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Abstract Electrical stimulation holds promise for enhancing neuronal differentiation of neural stem cells to treat traumatic brain injury. However, once the stem cells leave the stimulating material and migrate post transplantation, electrical stimulation on them is diminished. Here, we wrap the stem cells with wireless electrical nanopatches, the conductive graphene nanosheets. Under electromagnetic induction, electrical stimulation can thus be applied in-situ to individual nanopatch-wrapped stem cells on demand, stimulating their neuronal differentiation through a MAPK/ERK signaling pathway. Consequently, 41% of the nanopatch-wrapped stem cells differentiate into functional neurons in 5 days, as opposed to only 16.3% of the unwrapped ones. The brain injury male mice implanted with the nanopatch-wrapped stem cells and exposed to a rotating magnetic field 30 min/day exhibit significant recovery of brain tissues, behaviors, and cognitions, within 28 days. This study opens up an avenue to individualized electrical stimulation of transplanted stem cells for treating neurodegenerative diseases.

ObjectivesThe study aimed to determine how foot strike patterns and cutting angles affect lower extremity (LE) kinematics, kinetics, and muscle activity during side-step cutting.MethodsTwenty male college sport athletes participated in this research. Three-dimensional motion analysis featuring ground reaction force (GRF) and electromyography (EMG) of the dominant leg was used. LE kinematics, kinetics, and EMG data parameters were obtained during a 45° and 90° side-step cutting involving rearfoot strikes (RFS) and forefoot strikes (FFS).ResultsThe significant foot strike pattern × angle interactions were observed for the ankle eversion range of motion (ROM) at the loading phase. Cutting of 90° had greater knee flexion ROM, knee valgus ROM, and knee varus moment compared to that of 45°. RFS cutting had greater knee flexion, hip flexion, knee valgus, knee varus moment, knee varus moment, and ankle eversion ROM. FFS cutting produced a lower vertical GRF, lateral GRF, and a loading rate. Both vastus medialis and vastus lateralis muscle activities were remarkably greater during cutting of 90° than 45°. At the loading phase, semitendinosus, biceps femoris, and the lateral head of gastrocnemius muscle activities during FFS cutting were considerably greater than those during RFS cutting.ConclusionThe FFS pattern can better protect the anterior cruciate ligament (ACL) and improve the flexibility of athletes by increasing the plantarflexion torque of the ankle. The injury risk also increases with the larger cutting angle. The EMG activities of semitendinosus and biceps femoris are vital for the stability of knee joint during side-step cutting, which helps reduce ACL stress during buffering.

【Objective】 Xinjiang in northwestern China is scarce in freshwater and commonly uses drip irrigation in its agricultural production. In this paper we study the effect of irrigation amount on growth, yield and water use efficiency (WUE) of spring wheat in the north of Xinjiang. 【Method】 The experiment was conducted in a field with the No. 6 variety used as the model plant. During its growth period, the crop was irrigated six times with irrigation amount in each time being 30, 37.5, 45, 52.5, 60, 67.5 mm, respectively. In each irrigation treatment, we measured the growth, yield and WUE of the spring wheat. 【Result】 Plant height increased with irrigation amount until the irrigation amount was 45 mm, after which a further increase in irrigation amount did not have a significant effect on plant height (P>0.05). The leaf area index (LAI) and the above-ground dry matter accumulation both increased with irrigation amount, but started to decline when irrigation amount exceeded 52.5 mm. The water consumption of the crop increased with irrigation amount, peaking when irrigation amount was 67.5 mm. The effective spike numbers, grain numbers per spike, 1000-grain weight, yield and WUE of the crop increased first and then declined as the irrigation amount increased. Among all treatments we compared, irrigating 52.5 mm of water in each of the six irrigations gave the highest yield and WUE, reaching 7 233.2 kg/hm2 and 15.23 kg/(hm2·mm), respectively (P

Abstract The occurrence of nonenzymatic glycosylation reactions in skin fibroblasts can lead to severe impairment of skin health. To investigate the protective effects of the major functional ingredient from Gentianaceae, gentiopicroside (GPS) on fibroblasts, network pharmacology was used to analyse the potential pathways and targets underlying the effects of GPS on skin. At the biochemical and cellular levels, we examined the inhibitory effect of GPS on AGEs, the regulation by GPS of key ECM proteins and vimentin, the damage caused by GPS to the mitochondrial membrane potential and the modulation by GPS of inflammatory factors such as matrix metalloproteinases (MMP-2, MMP-9), reactive oxygen species (ROS), and IL-6 via the RAGE/NF-κB pathway. The results showed that GPS can inhibit AGE-induced damage to the dermis via multiple pathways. The results of biochemical and cellular experiments showed that GPS can strongly inhibit AGE production. Conversely, GPS can block AGE-induced oxidative stress and inflammatory responses in skin cells by disrupting AGE-RAGE signalling, maintain the balance of ECM synthesis and catabolism, and alleviate AGE-induced dysfunctions in cellular behaviour. This study provides a theoretical basis for the use of GPS as an AGE inhibitor to improve skin health and alleviate the damage caused by glycosylation, showing its potential application value in the field of skin care.

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life cycle. The covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic use. Effective antiviral drugs are needed to fight the pandemic, while non-covalent Mpro inhibitors could be promising alternatives due to their high selectivity and favorable druggability. Numerous non-covalent Mpro inhibitors with desirable properties have been developed based on available crystal structures of Mpro. In this article, we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent Mpro inhibitors, followed by a general overview and critical analysis of the available information. Prospective viewpoints and insights into current strategies for the development of non-covalent Mpro inhibitors are also discussed.

Eurasian dryland ecosystems consist mainly of cropland and grassland, and their changes are driven by both natural factors and human activities. This study utilized the normalized difference vegetation index (NDVI), gross primary productivity (GPP) and solar-induced chlorophyll fluorescence (SIF) to analyze the changing characteristics of vegetation activity in Eurasia over the past two decades. Additionally, we integrated the mean annual temperature (MAT), the mean annual precipitation (MAP), the soil moisture (SM), the vapor pressure deficit (VPD) and the terrestrial water storage (TWS) to analyze natural factors’ influence on the vegetation activity from 2003 to 2022. Through partial correlation and residual analysis, we quantitatively described the contributions of both natural and human factors to changes in vegetation activity. The results indicated an overall increasing trend in vegetation activity in Eurasia; the growth rates of vegetation greenness, productivity and photosynthetic capacity were 1.00 × 10−3 yr−1 (p < 0.01), 1.30 g C m−2 yr−2 (p < 0.01) and 1.00 × 10−3 Wm−2μm−1sr−1yr−1 (p < 0.01), respectively. Furthermore, we found that soil moisture was the most important natural factor influencing vegetation activity. Human activities were identified as the main driving factors of vegetation activity in the Eurasian drylands. The relative contributions of human-induced changes to NDVI, GPP and SIF were 52.45%, 55.81% and 74.18%, respectively. These findings can deepen our understanding of the impacts of current natural change and intensified human activities on dryland vegetation coverage change in Eurasia.

