bluuebunny/crossref_metadata_2025 huggingface dataset:
Are Social and Ethnic Reading Inequalities Increasing During School Closures?—The Mediating Role of Parental Involvement in Distance Learning
Authors: Weber Christoph , Helm Christoph , Kemethofer David
Published: December 2021

From spring 2020 many countries throughout Europe and beyond temporarily closed schools to tackle the spread of the coronavirus. First studies indicate that these school closures resulted in lower learning gains compared to learning gains in preceding years and widened social and ethnic disparities by affecting disadvantaged students more strongly than their more advantaged peers. Moreover, during school closures, parental involvement in distance learning is regarded as crucial for successful learning, especially for younger children. In the current study, we examine whether social and ethnic disparities in the reading achievement of primary school students widened during COVID-related school closures in spring 2020 and whether increased disparities are mediated by parental involvement in distance learning. We use data from 409 Austrian 2nd graders, whose teachers participated in an ongoing study on the use of learning progress assessment. Adopting a within-subject design, we first compare the effects of social and ethnic family background on reading achievement during a pre-lockdown period with the respective effects during a lockdown period of similar length. Controlling for pre-lockdown reading differences, we found that low socioeconomic status and non-German language use at home negatively predicted post-lockdown reading achievement, indicating that post-lockdown disparities were larger than expected due to disparities at pre-lockdown. In contrast, we found no such effects during the pre-lockdown period. Second, a series of mediation models did not provide any support for the hypothesis that parental involvement accounted for family background effects on reading achievement during the lockdown period.
Putrescine as a Novel Biomarker of Maternal Serum in First Trimester for the Prediction of Gestational Diabetes Mellitus: A Nested Case-Control Study
Authors: Liu Cheng , Wang Yuanyuan , Zheng Wei , Wang Jia , Zhang Ya , Song Wei , Wang Aili , Ma Xu , Li Guanghui
Published: December 2021

Aims

Early identification of gestational diabetes mellitus (GDM) aims to reduce the risk of adverse maternal and perinatal outcomes. Currently, no acknowledged biomarker has proven clinically useful for the accurate prediction of GDM. In this study, we tested whether serum putrescine level changed in the first trimester and could improve the prediction of GDM.

Methods

This study is a nested case-control study conducted in Beijing Obstetrics and Gynecology Hospital. We examined serum putrescine at 8-12 weeks pregnancy in 47 women with GDM and 47 age- and body mass index (BMI)-matched normoglycaemic women. Anthropometric, clinical and laboratory variables were obtained during the same period. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to assess the discrimination and calibration of the prediction models.

Results

Serum putrescine in the first trimester was significantly higher in women who later developed GDM. When using putrescine alone to predict the risk of GDM, the AUC of the nomogram was 0.904 (sensitivity of 100% and specificity of 83%, 95% CI=0.832–0.976, P<0.001). When combined with traditional risk factors (prepregnant BMI and fasting blood glucose), the AUC was 0.951 (sensitivity of 89.4% and specificity of 91.5%, 95% CI=0.906-0.995, P<0.001).

Conclusion

This study revealed that GDM women had an elevated level of serum putrescine in the first trimester. Circulating putrescine may serve as a valuable predictive biomarker for GDM.
A Low-Carbohydrate Diet Realizes Medication Withdrawal: A Possible Opportunity for Effective Glycemic Control
Authors: Han Yuxin , Cheng Bingfei , Guo Yanjun , Wang Qing , Yang Nailong , Lin Peng
Published: December 2021

Objective

Multiple studies have confirmed that diet restrictions can effectively realize glycemic control and reduce metabolic risks in patients with type 2 diabetes mellitus (T2DM). In 2018, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) stated that individuals can select a low-carbohydrate diet (LCD) according to their needs and preferences. Owing to the influence of Chinese traditional eating habits, only a small portion of patients in China have achieved their blood glucose goals. As a result, the Chinese government will incur huge expenditures.

Method

This study recruited 134 T2DM participants and randomly assigned them to the LCD group (n = 67) or the low-fat diet (LFD) group (n = 67). All of the patients had a fixed amount of exercise and were guided by clinicians. After a period of dietary washout, all of the patients received corresponding dietary education according to group. The follow-up time was 6 months. The indicators for anthropometry, glycemic control, and medication application parameters were collected and compared between the two groups.

Results

There were 121 participants who finally entered the study. The proportions of calories from three major nutrients the participants consumed met the requirements of LCD and LFD. Compared with baseline, the pre-postdifferences of body weight, BMI, and several other indicators were significant except for dosages of insulin used in the LCD group and MES in the LFD group. After the intervention, body weight, body weight index (BMI), fasting blood glucose (FBG), postprandial 2-h blood glucose (PPG), and glycosylated hemoglobin (HbA1c) levels in the LCD group decreased significantly (p < 0.05) compared with the LFD group. The number of patients using lipid-lowering agents was significant higher in the LCD group and lower in the LFD group. However, there was no significant difference between the two groups for antihypertensive, hormone-replacement, and other agents.

