s resistance to AA in UA detection. The frequency shift of the resonance peak in Comparative analysis is also carried out on sensors proposed in other works, as shown in All measured data are obtained from the transmissive metamaterial sensor in the THz band. The comparisons presented here are quite informative and show that our proposed device is capable of high sensing performance.For real testing situations, the stability issue has always been an important factor. In conclusion, a THz MSA metamaterial UA sensor is proposed and realized for enzyme-free detection of UA. The sensing theoretical model is validated in simulation and the fabrication is processed with femtosecond laser machining. Samples are characterized by a continuous wave THz-FDS. With the high Q factor and resonant frequency designed, high sensitivity and output linearity are found for UA detection. UA and AA can be effectively distinguished, as the sensor shows large variation in sensitivity. The test results of UA/AA mixture also demonstrate the resistance of the sensor to AA interference. This THz MSA metamaterial UA sensor has the advantages of small size, reusability, high detection sensitivity, low detection limit, and the capability to detect UA specifically, which is of great importance for the early detection and diagnosis of hyperuricemia in the future.


Unstable angina (UA) is a component of acute coronary syndrome that is only occasionally included in primary composite endpoints in clinical cardiovascular trials. The aim of this paper is to elucidate the potential benefits and disadvantages of including UA in such contexts.UA comprises <10% of patients with acute coronary syndromes in contemporary settings. Based on the pathophysiological similarities, it is ideal as a part of a composite endpoint along with myocardial infarction (MI). By adding UA as a component of a primary composite endpoint, the number of events and feasibility of the trial should increase, thus decreasing its size and cost. Furthermore, UA has both economic and quality of life implications on a societal and an individual level. However, there are important challenges associated with the use of UA as an endpoint. With the introduction of high-sensitivity troponins, the number of individuals diagnosed with UA has decreased to rather low levels, with a reciprocal increase in the number of MI. In addition, UA is particularly challenging to define given the subjective assessment of the index symptoms, rendering a high risk of bias. To minimize bias, strict criteria are warranted, and events should be adjudicated by a blinded endpoint adjudication committee.UA should only be chosen as a component of a primary composite endpoint in cardiovascular trials after thoroughly evaluating the pros and cons. If it is chosen to include UA, appropriate precautions should be taken to minimize possible bias. Unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI) comprise the three main presentations of acute coronary syndromes (ACS) . TraditiA diagnosis of UA is based on symptoms suggestive of myocardial ischemia and the absence of acute myocardial injury or necrosis  , 4, 5. UThe major international cardiovascular societies categorize UA and NSTEMI together using the term NSTE-ACS , 5. ACS During the last decades, better risk factor control, evolving MI definitions with widespread use of high-sensitivity troponins, and reperfusion strategies have changed the epidemiology and prognosis of patients diagnosed with UA. The 2002 Euro Heart Survey of ACS based on data from 25 countries reported that UA comprised 42% of patients with an ACS . ConversPatients with UA also appear to derive less benefit from intensified antiplatelet therapy and an invasive strategy within 72 h, although invasive coronary angiography is still recommended in patients with a high likelihood of UA . A conten = 8,992) found that the rate of incident nonfatal MI was similar in patients with UA and NSTEMI, but all-cause mortality was considerably lower in those with UA [n = 7,187, 38% with a diagnosis of UA) also reported substantially better outcomes in patients with UA compared with NSTEMI [Generally, the risks of subsequent death and cardiovascular events are lower in the UA setting compared with NSTEMI , 13. For with UA . Anotherh NSTEMI . NeverthHigh-sensitivity cardiac troponin assays have improved sensitivity and precision, enabling more rapid and accurate diagnosis in patients with suspected MI , 16. TheSerial troponin testing with exclusion of a significant rise or fall in its concentration is key as some patients with UA may present with chronically elevated high-sensitivity cardiac troponin levels, e.g., patients with known chronic kidney disease, chronic coronary syndrome, or heart failure. Still, it can be difficult to distinguish UA from NSTEMI, e.g., in very late presenters of MI, where the troponin release curve has flattened. As opposed to the aforementioned position on grouping UA as a subgroup of stable CAD, other studies have stated that UA and NSTEMI should be grouped together and patients should be managed depending on their cardiovascular risk