Abstract Nuclear receptors (NRs) are important transcriptional factors that mediate autophagy, preventing podocyte injury and the progression of diabetic kidney disease (DKD). However, the role of nuclear receptor coactivators that are powerful enhancers for the transcriptional activity of NRs in DKD remains unclear. In this study, a significant decrease in Nuclear Receptor Coactivator 3 (NCOA3) is observed in injured podocytes caused by high glucose treatment. Additionally, NCOA3 overexpression counteracts podocyte damage by improving autophagy. Further, Src family member, Fyn is identified to be the target of NCOA3 that mediates the podocyte autophagy process. Mechanistically, NCOA3 regulates the transcription of Fyn in a nuclear receptor, PPAR‐γ dependent way. Podocyte‐specific NCOA3 knockout aggravates albuminuria, glomerular sclerosis, podocyte injury, and autophagy in DKD mice. However, the Fyn inhibitor, AZD0530, rescues podocyte injury of NCOA3 knockout DKD mice. Renal NCOA3 overexpression with lentivirus can ameliorate podocyte damage and improve podocyte autophagy in DKD mice. Taken together, the findings highlight a novel target, NCOA3, that protects podocytes from high glucose injury by maintaining autophagy.

The direct utilization of low-light images hinders downstream visual tasks. Traditional low-light image enhancement (LLIE) methods, such as Retinex-based networks, require image pairs. A spiking-coding methodology called intensity-to-latency has been used to gradually acquire the structural characteristics of an image. convLSTM has been used to connect the features. This study introduces a simplified DCENet to achieve unsupervised LLIE as well as the spiking coding mode of a spiking neural network. It also applies the comprehensive coding features of convLSTM to improve the subjective and objective effects of LLIE. In the ablation experiment for the proposed structure, the convLSTM structure was replaced by a convolutional neural network, and the classical CBAM attention was introduced for comparison. Five objective evaluation metrics were compared with nine LLIE methods that currently exhibit strong comprehensive performance, with PSNR, SSIM, MSE, UQI, and VIFP exceeding the second place at 4.4% (0.8%), 3.9% (17.2%), 0% (15%), 0.1% (0.2%), and 4.3% (0.9%) on the LOL and SCIE datasets. Further experiments of the user study in five non-reference datasets were conducted to subjectively evaluate the effects depicted in the images. These experiments verified the remarkable performance of the proposed method.

Abstract Cardiovascular diseases (CVDs) continue to exert a significant impact on global mortality rates, encompassing conditions like pulmonary arterial hypertension (PAH), atherosclerosis (AS), and myocardial infarction (MI). Oxidative stress (OS) plays a crucial role in the pathogenesis and advancement of CVDs, highlighting its significance as a contributing factor. Maintaining an equilibrium between reactive oxygen species (ROS) and antioxidant systems not only aids in mitigating oxidative stress but also confers protective benefits on cardiac health. Herbal monomers can inhibit OS in CVDs by activating multiple signaling pathways, such as increasing the activity of endogenous antioxidant systems and decreasing the level of ROS expression. Given the actions of herbal monomers to significantly protect the normal function of the heart and reduce the damage caused by OS to the organism. Hence, it is imperative to recognize the significance of herbal monomers as prospective therapeutic interventions for mitigating oxidative damage in CVDs. This paper aims to comprehensively review the origins and mechanisms underlying OS, elucidate the intricate association between CVDs and OS, and explore the therapeutic potential of antioxidant treatment utilizing herbal monomers. Furthermore, particular emphasis will be placed on examining the cardioprotective effects of herbal monomers by evaluating their impact on cardiac signaling pathways subsequent to treatment. Graphical Abstract

Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering pathogenic actions of hHcys are not fully understood. The present study was mainly designed to investigate the role of HDACs in renal injury induced by hHcys. Firstly, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC9 was preferentially upregulated in the kidney from mice with hHcys. Deficiency or pharmacological inhibition of HDAC9 ameliorated renal injury in mice with hHcys. Moreover, podocyte-specific deletion of HDAC9 significantly attenuated podocyte injury and proteinuria. In vitro, gene silencing of HDAC9 attenuated podocyte injury by inhibiting apoptosis, reducing oxidative stress and maintaining the expressions of podocyte slit diaphragm proteins. Mechanically, we proved for the first time that HDAC9 reduced the acetylation level of H3K9 in the promoter of Klotho, then inhibited gene transcription of Klotho, finally aggravating podocyte injury in hHcys. In conclusion, our results indicated that targeting of HDAC9 might be an attractive therapeutic strategy for the treatment of renal injury induced by hHcys.

Abstract Background Hepatocellular carcinoma (HCC) is a highly malignant type of tumor that is insensitive to cytotoxic chemotherapy and often develops drug resistance. Nevadensin, a bioflavonoid, exhibits anti-cancer properties in some cancers. However, the precise underlying mechanism of nevadensin against liver cancer are poorly understood. We aim to evaluate the efficacy as well as the molecular mechanism of nevadensin in the treatment of liver cancer. Methods Effects of nevadensin on HCC cell proliferation and apoptosis were detected using EdU labeling and flow cytometry assays. The molecular mechanism of nevadensin on HCC was determined using RNAseq. The effects of nevadensin on hippo-Yap signaling were verified using western blot and RT-PCR. Results In this study, we show that nevadensin significantly inhibits growth of HCC cells via inducing cell cycle arrest and apoptosis. RNAseq analysis showed that nevadensin regulates multiple functional signaling pathways associated with cancer including Hippo signaling. Western Blot analysis revealed that nevadensin notably induces activation of the MST1/2- LATS1/2 kinase in HCC cells, further resulting in the primary effector molecule YAP phosphorylation and subsequent degradation. These results indicated that nevadensin might exert its anti-HCC activity through the Hippo-ON mechanism. Moreover, nevadensin could increase the sensitivity of HCC cells to sorafenib by down-regulating YAP and its downstream targets. Conclusions The present study indicates that nevadensin could be a potential effective approach to treating HCC, and overcoming sorafeni resistance via inducing activation of Hippo signaling.