Conclusions

The LCD diet can decrease body weight, glycemic levels, MES, and lipid-lowering agents more than the LFD diet, thus decreasing cost burden in Chinese patients with T2DM. Strict diet control and monitoring are the keys to managing diabetes.
Transfer-Based Deep Neural Network for Fault Diagnosis of New Energy Vehicles
Authors: Wang Yuping , Li Weidong
Published: December 2021

New energy vehicles are crucial for low carbon applications of renewable energy and energy storage, while effective fault diagnostics of their rolling bearings is vital to ensure the vehicle’s safe and effective operations. To achieve satisfactory rolling bearing fault diagnosis of the new energy vehicle, a transfer-based deep neural network (DNN-TL) is proposed in this study by combining the benefits of both deep learning (DL) and transfer learning (TL). Specifically, by first constructing the convolutional neural networks (CNNs) and long short-term memory (LSTM) to preprocess vibration signals of new energy vehicles, the fault-related preliminary features could be extracted efficiently. Then, a grid search method called step heapsort is designed to optimize the hyperparameters of the constructed model. Afterward, both feature-based and model-based TLs are developed for the fault condition classifications transfer. Illustrative results show that the proposed DNN-TL method is able to recognize different faults accurately and robustly. Besides, the training time is significantly reduced to only 18s, while the accuracy is still over 95%. Due to the data-driven nature, the proposed DNN-TL could be applied to diagnose faults of new energy vehicles, further benefitting low carbon energy applications.
Two Novel Disease-Causing Mutations in the LDLR of Familial Hypercholesterolemia
Authors: Hu Haochang , Shu Tian , Ma Jun , Chen Ruoyu , Wang Jian , Wang Shuangshuang , Lin Shaoyi , Chen Xiaomin
Published: December 2021

As an autosomal dominant disorder, familial hypercholesterolemia (FH) is mainly caused by pathogenic mutations in lipid metabolism-related genes. The aim of this study is to investigate the genetic mutations in FH patients and verify their pathogenicity. First of all, a pedigree investigation was conducted in one family diagnosed with FH using the Dutch Lipid Clinic Network criteria. The high-throughput sequencing was performed on three family members to explore genetic mutations. The effects of low-density lipoprotein receptor (LDLR) variants on their expression levels and activity were further validated by silico analysis and functional studies. The results revealed that LDLC levels of the proband and his daughter were abnormally elevated. The whole-exome sequencing and Sanger sequencing were used to confirm that there were two LDLR missense mutations (LDLR c.226 G > C, c.1003 G > T) in this family. Bioinformatic analysis (Mutationtaster) indicated that these two mutations might be disease-causing variants. In vitro experiments suggested that LDLR c.226 G > C and c.1003 G > T could attenuate the uptake of Dil-LDL by LDLR. In conclusion, the LDLR c.226 G > C and c.1003 G > T variants might be pathogenic for FH by causing uptake dysfunction of the LDLR.
Alpha-2-Macroglobulin in Inflammation, Immunity and Infections
Authors: Vandooren Jennifer , Itoh Yoshifumi
Published: December 2021

Alpha-2-macroglobulin is an extracellular macromolecule mainly known for its role as a broad-spectrum protease inhibitor. By presenting itself as an optimal substrate for endopeptidases of all catalytic types, alpha-2-macroglobulin lures active proteases into its molecular cage and subsequently ‘flags’ their complex for elimination. In addition to its role as a regulator of extracellular proteolysis, alpha-2-macroglobulin also has other functions such as switching proteolysis towards small substrates, facilitating cell migration and the binding of cytokines, growth factors and damaged extracellular proteins. These functions appear particularly important in the context of immune-cell function. In this review manuscript, we provide an overview of all functions of alpha-2-macroglobulin and place these in the context of inflammation, immunity and infections.
Sediment Features and Human Activities Structure the Surface Microbial Communities of the Venice Lagoon
Authors: Banchi Elisa , Del Negro Paola , Celussi Mauro , Malfatti Francesca
Published: December 2021

Sediment microbial communities play essential roles in marine ecosystem functioning. Their study is crucial to understand how environmental conditions affect microbial diversity and biogeochemical cycles. The Venice Lagoon, one of the largest Adriatic transitional systems, is subjected to different natural and anthropogenic stressors. In this study, surface sediments microbial communities were finely characterized using 16S rRNA gene amplicon sequencing and metagenomics. Samples were collected seasonally in 2019 and 2020 at different sites within Lagoon sub-basins. Our results indicated a stable spatial distribution of the sediment microbiome: salinity, grain size, and total organic carbon were found to be important drivers in shaping prokaryotic communities, while temperature had a minor role. We detected high microbial diversity at all stations, mainly due to low abundant taxa: bacteria represented the vast majority of the reads (∼96.1%), with Woeseia the most abundant genus (∼4.4%). The metagenomic analysis highlighted significant differences among sites in terms of biogeochemical processes (e.g., C, N, Fe, and S metabolism), and cell-cell interaction strategies (e.g., mobilome, regulations and cell signaling). Chioggia, a sandy site subjected to marine influence, presented the highest abundance of ammonia-oxidizing archaeon Candidatus Nitrosopumilus, in accordance with the highest amount of ammonia monooxygenase subunit genes. At the same site, sulfate-reducing bacteria (Desulfobacteria and Desulfobacterales) and sulfur-related genes were found in lower abundance. Marghera and Tresse, the most polluted sites, showed higher abundance of sewage-related bacteria and antibiotic and toxic compound resistance genes. Furthermore, these sites showed higher amount of genes related to cell-cell interaction, such as pathogenicity islands, transposable-elements, and biofilm formation. Our findings highlighted that sediment features and human-related activities have profound and long-term impacts on the surface sediment microbial communities of the Venice Lagoon.
A Robust Training Method for Pathological Cellular Detector via Spatial Loss Calibration
Authors: Li Hansheng , Kang Yuxin , Yang Wentao , Wu Zhuoyue , Shi Xiaoshuang , Liu Feihong , Liu Jianye , Hu Lingyu , Ma Qian , Cui Lei , Feng Jun , Yang Lin
Published: December 2021