factors instead of the diagnosis , 13. ThiThe ideal endpoint of a clinical trial is based on several considerations. It should be well-defined, easy to evaluate, clinically relevant to the intervention and the patient, and have a low risk of ascertainment and reporting bias. In addition, it should occur at a suitable frequency within a limited time frame for a trial to be feasible. All-cause mortality has fulfilled all these criteria. However, a declining mortality rate in the general population, including a declining proportion of mortality caused by cardiovascular disease, makes all-cause mortality less sensitive to interventions that primarily exert their beneficial effects through cardiovascular outcomes , 23. ImpThe differences in the event rate of each component of a composite endpoint must be as small as possible since the overall effect of an intervention will largely be determined by the dominant event , 25. SevThrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial [A commonly used composite endpoint in cardiovascular trials is major adverse cardiovascular events (MACE). Although it has not been defined strictly, it usually comprises a composite of death from cardiovascular causes, MI, and stroke . Indeed,R) trial . The keyAs seen in Figure An important caveat of using UA as an endpoint in cardiovascular trials is the extent of ascertainment and reporting bias, particularly with respect to symptom description. The clinical distinction between UA, NSTEMI, and noncardiac chest pain can be challenging, even when applying current guideline recommendations. Limited information on symptom description and duration of ischemic symptoms may lead to refuted events due to a lack of event-specific data . CompareIn 2017, the Standardized Data Collection for Cardiovascular Trials Initiative established by the FDA proposed definitions for cardiovascular endpoints including hospitalization for UA to simplify the design and conduct of clinical trials and to enhance the ability to aggregate and compare data from multiple trials . The fulReduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), which randomized statin-treated patients with elevated triglycerides to icosapent ethyl or placebo [the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial [An example of a trial using these criteria is the  placebo . The com placebo . Investi placebo . AnotherY) trial . It was Y) trial , 41, 42.The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) is an example of a trial expanding the primary endpoint by including UA in an attempt to increase feasibility [Several large trials have used UA as a component of a primary composite endpoint. Notable examples are seen in Table sibility . Interessibility . Indeed,The Fractional Flow Reserve-Guided PCI versus Medical Therapy in Stable Coronary Disease (FAME-2) trial included unplanned hospitalization leading to urgent revascularization as part of the primary composite endpoint consisting otherwise of death from any cause or nonfatal MI [An alternative approach might be to use revascularization, as UA is closely linked to urgent revascularization. As an endpoint, revascularization is clinically feasible and pathophysiologically relevant. It is easy to evaluate, has a higher event rate than UA, and the use of an adjudication committee may not be as essential. Examples of clinical trials using revascularization as a component of a primary endpoint are presented in Table fatal MI . This adfatal MI , 59. Thefatal MI . FurtherRecently, there has been an increasing interest in randomized controlled trials with registry-based follow-up as they are more feasible, cheaper, and allow for longer-term follow-up . The diaThis review summarizes the challenges and opportunities associated with using UA as a component of a primary composite endpoint in cardiovascular clinical trials. Arguments favoring the use of UA rely on its pathophysiological similarities to MI, the ability to enhance statistical power, the impact on quality of life, and the health care burden. However, widespread use of high-sensitivity troponins has reduced the incidence of UA. UA may also be subject to ascertainment bias, reporting bias, and discordance between clinicians. Therefore, we recommend that UA events should be adjudicated with strict criteria by a blinded endpoint adjudication committee, or alternatively be defined in combination with revascularization, resulting in a limited number of events. If UA is considered as an endpoint in clinical trials, we recommend evaluating our list of pros and cons in Figure Dr. Manan Pareek declares the following disclosures : Advisory Board − AstraZeneca, Janssen-Cilag; Speaker's Fee − AstraZeneca, Bayer, Boehringer Ingelheim, Janssen-Cilag. The other authors have no conflicts of interest to declare.There are no sources of funding.Anna Meta Dyrvig Kristensen, Manan Pareek, and Eva Irene Bossano Prescott drafted the manuscript. Anna Meta Dyrvig Kristensen, Manan Pareek, Eva Irene Bossano Prescott, Kristian Hay Kragholm, Thomas Steen Gyldenstierne Sehested, and Michael Hecht Olsen revised the manuscript for important intellectual content.