Abstract Renal tubular epithelial cells (TECs) play a key role in kidney fibrosis by mediating cycle arrest at G2/M. However, the key HDAC isoforms and the underlying mechanism that are involved in G2/M arrest of TECs remain unclear. Here, we find that Hdac9 expression is significantly induced in the mouse fibrotic kidneys, especially in proximal tubules, induced by aristolochic acid nephropathy (AAN) or unilateral ureter obstruction (UUO). Tubule-specific deletion of HDAC9 or pharmacological inhibition by TMP195 attenuates epithelial cell cycle arrest in G2/M, then reduces production of profibrotic cytokine and alleviates tubulointerstitial fibrosis in male mice. In vitro, knockdown or inhibition of HDAC9 alleviates the loss of epithelial phenotype in TECs and attenuates fibroblasts activation through inhibiting epithelial cell cycle arrest in G2/M. Mechanistically, HDAC9 deacetylates STAT1 and promotes its reactivation, followed by inducing G2/M arrest of TECs, finally leading to tubulointerstitial fibrosis. Collectively, our studies indicate that HDAC9 may be an attractive therapeutic target for kidney fibrosis.

Abstract Stroke has caused tremendous social stress worldwide, yet despite decades of research and development of new stroke drugs, most have failed and rt-PA (Recombinant tissue plasminogen activator) is still the accepted treatment for ischemic stroke. the complexity of the stroke mechanism has led to unsatisfactory efficacy of most drugs in clinical trials, indicating that there are still many gaps in our understanding of stroke. Pyroptosis is a programmed cell death (PCD) with inflammatory properties and are thought to be closely associated with stroke. Pyroptosis is regulated by the GSDMD of the gasdermin family, which when cleaved by Caspase-1/Caspase-11 into N-GSDMD with pore-forming activity can bind to the plasma membrane to form small 10–20 nm pores, which would allow the release of inflammatory factors IL-18 and IL-1β before cell rupture, greatly exacerbating the inflammatory response. The pyroptosis occurs mainly in the border zone of cerebral infarction, and glial cells, neuronal cells and brain microvascular endothelial cells (BMECs) all undergo pyroptosis after stroke, which largely exacerbates the breakdown of the blood-brain barrier (BBB) and thus aggravates brain injury. Therefore, pyroptosis may be a good direction for the treatment of stroke. In this review, we focus on the latest mechanisms of action of pyroptosis and the process by which pyroptosis regulates stroke development. We also suggest potential therapeutic stroke drugs that target the pyroptosis pathway, providing additional therapeutic strategies for the clinical management of stroke. The role of pyroptosis after stroke. After stroke, microglia first rush to the damaged area and polarize into M1 and M2 types. Under the influence of various stimuli, microglia undergo pyroptosis, release pro-inflammatory factors, and are converted to the M1 type; astrocytes and neuronal cells also undergo pyroptosis under the stimulation of various pro-inflammatory factors, leading to astrocyte death due to increased osmotic pressure in the membrane, resulting in water absorption and swelling until rupture. BMECs, the main structural component of the BBB, also undergo pyroptosis when stimulated by pro-inflammatory factors released from microglia and astrocytes, leading to the destruction of the structural integrity of the BBB, ultimately causing more severe brain damage. In addition, GSDMD in neutrophils mainly mediate the release of NETs rather than pyroptosis, which also aggravates brain injury. IL-10=interleukin-10; TGF-β = transforming growth factor-β; IL-18=interleukin-18; IL-1β = interleukin-1β; TNF-α = tumor necrosis factor-α; iNOS=induced nitrogen monoxide synthase; MMPs=Matrix metalloproteinases; GSDMD = gasdermin D; BMECs=brain microvascular endothelial cells; BBB = blood-brain barrier.

Summary: Background: Alzheimer's disease (AD) is a heterogeneously progressive neurodegeneration disorder with varied rates of deterioration, either between subjects or within different stages of a certain subject. Estimating the course of AD at early stages has treatment implications. We aimed to analyze disease progression to identify distinct patterns in AD trajectory. Methods: We proposed a deep learning model to identify underlying patterns in the trajectory from cognitively normal (CN) to a state of mild cognitive impairment (MCI) to AD dementia, by jointly predicting time-to-conversion and clustering out distinct subgroups characterized by comprehensive features as well as varied progression rates. We designed and validated our model on the ADNI dataset (1370 participants). Prediction of time-to-conversion in AD trajectory was used to validate the expression of the identified patterns. Causality between patterns and time-to-conversion was further inferred using Mendelian randomization (MR) analysis. External validation was performed on the AIBL dataset (233 participants). Findings: The proposed model clustered out patterns characterized by significantly different biomarkers and varied progression rates. The discovered patterns also showed a strong prediction ability, as indicated by hazard ratio (CN→MCI, HR = 3.51, p

Abstract Pulmonary hypertension (PH) was a cardiovascular disease with high morbidity and mortality. PH was a chronic disease with complicated pathogenesis and uncontrollable factors. PH was divided into five groups according to its pathogenesis and clinical manifestations. Although the treatment and diagnosis of PH has made great progress in the past ten years. However, the diagnosis and prognosis of the PAH had a great contrast, which was not conducive to the diagnosis and treatment of PH. If not treated properly, it will lead to right ventricular failure or even death. Therefore, it was necessary to explore the pathogenesis of PH. The problem we urgently need to solve was to find and develop drugs for the treatment of PH. We reviewed the PH articles in the past 10 years or so as well as systematically summarized the recent advance. We summarized the latest research on the key regulatory factors (pyroptosis, apoptosis, necroptosis, ferroptosis, and endoplasmic reticulum stress) involved in PH. To provide theoretical basis and basis for finding new therapeutic targets and research directions of PH.