Computer-aided diagnosis of pathological images usually requires detecting and examining all positive cells for accurate diagnosis. However, cellular datasets tend to be sparsely annotated due to the challenge of annotating all the cells. However, training detectors on sparse annotations may be misled by miscalculated losses, limiting the detection performance. Thus, efficient and reliable methods for training cellular detectors on sparse annotations are in higher demand than ever. In this study, we propose a training method that utilizes regression boxes' spatial information to conduct loss calibration to reduce the miscalculated loss. Extensive experimental results show that our method can significantly boost detectors' performance trained on datasets with varying degrees of sparse annotations. Even if 90% of the annotations are missing, the performance of our method is barely affected. Furthermore, we find that the middle layers of the detector are closely related to the generalization performance. More generally, this study could elucidate the link between layers and generalization performance, provide enlightenment for future research, such as designing and applying constraint rules to specific layers according to gradient analysis to achieve “scalpel-level” model training.
Environmental Biofilms as Reservoirs for Antimicrobial Resistance
Authors: Flores-Vargas Gabriela , Bergsveinson Jordyn , Lawrence John R. , Korber Darren R.
Published: December 2021

Characterizing the response of microbial communities to a range of antibiotic concentrations is one of the strategies used to understand the impact of antibiotic resistance. Many studies have described the occurrence and prevalence of antibiotic resistance in microbial communities from reservoirs such as hospitals, sewage, and farm feedlots, where bacteria are often exposed to high and/or constant concentrations of antibiotics. Outside of these sources, antibiotics generally occur at lower, sub-minimum inhibitory concentrations (sub-MICs). The constant exposure to low concentrations of antibiotics may serve as a chemical “cue” that drives development of antibiotic resistance. Low concentrations of antibiotics have not yet been broadly described in reservoirs outside of the aforementioned environments, nor is the transfer and dissemination of antibiotic resistant bacteria and genes within natural microbial communities fully understood. This review will thus focus on low antibiotic-concentration environmental reservoirs and mechanisms that are important in the dissemination of antibiotic resistance to help identify key knowledge gaps concerning the environmental resistome.
Choosing the Right Life Partner: Ecological Drivers of Lichen Symbiosis
Authors: Vančurová Lucie , Malíček Jiří , Steinová Jana , Škaloud Pavel
Published: December 2021

Lichens are an iconic example of symbiotic systems whose ecology is shaped by the requirements of the symbionts. Previous studies suggest that fungal (mycobionts) as well as photosynthesizing (phycobionts or cyanobionts) partners have a specific range of acceptable symbionts that can be chosen according to specific environmental conditions. This study aimed to investigate the effects of climatic conditions and mycobiont identity on phycobiont distribution within the lichen genera Stereocaulon, Cladonia, and Lepraria. The study area comprised the Canary Islands, Madeira, Sicily, and the Aeolian Islands, spanning a wide range of climatic conditions. These islands are known for their unique and diverse fauna and flora; however, lichen phycobionts have remained unstudied in most of these areas. In total, we genetically analyzed 339 lichen samples. The phycobiont pool differed significantly from that outside the studied area. Asterochloris mediterranea was identified as the most abundant phycobiont. However, its distribution was limited by climatic constraints. Other species of Asterochloris and representatives of the genera Chloroidium, Vulcanochloris, and Myrmecia were also recovered as phycobionts. The selection of symbiotic partners from the local phycobiont pool was driven by mycobiont specificity (i.e., the taxonomic range of acceptable partners) and the environmental conditions, mainly temperature. Interestingly, the dominant fungal species responded differently in their selection of algal symbionts along the environmental gradients. Cladonia rangiformis associated with its phycobiont A. mediterranea in a broader range of temperatures than Stereocaulon azoreum, which favors other Asterochloris species along most of the temperature gradient. Stereocaulon vesuvianum associated with Chloroidium spp., which also differed in their temperature optima. Finally, we described Stereocaulon canariense as a new endemic species ecologically distinct from the other Stereocaulon species on the Canary Islands.
Combination of Radiosensitivity Gene Signature and PD-L1 Status Predicts Clinical Outcome of Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma: A Study Based on The Cancer Genome Atlas Dataset
Authors: Dai Dongjun , Guo Yinglu , Shui Yongjie , Li Jinfan , Jiang Biao , Wei Qichun
Published: December 2021

Aim: The aim of our study was to investigate the potential predictive value of the combination of radiosensitivity gene signature and PD-L1 expression for the prognosis of locally advanced head and neck squamous cell carcinoma (HNSCC).