Abstract Background The role of systemic inflammation in promoting cardiovascular diseases has attracted attention, but its correlation with various arrhythmias remains to be clarified. We aimed to comprehensively assess the association between various indicators of systemic inflammation and atrial fibrillation/flutter (AF), ventricular arrhythmia (VA), and bradyarrhythmia in the UK Biobank cohort. Methods After excluding ineligible participants, a total of 478,524 eligible individuals (46.75% male, aged 40–69 years) were enrolled in the study to assess the association between systemic inflammatory indicators and each type of arrhythmia. Results After covariates were fully adjusted, CRP levels were found to have an essentially linear positive correlation with the risk of various arrhythmias; neutrophil count, monocyte count, and NLR showed a non-linear positive correlation; and lymphocyte count, SII, PLR, and LMR showed a U-shaped association. VA showed the strongest association with systemic inflammation indicators, and it was followed sequentially by AF and bradyarrhythmia. Conclusions Multiple systemic inflammatory indicators showed strong associations with the onset of AF, VA, and bradyarrhythmia, of which the latter two have been rarely studied. Active systemic inflammation management might have favorable effects in reducing the arrhythmia burden and further randomized controlled studies are needed.

In this paper, the response surface method was used to study the technology of dyeing wool fiber with walnut green peel pigment under the microwave-assisted method. The optimized pigment extraction process were: ethanol volume fraction 60%, extraction time 1 min, liquid-material ratio 24:1, microwave power 450 W, and the optimized mordant fixation process were: mordant fixation time 3 min, microwave power 270 W, amount of mordant fixing agent 7%, reducing agent dosage 22 g/L. The results showed that the use of microwave-assisted and new mordant fixing agent lanthanum chloride greatly improved the extraction efficiency of pigments, saved extraction costs, and significantly shortened the mordant fixation time, resulting in an environmentally friendly mordant fixation process.

Objective: The glycation inhibition of 8 different non-Camellia teas was evaluated by detecting the content of non-enzymatic advanced glycation end-products (AGEs) and the inhibition mechanism of different teas with good inhibition effect on AGEs formation at various stages were investigated. Methods: Firstly, the total flavonoid content of the water extracts of 8 non-Camellia teas water extracts were detected, then all teas were tested by constructing an in vitro protein non-enzymatic glycation model experiment to evaluate the ability of inhibit the production of AGEs. Finally, the inhibitory ability of fructosamine (early glycation product), active carbonyl compound (intermediate glycation product), and the protein cross-linking were determined to explore the inhibitory mechanism of the non-enzymatic glycation reaction. Results: The inhibitory effect of Ilex latifolia tea and Rubus suavissimus tea on AGEs showed more prominent among the eight non-Camellia teas, and the inhibitory rate of AGEs reached at 76.31%±0.87% and 81.75%±0.41% at 50 µg/mL respectively. Further experimental results showed that Ilex latifolia tea and Rubus suavissimus tea mainly reduced the production of AGEs by inhibiting the formation of early and intermediate products of glycation, and 500 μg/mL Rubus suavissimus tea had the highest inhibition rate of fructosamine(59.12%) and protein cross-linking inhibition rate (81.41%), 5000 μg/mL Ilex latifolia tea had the highest inhibition rate of active carbonyl compounds (94.24%). Conclusion: Ilex latifolia tea and Rubus suavissimus tea could be used as functional foods to inhibit glycation reaction. This study could provide a theoretical basis for the comprehensive development and utilization of anti-glycation diet materials.

Although recent studies have indicated that mutations in the gene encoding diacylglycerol kinase epsilon (DGKE) result in some proteinuria related hereditary kidney diseases, the DGKE expression pattern in the kidney and its contribution to acute kidney injury (AKI) remain unknown. Therefore, the present study was designed to detect the role of DGKE in mice with AKI. DGKE expression was time-dependently altered in the kidneys of mice with renal ischemia/reperfusion injury (IRI). Compared with wild-type (WT) mice, DGKE- overexpressing mice (Rosa26-Dgke+/+) exhibited protective effects against renal IRI, including reduced serum creatinine, blood urea concentration, tubular cell death and inflammatory responses as well as improved morphological injuries. Consistently, in vitro, DGKE overexpression in human renal proximal tubule (HK-2) cells also protected against oxygen-glucose deprivation (OGD)/reoxygenation-induced cell death. Mechanistically, DGKE regulated Klotho expression, at least partly via the transcription factor Krüppel-like factor (KLF) 15. Moreover, a significant reduction in DGKE was also found in kidneys from patients with ischemia-associated acute tubular necrosis (ATN). Collectively, our studies demonstrate that DGKE protects against AKI in mice at least partly through KLF15/Klotho signaling pathway, indicating that DGKE may present an innovative therapeutic strategy for treating patients with AKI.

Abstract Geographical, environmental and pollution conditions affect facial skin health, but their effects on skin appearance have not been elucidated. This study aimed to describe the skin barrier and skin tone characteristics of Chinese subjects according to lifestyle and environmental conditions using in vitro measurements. In total, 1092 women aged 22–42 years were recruited from 7 representative Chinese cities. Eight skin parameters (hydration, sebum, pH, transdermal water loss, individual type angle, melanin index, erythema index, yellowness) were measured using noninvasive instruments; individual lifestyle data were also collected. Data on four meteorological factors (air temperature, relative humidity, sunshine duration, wind speed) and seven air pollution indicators (air quality index, fine particulate matter, breathable particulate matter, sulfur dioxide, nitrogen dioxide, carbon monoxide and ozone) were collected in each city from the China Meteorological Administration. Facial skin characteristics differed significantly between cities. Facial skin barrier characteristics and skin tones showed regional differences, with a better skin barrier associated with the western region, as indicated by high skin hydration and sebum secretion and a low pH value. According to the value of transdermal water loss, lighter and darker skin tones were found in the western and southern regions, respectively. Environmental conditions affected facial skin status. Air pollution induced facial skin issues, with fine particulate matter and nitrogen dioxide contributing the most. Individual lifestyles affected the facial skin barrier and skin tone.

【Background and objective】 Soil water is the main water resource for plants grown in the semi-arid loess plateau in northwestern China. Understanding its dynamics in response to environment and management changes is important to improve its use efficiency. The aim of this paper is to investigate the combined effect of land usage and topography on soil moisture. 【Method】 The experiment was conducted at a loess area in Ningwu county, Shanxi province. We measured soil water content in the depth of 0~200 cm under different conditions from July to September in 2020. The effect of land usage including artificial forest, natural grassland and cultivated land, on soil moisture at different locations in slopes and slope direction was analyzed and discussed. 【Result】 ①Temporal variation in soil moisture and precipitation was consistently correlated. With the increase in soil depth, soil moisture content decreased first followed by stabilization or increase at both the up-slope and the down-slope. In contrast, the change in soil moistures along the soil profiles in the gully bed was variable and did show any identifiable trend. ②Soil moisture content varied with land usage due to the difference in water consumption between the plants, with the soil moisture in the uphill varying with land usage in the order of natural grassland > cultivated land > artificial forest. In contrast, the soil moisture content at the gully bed varied with land usage in the order of forest land > cultivated land > natural grassland due to the low elevation of the artificial forest and its closeness to a river. ③On average, soil moisture content increased from the uphill to the gully bed, and the soil moisture in the shady slopes was greater than in the sunny slopes. 【Conclusion】 Our results show that to maintain soil moisture at ecologically functional levels, the best solution is to plant artificial forest with high water consumption at the downhill, gully bed and the shady slope, while letting the plants to grow naturally is suitable for the uphill and sunny slopes.

GIFs, short audio-free loops of moving sequences, are active members of social semiotic resources in the era of Internet 2.0 that could generate humor, mediate power and signal identity. This paper proposes the perspective of visual nominalization and visual telicity as GIF properties that, in the environment of social media technologies, become capable of expressing polyphonic evaluation, transcontexualized polysemy, and dual deixis. Visual nominalization expresses the freeing of movement from integration into a time-dependent narrative and the abstraction resulting in deemphasized participants and emphasized processes. These traits are activated and realized by visual telicity, which is looping movement that can be conceptualized as an atelic visual container which packages and expresses both telic and atelic processes. This paper argues that visual nominalization and visual telicity are what establishes GIFs’ semiotic differences from still images and film videos, and facilitates their integration with written language in online and computer-mediated discourse.

The areas affected by the L1 transfer to L2, such as phonotactics and stress, appear to have different degrees of erasability through training and practice. This paper attempts a theoretical analysis to account for empirical observations of L1 transfer in diphthong-coda coalescence and in sentence stress for Chinese learners of English in an American accent training course. Using the framework and tableau method of Optimality Theory (Prince and Smolensky 1993), the phonological paradigm that views languages’ differences as symptomatic of differences in rankings of a set of universal violable constraints, this paper posits the underlying ranking at work in (a) the segmental case where [aŋ] is the observed output for /aʊn/; (b) the suprasegmental case where no stress contrast is observed for a pair of phonologically similar sentences with contrastive stress. It is argued that, in the segmental case, the coalescence of the second vowel of a diphthong with an alveolar nasal coda results from the high ranking of markedness constraints, including Complex Syllable; and in the suprasegmental case, sentence stress is greatly affected by changes in the ranking of the constraint culminativity. Aside from shedding light on the understudied issue of diphthong-coda coalescence, this research also contributes to the discussion of the comparative erasability of L1 transfer for the two areas and demonstrates how a deduction-based theoretical method may actually have practical implications for guiding the design of L2 teaching methodology of English pronunciation as well as for promoting native English speakers’ clearer understanding of Chinese learners of English on the global stage.

Background: Kidney diseases are a prevalent health problem worldwide. Although substantial progress has been made in understanding the pathophysiology of kidney disease, currently there is no satisfactory clinical treatment available to prevent or treat kidney disease. Therefore, strategies to establish early diagnosis, identify the key molecules, and develop novel therapeutic interventions to slow the progression of kidney diseases and reduce their complications are encouraged. Summary: The growth factors play a crucial role in the development of kidney diseases. The altered levels of growth factors are usually detected in circulation and urine in the disease course. A growing body of studies has suggested that growth factors, receptors, and related regulators are promising biomarkers for the diagnosis and/or prognosis and potential therapeutic targets for the treatment of kidney diseases. In this review, we summarize recent advances in the potential applications of growth factors for diagnostic biomarkers and therapeutic targets in kidney diseases and highlight their performances in clinical trials. Key Messages: Most diagnostic and therapeutic strategies targeting growth factors are still far from clinical implementation. The better understanding of growth factor-regulated pathophysiology and the progress of new intervention approaches are expected to facilitate the clinical translation of growth factor-based diagnosis and therapy of kidney diseases.

Summary: Diabetic kidney disease (DKD) is the most prevalent chronic kidney disease. Macrophage infiltration in the kidney is critical for the progression of DKD. However, the underlying mechanism is far from clear. Cullin 4B (CUL4B) is the scaffold protein in CUL4B-RING E3 ligase complexes. Previous studies have shown that depletion of CUL4B in macrophages aggravates lipopolysaccharide-induced peritonitis and septic shock. In this study, using two mouse models for DKD, we demonstrate that myeloid deficiency of CUL4B alleviates diabetes-induced renal injury and fibrosis. In vivo and in vitro analyses reveal that loss of CUL4B suppresses migration, adhesion, and renal infiltration of macrophages. Mechanistically, we show that high glucose upregulates CUL4B in macrophages. CUL4B represses expression of miR-194-5p, which leads to elevated integrin α9 (ITGA9), promoting migration and adhesion. Our study suggests the CUL4B/miR-194-5p/ITGA9 axis as an important regulator for macrophage infiltration in diabetic kidneys.

Summary: Background: Only a minority of melanoma patients experience durable responses to immunotherapies due to inter- and intra-tumoral heterogeneity in melanoma. As a result, there is a pressing need for suitable preclinical models to investigate resistance mechanisms and enhance treatment efficacy. Methods: Here, we report two different methods for generating melanoma patient-derived organoids (MPDOs), one is embedded in collagen gel, and the other is inlaid in Matrigel. MPDOs in Matrigel are used for assessing the therapeutic effects of anti-PD-1 antibodies (αPD-1), autochthonous tumor infiltrating lymphocytes (TILs), and small molecule compounds. MPDOs in collagen gel are used for evaluating the chemotaxis and migratory capacity of TILs. Finding: The MPDOs in collagen gel and Matrigel have similar morphology and immune cell composition to their parental melanoma tissues. MPDOs show inter- and intra-tumoral heterogeneity and contain diverse immune cells such as CD4+, CD8+ T, Treg, CD14+ monocytic, CD15+, and CD11b+ myeloid cells. The tumor microenvironment (TME) in MPDOs is highly immunosuppressive, and the lymphoid and myeloid lineages express similar levels of PD-1, PD-L1, and CTLA-4 as their parental melanoma tissues. Anti-PD-1 antibodies (αPD-1) reinvigorate CD8+ T cells and induce melanoma cell death in the MPDOs. TILs expanded by IL-2 and αPD-1 show significantly lower expression of TIM-3, better migratory capacity and infiltration of autochthonous MPDOs, and more effective killing of melanoma cells than TILs expanded by IL-2 alone or IL-2 with αCD3. A small molecule screen discovers that Navitoclax increases the cytotoxicity of TIL therapy. Interpretation: MPDOs may be used to test immune checkpoint inhibitors and cellular and targeted therapies. Funding: This work was supported by the NIH grants CA114046, CA261608, CA258113, and the Tara Miller Melanoma Foundation.