Methods: The cohort was selected from The Cancer Genome Atlas (TCGA) and classified into the radiosensitive (RS) group and radioresistant (RR) group by a radiosensitivity-related gene signature. The cohort was also grouped as PD-L1-high or PD-L1-low based on PD-L1 mRNA expression. The least absolute shrinkage and selection operator (lasso)-based Cox model was used to select hub survival genes. An independent validation cohort was obtained from the Gene Expression Omnibus (GEO) database.

Results: We selected 288 locally advanced HNSCC patients from TCGA. The Kaplan–Meier method found that the RR and PD-L1-high group had a worse survival than others (p = 0.033). The differentially expressed gene (DEG) analysis identified 553 upregulated genes and 486 downregulated genes (p < 0.05, fold change >2) between the RR and PD-L1-high group and others. The univariate Cox analysis of each DEG and subsequent lasso-based Cox model revealed five hub survival genes (POU4F1, IL34, HLF, CBS, and RNF165). A further hub survival gene-based risk score model was constructed, which was validated by an external cohort. We observed that a higher risk score predicted a worse prognosis (p = 0.0013). The area under the receiver operating characteristic curve (AUC) plots showed that this risk score model had good prediction value (1-year AUC = 0.684, 2-year AUC = 0.702, and 3-year AUC = 0.688). Five different deconvolution methods all showed that the B cells were lower in the RR and PD-L1-high group (p < 0.05). Finally, connectivity mapping analysis showed that the histone deacetylase (HDAC) inhibitor trichostatin A might have the potential to reverse the phenotype of RR and PD-L1-high in locally advanced HNSCC (p < 0.05, false discovery rate <0.1).

Conclusion: The combination of 31-gene signature and the PD-L1 mRNA expression had a potential predictive value for the prognosis of locally advanced HNSCC who had RT. The B cells were lower in the RR and PD-L1-high group. The identified risk gene signature of locally advanced HNSCC and the potential therapeutic drug trichostatin A for the RR and PD-L1-high group are worth being further studied in a prospective homogenous cohort.
Stabilization of the SNARE Core by Complexin-1 Facilitates Fusion Pore Expansion
Authors: Pierson Josh , Shin Yeon-Kyun
Published: December 2021

In the neuron, neurotransmitter release is an essential function that must be both consistent and tightly regulated. The continuity of neurotransmitter release is dependent in large part on vesicle recycling. However, the protein factors that dictate the vesicle recycling pathway are elusive. Here, we use a single vesicle-to-supported bilayer fusion assay to investigate complexin-1 (cpx1)’s influence on SNARE-dependent fusion pore expansion. With total internal reflection (TIR) microscopy using a 10 kDa polymer fluorescence probe, we are able to detect the presence of large fusion pores. With cpx1, however, we observe a significant increase of the probability of the formation of large fusion pores. The domain deletion analysis reveals that the SNARE-binding core domain of cpx1 is mainly responsible for its ability to promote the fusion pore expansion. In addition, the results show that cpx1 helps the pore to expand larger, which results in faster release of the polymer probe. Thus, the results demonstrate a reciprocal relationship between event duration and the size of the fusion pore. Based on the data, a hypothetical mechanistic model can be deduced. In this mechanistic model, the cpx1 binding stabilizes the four-helix bundle structure of the SNARE core throughout the fusion pore expansion, whereby the highly curved bilayer within the fusion pore is stabilized by the SNARE pins.
Molecular Identity and Location Influence Purkinje Cell Vulnerability in Autosomal-Recessive Spastic Ataxia of Charlevoix-Saguenay Mice
Authors: Toscano Márquez Brenda , Cook Anna A. , Rice Max , Smileski Alexia , Vieira-Lomasney Kristen , Charron François , McKinney R. Anne , Watt Alanna J.
Published: December 2021

Patterned cell death is a common feature of many neurodegenerative diseases. In patients with autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and mouse models of ARSACS, it has been observed that Purkinje cells in anterior cerebellar vermis are vulnerable to degeneration while those in posterior vermis are resilient. Purkinje cells are known to express certain molecules in a highly stereotyped, patterned manner across the cerebellum. One patterned molecule is zebrin, which is expressed in distinctive stripes across the cerebellar cortex. The different zones delineated by the expression pattern of zebrin and other patterned molecules have been implicated in the patterning of Purkinje cell death, raising the question of whether they contribute to cell death in ARSACS. We found that zebrin patterning appears normal prior to disease onset inSacs–/–mice, suggesting that zebrin-positive and -negative Purkinje cell zones develop normally. We next observed that zebrin-negative Purkinje cells in anterior lobule III were preferentially susceptible to cell death, while anterior zebrin-positive cells and posterior zebrin-negative and -positive cells remained resilient even at late disease stages. The patterning of Purkinje cell innervation to the target neurons in the cerebellar nuclei (CN) showed a similar pattern of loss: neurons in the anterior CN, where inputs are predominantly zebrin-negative, displayed a loss of Purkinje cell innervation. In contrast, neurons in the posterior CN, which is innervated by both zebrin-negative and -positive puncta, had normal innervation. These results suggest that the location and the molecular identity of Purkinje cells determine their susceptibility to cell death in ARSACS.
Effects of High-Frequency Repetitive Transcranial Magnetic Stimulation on Upper Limb Dystonia in Patients With Wilson's Disease: A Randomized Controlled Trial
Authors: Hao Wenjie , Wei Taohua , Yang Wenming , Yang Yue , Cheng Ting , Li Xiang , Dong Wei , Jiang Hailin , Qian Nannan , Wang Han , Wang Meixia
Published: December 2021

Background: Upper limb dystonia is a frequent complication of Wilson's disease (WD). It can lead to poor quality of life and disability. Currently, no effective treatment for it exists. Therefore, we carried out a clinical trial to determine whether high frequency repetitive transcranial magnetic stimulation (rTMS) on the primary motor cortex alleviates upper limb dystonia in WD patients.