Objective To investigate the efficacy and safety of combined anticoagulants with endovascular treatment for subacute and chronic cerebral venous sinus thrombosis (CVST) under the assistance of high resolution magnetic resonance black⁃blood thrombus imaging (MRBTI). Methods and Results A retrospective study was performed on the patients with CVST who were treated at Department of Neurosurgery of Tianjin Huanhu Hospital from January 2019 to January 2021. Preoperative high resolution MRBTI confirmed 15 patients with subacute and chronic CVST, and endovascular treatment was performed on the basis of systemic anticoagulant therapy. The results showed that 10 cases were in subacute stage and 5 cases were in chronic stage. After treatment, the venous sinus was completely recanalized in 4 cases and partially recanalized in 11 cases. Complications occurred in 2 cases (intracranial hematoma enlarged in one case, microguide wire penetrated straight sinus wall during surgery in one case), contact thrombolytic therapy was continued after the condition stabilized. The mean indwelling time of microcatheter in straight sinus was (6.27 ± 0.21) d and the mean length of hospital stay was (11.53 ± 1.30) d. The degree of impairment of consciousness [Glasgow Coma Scale (GCS) score] was improved at discharge [at discharge (13.67 ± 2.02) score vs. at admission (11.67 ± 2.13) score; t = 9.165, P = 0.000], the degree of neurological impairment [modified Rankin Scale (mRS) score] was improved 6 months after surgery [at 6 months after surgery 1 (0, 2) score vs. at admission 3 (2, 4) score; Z = ⁃ 3.624, P = 0.000]. Conclusions High resolution MRBTI is an effective technique to identify subacute and chronic CVST patients. For these patients, the combination of systemic anticoagulation and endovascular treatment can reduce venous sinus thrombosis load and improve symptoms in a short time, which is a safe, effective and preferred treatment.

Oasis vegetation contains a variety of ecological functions and can quickly indicate changes in the environment. According to the vegetation dynamics of natural oasis, this study constructed a natural oasis ecological vulnerability assessment model (NOEV) The model is based on Pressure-Sensitivity-Resilience framework, combined with redundancy analysis, minimum cumulative resistance model, and ecological risk sensitivity index to effectively assess the ecological vulnerability of natural oasis. The results showed that human activities, represented by the expansion of farmland and population growth, were the main factors affecting the vegetation dynamics of natural oasis in the last 30 years, and their contribution to the change of vegetation area is 42.08%. In the temporal dynamics, a serie of economic and environmental policies implemented by the government after the 21st century have promoted the recovery of vegetation. Vulnerability decreased on the whole oasis but increased in some local areas during 2005–2020. In the spatial dynamics, the transition zone of vulnerability from high to low occurred, it a distance of approximately 30 km from an artificial oasis located also in the area. We suggest that the governments should set up an ecological buffer zone in this area and implement different environmental protection policies inside and outside the buffer zone. Few vulnerability assessment models have been constructed for oasis ecosystems, and the NOEV model constructed in this study helps to formulate more direct and effective policy recommendations for the government's ecological protection and restoration work.

The extraction of active substances and other nutrient elements from Lycium barbarum and their application in food, medicine, and cosmetics have always been one of the hot topics for scholars in related fields. However, the residue after the extraction still contains melanoidin, which is an important substance that can be used as an environmentally friendly pigment in the coloring of textiles. Therefore, the rational utilization of the by-products after the processing of Lycium barbarum is the key to sustainable development. For this reason, Lycium barbarum residue was used as the raw material to extract textile-grade dyestuff in this work. The phospholipid microcapsules dyeing process of melanoidin dyestuff from Lycium barbarum residue was optimized by the response surface optimization as follows: liquor ratio of 1:35.15, pH of 4.22 and dyeing temperature of 75.8°C. The results showed that the dyeing temperature reduced by 15°C during the dyeing process by using melanoidins microcapsules dyestuff. Dyed wool fabric with biomordant (pomegranate skin) and after-chrome dyeing has high color fastness, antioxidant, and antibacterial property, which greatly increases the added value of the dyed products.

Exploiting their sensitivity to cloud droplets and small raindrops, Ka-band cloud radar observations are used to investigate weak stratiform precipitation over Wuhan during cooling on 16–17 February 2022. During cooling, the surface temperature drops by about 8 °C with the lowest value less than 0 °C because of the strong cold air from the north. The cold air lifts the warm and humid air transported by the southeasterly and southwesterly winds, causing thick stratiform clouds and persistent weak precipitation. The Ka-band radar captures the full process of stratiform cloud occurrence; light rain and then mixed rain and snow; and the characteristics of clouds and precipitation at each stage due to its fine sensitivity to small hydrometeors, whereas the reanalysis data alone cannot capture the transition to the mixed rain and snow regime, which can cause dangerous freezing rain or sleet on the ground. Hence, a detailed analysis of cooling and cold surges and their hazards to society, and their reproduction in numerical predictions, needs to use high-sensitivity radar data as much as possible.

Based on Microwave Radiometer (MWR) observations in Wuhan over the course of 21 months, we compared the temperature and water vapor levels with those from radiosonde (RS) sounding data at 00:00 and 12:00 UTC, and then analyzed the seasonal and diurnal changes of temperature and water vapor levels from the MWR data. The MWR and RS mean temperatures and dew points are roughly consistent with each other below 2 km, whereas above 2 km, the MWR temperature is slightly lower than the RS temperature. The difference in their water vapor densities decreases quickly with height, and the bias of their relative humidities is generally in the range of −15% to 20%. The MWR observations show that in autumn, the surface temperature is 6.8 K lower during precipitation events than during non-precipitation events, indicating that precipitation in autumn is mainly caused by cold air from the north. The relative humidity during precipitation events exceeds 90% from the ground to 5 km, which is obviously larger than during non-precipitation events. During non-precipitation events, the seasonal mean water vapor density at 0–1.0 km shows an approximately linear increase with the mean temperature; however, their diurnal changes are opposite due to the effect of the boundary layer. At 4.5–5.5 km and 8.5–9.5 km, the mean temperature shows a synchronized diurnal evolution, with the maximum value prior to that at 0–1.0 km, indicating the strong influence of the air–land interaction on the temperature near the ground. Hence, this study is helpful for deepening our understanding of temperature and humidity variabilities over Wuhan.

Background: Podocytes, functionally specialized and terminally differentiated glomerular visceral epithelial cells, are critical for maintaining the structure and function of the glomerular filtration barrier. Podocyte injury is considered as the most important early event contributing to proteinuric kidney diseases such as obesity-related renal disease, diabetic kidney disease, focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. Although considerable advances have been made in the understanding of mechanisms that trigger podocyte injury, cell-specific and effective treatments are not clinically available. Summary: Emerging evidence has indicated that the disorder of podocyte lipid metabolism is closely associated with various proteinuric kidney diseases. Excessive lipid accumulation in podocytes leads to cellular dysfunction which is defined as lipotoxicity, a phenomenon characterized by mitochondrial oxidative stress, actin cytoskeleton remodeling, insulin resistance, and inflammatory response that can eventually result in podocyte hypertrophy, detachment, and death. In this review, we summarize recent advances in the understanding of lipids in podocyte biological function and the regulatory mechanisms leading to podocyte lipid accumulation in proteinuric kidney disease. Key Messages: Targeting podocyte lipid metabolism may represent a novel therapeutic strategy for patients with proteinuric kidney disease.

Traditional Chinese medicine has been proven to be of great significance in cardioprotective effects. Clinopodium chinense (Lamiaceae) has unique advantages in the treatment and prevention of cardiovascular diseases. Tournefolic acid B (TAB) was proven to be a potent component against myocardial ischemia reperfusion injury (MIRI) from Clinopodium chinense (Lamiaceae). This article will attempt to establish a gram-scale synthesis method of TAB and discuss the structure-activity relationship of its analogs. The total synthesis of TAB was completed in 10 steps with an overall yield of 13%. In addition, analogs were synthesized, and their cardioprotective activity was evaluated on the hypoxia/reoxygenation of H9c2 cells. Amidation of the acid position is helpful to the activity, while methylation of phenolic hydroxyl groups greatly decreased the cardioprotective activity. The easily prepared azxepin analogs also showed cardioprotective activity. Most of the clogP values calculated by Molinspiration ranged from 2.5 to 5, which is in accordance with Lipinski’s rule of 5. These findings represent a novel kind of cardioprotective agent that is worthy of further study.

Abstract In the recent two decades, the progressive collapse of reinforced concrete (RC) frame structures attracted unprecedented research interests in the structural engineering community. Experiments are regarded as an essential method in this field since actual cases can barely provide sufficient and effective data to support rigorous research. In this paper, prevailing experimental assumptions and configurations among over 100 series of experiments are quantitatively revealed by a bibliometric collection based on systematic search in an academic database. Since numerous experiments have been reported on the progressive collapse of RC frame structures, this paper subsequently presents a state-of-the-art review summarizing both experimental consensuses and controversies constituted by three main aspects: (a) static mechanisms, (b) dynamic behavior, and (c) threat-dependent research. The significance of secondary mechanisms, existing problems of dynamic effects, and potential flaws of the threat-independent assumption are discussed in detail with experimental findings. Future needs are emphasized on research targets, correlations between experiments and design, dynamic effects, threat-dependent issues, and retrofitting. These recommendations might help researchers or designers realize a more reliable and realistic progressive collapse design of RC frame structures in the future.

BackgroundUrinary tract infections (UTIs) are one of the most common infections worldwide, but little is known about their global scale and long-term trends. We aimed to estimate the spatiotemporal patterns of UTIs' burden along with its attributable risk factors at a global level, as well as the variations of the burdens according to socio-demographic status, regions, nations, sexes, and ages, which may be helpful in guiding targeted prevention and treatment programs.MethodsData from the Global Burden of Disease Study 2019 were analyzed to depict the incidence, mortality, and disability-adjusted life years (DALYs) of UTIs in 204 countries and territories from 1990 to 2019 by socio-demographic status, nations, region, sex, and age.ResultsGlobally, 404.61 million cases, 236,790 deaths, and 520,200 DALYs were estimated in 2019. In particular, 2.4 times growth in deaths from 1990 to 2019 was observed, along with an increasing age-standardized mortality rate (ASMR) from 2.77/100,000 to 3.13/100,000. Age-standardized incidence rate (ASIR) was consistently pronounced in regions with higher socio-demographic index (SDI), which presented remarkable upward trends in ASMR and age-standardized DALY rate (ASDR). In contrast, countries with a low SDI or high baseline burden achieved a notable decline in burden rates over the past three decades. Although the ASIR was 3.6-fold higher in females than males, there was no sex-based difference in ASMR and ASDR. The burden rate typically increased with age, and the annual increasing trend was more obvious for people over 60 years, especially in higher SDI regions.ConclusionsThe burden of UTIs showed variations according to socio-demographic status, nation, region, sex, and age in the last three decades. The overall increasing burden intimates that proper prevention and treatment efforts should be strengthened, especially in high-income regions and aging societies.

Although macrophages are undoubtedly attractive therapeutic targets for acute kidney injury (AKI) because of their critical roles in renal inflammation and repair, the underlying mechanisms of macrophage phenotype switching and efferocytosis in the regulation of inflammatory responses during AKI are still largely unclear. The present study elucidated the role of junctional adhesion molecule–like protein (JAML) in the pathogenesis of AKI. We found that JAML was significantly upregulated in kidneys from 2 different murine AKI models including renal ischemia/reperfusion injury (IRI) and cisplatin-induced AKI. By generation of bone marrow chimeric mice, macrophage-specific and tubular cell–specific Jaml conditional knockout mice, we demonstrated JAML promoted AKI mainly via a macrophage-dependent mechanism and found that JAML-mediated macrophage phenotype polarization and efferocytosis is one of the critical signal transduction pathways linking inflammatory responses to AKI. Mechanistically, the effects of JAML on the regulation of macrophages were, at least in part, associated with a macrophage-inducible C-type lectin–dependent mechanism. Collectively, our studies explore for the first time to our knowledge new biological functions of JAML in macrophages and conclude that JAML is an important mediator and biomarker of AKI. Pharmacological targeting of JAML-mediated signaling pathways at multiple levels may provide a novel therapeutic strategy for patients with AKI.

Ubiquitination has an important function in the regulation of antiviral immunity involving the signalling molecule MAVS. Here the authors investigate deubiquitinating enzymes and show USP18 regulates MAVS mediated antiviral signalling through modulating the ubiquitination of MAVS via promotion of interaction between MAVS and TRIM31.