Methods: This study was a single-center, double-blind, randomized clinical study, included 60 WD patients with upper limb dystonia from a research base of WD in Hefei, China. Participants were randomly divided into a treatment group (TG) and a control group (CG). The TG received rTMS at 10 Hz, while the CG received sham stimulation for 7 consecutive days. Participants were assessed at baseline, after the seventh treatment session, and at 2 and 4 weeks after the seventh treatment session. The primary outcomes included patients' objective muscle tension and stiffness as measured with the MyotonPRO device. The secondary results were scores on clinical scales assessing muscle spasm and motor symptoms, which included the Modified Ashworth Scale (MAS), Unified Wilson's Disease Rating Scale (UWDRS), Burke Fahn Marsden Scale (BFM), and the Activities of Daily Living (ADL) scale.

Results: The analysis revealed that after 10 Hz rTMS, muscle tension (P < 0.01) and stiffness (P < 0.01) as measured by the MyotonPRO device decreased significantly in the TG compared to the CG. Moreover, clinically relevant scale scores, including the MAS (P < 0.01), UWDRS (P < 0.01), BFM (P < 0.01), and ADL (P < 0.01) were also significantly reduced.

Conclusion: High-frequency rTMS over the primary motor cortex may be an effective complementary and alternative therapy to alleviating upper limb dystonia in WD patients.

Clinical Trial Registration:http://www.chictr.org.cn/, identifier: ChiCTR2100046258.
Cerebral Representation of Sound Localization Using Functional Near-Infrared Spectroscopy
Authors: Tian Xuexin , Liu Yimeng , Guo Zengzhi , Cai Jieqing , Tang Jie , Chen Fei , Zhang Hongzheng
Published: December 2021

Sound localization is an essential part of auditory processing. However, the cortical representation of identifying the direction of sound sources presented in the sound field using functional near-infrared spectroscopy (fNIRS) is currently unknown. Therefore, in this study, we used fNIRS to investigate the cerebral representation of different sound sources. Twenty-five normal-hearing subjects (aged 26 ± 2.7, male 11, female 14) were included and actively took part in a block design task. The test setup for sound localization was composed of a seven-speaker array spanning a horizontal arc of 180° in front of the participants. Pink noise bursts with two intensity levels (48 dB/58 dB) were randomly applied via five loudspeakers (–90°/–30°/–0°/+30°/+90°). Sound localization task performances were collected, and simultaneous signals from auditory processing cortical fields were recorded for analysis by using a support vector machine (SVM). The results showed a classification accuracy of 73.60, 75.60, and 77.40% on average at –90°/0°, 0°/+90°, and –90°/+90° with high intensity, and 70.60, 73.6, and 78.6% with low intensity. The increase of oxyhemoglobin was observed in the bilateral non-primary auditory cortex (AC) and dorsolateral prefrontal cortex (dlPFC). In conclusion, the oxyhemoglobin (oxy-Hb) response showed different neural activity patterns between the lateral and front sources in the AC and dlPFC. Our results may serve as a basic contribution for further research on the use of fNIRS in spatial auditory studies.
Transcriptomic and Metabolomic Profiling Reveals the Effect of LED Light Quality on Fruit Ripening and Anthocyanin Accumulation in Cabernet Sauvignon Grape
Authors: Zhang Peian , Lu Suwen , Liu Zhongjie , Zheng Ting , Dong Tianyu , Jin Huanchun , Jia Haifeng , Fang Jingggui
Published: December 2021