The intracranial blood blister⁃like aneurysms (BBA) arising from the supraclinoid segment of internal carotid artery are very rary, and grow aggressively with high reruptured rate and mortality. Currently, the treatment methods of BBA are various but achieve no consensus, although including microsurgery and interventional therapy. The article collects the recent research and makes a review of the therapeutic progress of BBA, in order to provide clinical basis for the treatment of BBA and improve its therapeutic effect. doi：10.3969/j.issn.1672⁃6731.2021.04.016

Objective To investigate the role of P2X3 receptor in dorsal root ganglion (DRG) in bladder micturition function due to colitis-induced bladder dysfunction in the rat model of 2, 4, 6-trinitrosulfonic acid (TNBS)-induced colitis. Methods Female SD rats were randomly divided into control group, TNBS-3d and TNBS-7d groups. The rat model of colitis was induced with 50% TNBS ethanol solution (100 mg/kg) by clyster, and the rats from the control group were clystered by isopyknic normal saline. In 3 or 7 d after clyster, the colon and bladder tissue of rats were collected for HE staining and Nissl Staining. Cystometry was performed to observe the bladder micturition function. Immunofluorescence staining was carried out to detect the expression of P2X3 receptor in DRG. The effect of P2X3 on colitis-induced bladder dysfunction was observed by intrathecal injection of P2X3 receptor inhibitor A-317491. Results The colons of TNBS-induced colitis rats showed mucosal hyperemia and edema and inflammatory cell infiltration. There were no histopathological changes in the bladder among the 3 groups. Compared to the control group, there were larger number of mast cells observed in the bladder from the TNBS-3d and TNBS-7d groups. The results of cystometry showed that the intercontractile interval of bladder (ICI) was significantly decreased and maximum bladder pressure (MBP) was obviously increased in the TNBS-3d group than the control group (P < 0.01). Similarly, the ICI in TNBS-7d group was significantly decreased (P < 0.01), but MBP did not differ from the control group. The number of P2X3 positive neurons in DRG from the TNBS-3d and TNBS-7d groups was increased significantly compared to the control group (P < 0.01). Intrathecal injection of P2X3 inhibitor A-317491 significantly prolonged the interval of micturition (P < 0.01) in the TNBS-3d and TNBS-7d groups and reduced the maximum bladder pressure in TNBS-3d groups (P < 0.05). Conclusion P2X3 receptor in DRG plays an important role in the pathophysiological process of bladder overactivity induced by colitis, and inhibition of P2X3 receptor in DRG may be an effective treatment strategy for the overactive bladder.

Advanced glycation end products (AGEs) are a series of stable compounds produced under non-enzymatic conditions by the amino groups of biomacromolecules and the free carbonyl groups of glucose or other reducing sugars commonly produced by thermally processed foods. AGEs can cause various diseases, such as diabetes, atherosclerosis, neurodegeneration, and chronic kidney disease, by triggering the receptors of AGE (RAGEs) in the human body. There is evidence that AGEs can also affect the different structures and physiological functions of the skin. However, the mechanism is complicated and cumbersome and causes various harms to the skin. This article aims to identify and summarise the formation and characteristics of AGEs, focussing on the molecular mechanisms by which AGEs affect the composition and structure of normal skin substances at different skin layers and induce skin issues. We also discuss prevention and inhibition pathways, provide a systematic and comprehensive method for measuring the content of AGEs in human skin, and summarise and analyse their advantages and disadvantages. This work can help researchers acquire a deeper understanding of the relationship between AGEs and the skin and provides a basis for the development of effective ingredients that inhibit glycation.

BackgroundFacial skin is exposed to the environment, which marks it with obvious signs of aging. Based on multi-dimensional non-invasive evaluation data, female facial skin can be characterized in detail. However, there are few studies on the general aging rules of facial skin. Most skin aging studies divide the ages into 5–10-year intervals, so they have lacked dynamic matching with facial skin aging.AimTo explore facial skin aging rules, discuss the main parameters of facial skin aging, propose an unequal-distance aging division method based on the main skin parameters, and study the skin characteristics of Chinese women of different aging stages.MethodsWe comprehensively described the skin status as 24 non-invasive skin parameters belonging to five dimensions: skin wrinkles, texture, stain, color and barrier function. We performed polynomial fitting on the 21 skin parameters that were significantly correlated with age and derived the rules of aging in the different dimensions. Based on the wrinkle dimension, the facial skin aging process was divided into four stages, and the skin characteristics of the different stages were compared.ResultsSkin wrinkles increased, texture deteriorated, acne decreased, pigment spots increased, skin tone darkened, and sebum secretion decreased with age, according to the polynomial fitting. The aging stage was divided into an incubation period (18–30 years old), an aging occurrence period (31–42 years old), a rapid aging period (43–47 years old), and a stable aging period (48–60 years old), according to the wrinkles. Different aging stages had different skin characteristics.ConclusionThe incubation period is the critical period for the appearance of skin stains; the skin texture gradually deteriorates during the aging occurrence period; the rapid aging period is a critical period for the aging of skin parameters; skin status during the stable aging period is the worst.

BackgroundLymphopenia is a known significant factor for treatment outcome in cancer patients, with underlying risk factor poorly understood in breast cancer. We hypothesize that the effective dose to the circulating immune cells (EDIC) which was related with lymphopenia in lung cancer will also have significant effect for radiation induced lymphopenia (RIL) in patients with breast cancer.Material and MethodsPatients treated with adjuvant radiotherapy (RT) and with complete blood tests within one week from RT end/start (post/preRT) were eligible in this study. Radiation dosimetric factors were collected retrospectively, and EDIC for each patient was calculated based on the doses to lung, heart and total body according to the model description, as previously reported. RIL was defined by the CTCAE5.0 based on postRT peripheral lymphocyte count (PLC). Linear regression was first used to test the correlation between EDIC with post/preRT PLC ratio and postRT PLC, using all these as continuous variables. Normal tissue complication probability (NTCP) was used to develop models that predict the CTCAE graded RIL from EDIC.ResultsA total of 735 patients were eligible. The mean post/preRT PLC ratio was 0.66 (95% CI: 0.64-0.68) and mean EDIC of breast cancer was 1.70Gy (95% CI: 1.64-1.75). Both post/preRT PLC ratio and postRT PLC were significantly correlated with EDIC (P