Different light qualities have various impacts on the formation of fruit quality. The present study explored the influence of different visible light spectra (red, green, blue, and white) on the formation of quality traits and their metabolic pathways in grape berries. We found that blue light and red light had different effects on the berries. Compared with white light, blue light significantly increased the anthocyanins (malvidin-3-O-glucoside and peonidin-3-O-glucoside), volatile substances (alcohols and phenols), and soluble sugars (glucose and fructose), reduced the organic acids (citric acid and malic acid), whereas red light achieved the opposite effect. Transcriptomics and metabolomics analyses revealed that 2707, 2547, 2145, and 2583 differentially expressed genes (DEGs) and (221, 19), (254, 22), (189, 17), and (234, 80) significantly changed metabolites (SCMs) were filtered in the dark vs. blue light, green light, red light, and white light, respectively. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, most of the DEGs identified were involved in photosynthesis and biosynthesis of flavonoids and flavonols. Using weighted gene co-expression network analysis (WGCNA) of 23410 highly expressed genes, two modules significantly related to anthocyanins and soluble sugars were screened out. The anthocyanins accumulation is significantly associated with increased expression of transcription factors (VvHY5, VvMYB90, VvMYB86) and anthocyanin structural genes (VvC4H, Vv4CL, VvCHS3, VvCHI1, VvCHI2, VvDFR), while significantly negatively correlated withVvPIF4. VvISA1, VvISA2, VvAMY1, VvCWINV, VvβGLU12, andVvFK12were all related to starch and sucrose metabolism. These findings help elucidate the characteristics of different light qualities on the formation of plant traits and can inform the use of supplemental light in the field and after harvest to improve the overall quality of fruit.
Efficacy and Safety of Docetaxel and Sodium Cantharidinate Combination vs. Either Agent Alone as Second-Line Treatment for Advanced/Metastatic NSCLC With Wild-Type or Unknown EGFR Status: An Open-Label, Randomized Controlled, Prospective, Multi-Center Phase III Trial (Cando-L1)
Authors: Wu Lin , Deng Chao , Zhang Hui , Weng Jie , Wu Youhua , Zeng Shan , Tang Tiegang , Cao Peiguo , Qiu Bo , Zhang Li , Duan Huaxin , Zhang Bing , Zhang Dong , Zhang Taotao , Hu Chunhong
Published: December 2021

Second-line treatment options for advanced/metastatic non-small cell lung cancer (NSCLC) patients are limited. We aimed to evaluate the efficacy and safety of docetaxel/sodium cantharidinate combination vs. either agent alone as second-line treatment for advanced/metastatic NSCLC patients with wild-type or unknown EGFR status. A randomized, open-label, phase III study was performed at 12 institutions. Patients with failure of first-line platinum regimens were randomized to receive either single-agent sodium cantharivsdinate (SCA) or single-agent docetaxel (DOX) or docetaxel/sodium cantharidinate combination (CON). The primary endpoints were centrally confirmed progression-free survival (PFS) and overall survival (OS). The secondary endpoints were objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. A total of 148 patients were enrolled in our study between October 2016 and March 2020. After a median follow-up time of 8.02 months, no significant difference was observed among the three groups in ORR (SCA vs. DOX vs. CON: 6.00% vs. 8.33% vs. 10.00%, respectively; p=0.814) and DCR (74.00% vs. 52.00% vs. 62.50%, respectively; p=0.080). In additional, the mOS was significantly higher in the CON group, compared with the single-agent groups (7.27 vs. 5.03 vs. 9.83 months, respectively; p=0.035), while no significant differences were observed in terms of PFS (2.7 vs. 2.9 vs. 3.1 months, respectively; p=0.740). There was no significant difference in the baseline QoL scores between the three groups (p>0.05); after treatment, life quality in SCA and CON group was significantly better than that in the DOX group (p<0.05). Furthermore, the incidence of adverse events (AEs) in the SCA group was significantly lower (46.00 vs. 79.17 vs. 25.00%, respectively; p=0.038) and the incidence of grade ≥3 AEs was also significantly lower in the SCA group compared with the DOX and CON groups (10.00 vs. 82.00 vs. 30.00%, respectively; p=0.042). Single-agent SCA and single-agent DOX has similar therapeutic efficacy in the second-line treatment of advanced/metastatic NSCLC with wild-type or unknown EGFR status, but single-agent SCA has fewer AEs and better QoL. Also, SCA plus DOX can significantly improve OS and exerted a significant synergistic effect, with good safety and tolerance profile.
Yi Shen Juan Bi Pill Regulates the Bone Immune Microenvironment via the JAK2/STAT3 Signaling Pathway in Vitro
Authors: Xia Ya , Fan Danping , Li Xiaoya , Lu Xiangchen , Ye Qinbin , Xi Xiaoyu , Wang Qiong , Zhao Hongyan , Xiao Cheng
Published: December 2021

Rheumatoid arthritis (RA) is characterized by an impaired articular bone immune microenvironment, which is associated with regulatory T cells (Tregs) hypofunction and osteoclasts (OCs) hyperfunction and leads to articular bone erosion and systemic bone loss. Studies have shown that Tregs slow bone loss in RA by regulating the bone resorption function of OCs and the JAK/STAT signaling pathway can regulate the immunosuppressive function of Tregs and reduce the bone erosion function of OCs. Yi Shen Juan Bi Pill (YSJB) is a classic Chinese herbal compound for the treatment of RA. However, whether YSJB regulates bone immune microenvironment homeostasis through JAK/STAT signaling pathway remains unclear. Based on in vitro OC single culture, Treg single culture and OC-Treg coculture systems, treatments were performed using drug-containing serum, AG490 and JAK2 siRNA to explore whether YSJB-containing serum regulates the homeostasis of the bone immune microenvironment through the JAK/STAT signaling pathway. In vitro, YSJB treatment decreased the number of TRAP+ cells and the areas of bone resorption and inhibited the expression of RANK, NFATc1, c-fos, JAK2, and STAT3 in both the OC single culture system and the OC-Treg coculture system. Tregs further reduced the number of TRAP+ cells and the areas of bone resorption in the coculture system. YSJB promoted the secretion of IL-10 while inhibiting the expression of JAK2 and STAT3 in Tregs. Moreover, inhibiting the expression of JAK2 with the JAK2 inhibitor AG490 and JAK2 siRNA improved the immunosuppressive functions of Treg, inhibited OC differentiation and bone resorption. Our study demonstrates that YSJB can regulate OC-mediated bone resorption and Treg-mediated bone immunity through the JAK2/STAT3 signaling pathway. This study provides a new strategy for regulating the bone immune microenvironment in RA with traditional Chinese medicine.
Study on the Molecular Basis of Huanglian Jiedu Decoction Against Atopic Dermatitis Integrating Chemistry, Biochemistry, and Metabolomics Strategies
Authors: Chen Jing , Chen Saizhen , Chen Jinguang , Shen Bixin , Jiang Zhengli , Xu Yubin
Published: December 2021

Atopic dermatitis (AD) is a common chronic relapsing skin inflammation, which severely affect the quality of life of patients. Inhibiting itching and enhancing immunity to mitigate scratching are key elements in the fight against AD. Huanglian Jiedu decoction (HLJDD) has multiple pharmacological effects in the treatment of AD. However, the effective ingredients and underlying molecular mechanisms have not yet been fully explored. Thus, this study integrates chemistry, biochemistry, and metabolomics strategies to evaluate the active substance basis of HLJDD against AD. First, HLJDD was split to five fractions (CPF, 40AEF, 90AEF, PEF and WEF) and 72 chemical components were identified. NSD (Non-similarity degree) among the different fractions showed significant chemical differences (>81%). Interleukin IL-13, IL-17A, IL-3, IL-31, IL-33, IL4, IL-5, TSLP, IgE, and histamine in the serum, and IL-4Rα, JAK1, and HRH4 levels in skin, participating in inhibiting itching and regulating immunity signaling, were found to be restored to varying degrees in AD treating with HLJDD and its fractions, especially 40AEF and CPF. Untargeted metabolomics analysis demonstrated that forty metabolites were differential metabolites in plasma between the HLJDD-treated group and the AD group, involving in histidine metabolism, arginine biosynthesis, pyrimidine metabolism, and so on. Further, targeted metabolomics analysis revealed that eleven differential metabolites, associating with physiological and biochemical indices, were significant improved in the HLJDD and its fractions groups. In conclusion, HLJDD exhibited anti-AD effects by inhibiting itching and enhancing immunity, which in turn regulating the levels of relative metabolites, and CPF and 40AEF were considered the most important components of HLJDD.
Exosome-Enriched Plasma Analysis as a Tool for the Early Detection of Hypertensive Gestations
Authors: Weingrill Rodrigo Barbano , Paladino Sandra Luft , Souza Matheus Leite Ramos , Pereira Eduardo Manoel , Marques Aldilane Lays Xavier , Silva Elaine Cristina Oliveira , da Silva Fonseca Eduardo Jorge , Ursulino Jeferson Santana , Aquino Thiago Mendonça , Bevilacqua Estela , Urschitz Johann , Silva Jean Carl , Borbely Alexandre Urban
Published: December 2021

Hypertensive disorders of pregnancy are closely associated with prematurity, stillbirth, and maternal morbidity and mortality. The onset of hypertensive disorders of pregnancy (HDP) is generally noticed after the 20th week of gestation, limiting earlier intervention. The placenta is directly responsible for modulating local and systemic physiology by communicating using mechanisms such as the release of extracellular vesicles, especially exosomes. In this study, we postulated that an analysis of exosome-enriched maternal plasma could provide a more focused and applicable approach for diagnosing HDP earlier in pregnancy. Therefore, the peripheral blood plasma of 24 pregnant women (11 controls, 13 HDP) was collected between 20th and 24th gestational weeks and centrifuged for exosome enrichment. Exosome-enriched plasma samples were analyzed by Raman spectroscopy and by proton nuclear magnetic resonance metabolomics (1H NMR). Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were used to analyze the Raman data, from the spectral region of 600–1,800 cm–1, to determine its potential to discriminate between groups. Using principal component analysis, we were able to differentiate the two groups, with 89% of all variances found in the first three principal components. In patients with HDP, most significant differences in Raman bands intensity were found for sphingomyelin, acetyl CoA, methionine, DNA, RNA, phenylalanine, tryptophan, carotenoids, tyrosine, arginine, leucine, amide I and III, and phospholipids. The 1H NMR analysis showed reduced levels of D-glucose, L-proline, L-tyrosine, glycine, and anserine in HDP, while levels of 2-hydroxyvalerate, polyunsaturated fatty acids, and very-low-density lipoprotein (VLDL) were increased. 1H NMR results were able to assign an unknown sample to either the control or HDP groups at a precision of 88.3% using orthogonal partial least squares discriminant analysis and 87% using logistic regression analysis. Our results suggested that an analysis of exosome-enriched plasma could provide an initial assessment of placental function at the maternal-fetal interface and aid HDP diagnosis, prognosis, and treatment, as well as to detect novel, early biomarkers for HDP.
Markers of Cardiac Autonomic Function During Consecutive Day Peak Exercise Tests in People With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Nelson Maximillian J. , Buckley Jonathan D. , Thomson Rebecca L. , Bellenger Clint R. , Davison Kade
Published: December 2021

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) have been shown to exhibit altered ventilatory characteristics on the second of two progressive maximal cardiopulmonary exercise tests (CPET) performed on consecutive days. However, maximal exercise can exacerbate symptoms for ME/CFS patients and cause significant post-exertional malaise. Assessment of heart rate (HR) parameters known to track post-exertional fatigue may represent more effective physiological markers of the condition and could potentially negate the need for maximal exercise testing. Sixteen ME/CFS patients and 10 healthy controls underwent a sub-maximal warm-up followed by CPET on two consecutive days. Ventilation, ratings of perceived exertion, work rate (WR) and HR parameters were assessed throughout on both days. During sub-maximal warm-up, a time effect was identified for the ratio of low frequency to high frequency power of HR variability (p=0.02) during sub-maximal warm-up, and for HR at ventilatory threshold (p=0.03), with both being higher on Day Two of testing. A significant group (p<0.01) effect was identified for a lower post-exercise HR recovery (HRR) in ME/CFS patients. Receiver operator characteristic curve analysis of HRR revealed an area under the curve of 74.8% (p=0.02) on Day One of testing, with a HRR of 34.5bpm maximising sensitivity (63%) and specificity (40%) suggesting while HRR values are altered in ME/CFS patients, low sensitivity and specificity limit its potential usefulness as a biomarker of the condition.
Heterogeneity of Hematological Response to Hypoxia and Short-Term or Medium-Term Bed Rest
Authors: Royal Joshua T. , Eiken Ola , Keramidas Michail E. , McDonnell Adam C. , Mekjavic Igor B.
Published: December 2021

Hematological changes are commonly observed following prolonged exposure to hypoxia and bed rest. Typically, such responses have been reported as means and standard deviations, however, investigation into the responses of individuals is insufficient. Therefore, the present study retrospectively assessed individual variation in the hematological responses to severe inactivity (bed rest) and hypoxia. The data were derived from three-bed rest projects: two 10-d (LunHab project: 8 males; FemHab project: 12 females), and one 21-d (PlanHab project: 11 males). Each project comprised a normoxic bed rest (NBR; PIO2=133mmHg) and hypoxic bed rest (HBR; PIO2=91mmHg) intervention, where the subjects were confined in the Planica facility (Rateče, Slovenia). During the HBR intervention, subjects were exposed to normobaric hypoxia equivalent to an altitude of 4,000m. NBR and HBR interventions were conducted in a random order and separated by a washout period. Blood was drawn prior to (Pre), during, and post bed rest (R1, R2, R4) to analyze the individual variation in the responses of red blood cells (RBC), erythropoietin (EPO), and reticulocytes (Rct) to bed rest and hypoxia. No significant differences were found in the mean ∆(Pre-Post) values of EPO across projects (LunHab, FemHab, and PlanHab; p>0.05), however, female EPO responses to NBR (Range - 17.39, IQR – 12.97 mIU.ml−1) and HBR (Range – 49.00, IQR – 10.91 mIU.ml−1) were larger than males (LunHab NBR Range – 4.60, IQR – 2.03; HBR Range – 7.10, IQR – 2.78; PlanHab NBR Range – 7.23, IQR – 1.37; HBR Range – 9.72, IQR – 4.91 mIU.ml−1). Bed rest duration had no impact on the heterogeneity of EPO, Rct, and RBC responses (10-d v 21-d). The resultant hematological changes that occur during NBR and HBR are not proportional to the acute EPO response. The following cascade of hematological responses to NBR and HBR suggests that the source of variability in the present data is due to mechanisms related to hypoxia as opposed to inactivity alone. Studies investigating hematological changes should structure their study design to explore these mechanistic responses and elucidate the discord between the EPO response and hematological cascade to fully assess heterogeneity.
Benchmarking Human Performance for Visual Search of Aerial Images
Authors: Rhodes Rebecca E. , Cowley Hannah P. , Huang Jay G. , Gray-Roncal William , Wester Brock A. , Drenkow Nathan
Published: December 2021

Aerial images are frequently used in geospatial analysis to inform responses to crises and disasters but can pose unique challenges for visual search when they contain low resolution, degraded information about color, and small object sizes. Aerial image analysis is often performed by humans, but machine learning approaches are being developed to complement manual analysis. To date, however, relatively little work has explored how humans perform visual search on these tasks, and understanding this could ultimately help enable human-machine teaming. We designed a set of studies to understand what features of an aerial image make visual search difficult for humans and what strategies humans use when performing these tasks. Across two experiments, we tested human performance on a counting task with a series of aerial images and examined the influence of features such as target size, location, color, clarity, and number of targets on accuracy and search strategies. Both experiments presented trials consisting of an aerial satellite image; participants were asked to find all instances of a search template in the image. Target size was consistently a significant predictor of performance, influencing not only accuracy of selections but the order in which participants selected target instances in the trial. Experiment 2 demonstrated that the clarity of the target instance and the match between the color of the search template and the color of the target instance also predicted accuracy. Furthermore, color also predicted the order of selecting instances in the trial. These experiments establish not only a benchmark of typical human performance on visual search of aerial images but also identify several features that can influence the task difficulty level for humans. These results have implications for understanding human visual search on real-world tasks and when humans may benefit from automated approaches.