bluuebunny/crossref_metadata_2025 huggingface dataset:
The potential roles of JAK/STAT signaling in the progression of osteoarthritis
Authors: Zhou Qingluo , Ren Qun , Jiao Linhui , Huang Jishang , Yi Jun , Chen Jincai , Lai Jinliang , Ji Guanglin , Zheng Tiansheng
Published: November 2022

Osteoarthritis (OA) is an age-related chronic progressive degenerative disease that induces persistent pain and disabilities. The development of OA is a complex process, and the risk factors are various, including aging, genetics, trauma and altered biomechanics. Inflammation and immunity play an important role in the pathogenesis of OA. JAK/STAT pathway is one of the most prominent intracellular signaling pathways, regulating cell proliferation, differentiation, and apoptosis. Inflammatory factors can act as the initiators of JAK/STAT pathway, which is implicated in the pathophysiological activity of chondrocyte. In this article, we provide a review on the importance of JAK/STAT pathway in the pathological development of OA. Potentially, JAK/STAT pathway becomes a therapeutic target for managing OA.
Epigenomic signatures associated with spontaneous and replication stress-induced DNA double strand breaks
Authors: Kodali Sravan , Meyer-Nava Silvia , Landry Stephen , Chakraborty Arijita , Rivera-Mulia Juan Carlos , Feng Wenyi
Published: November 2022

Common fragile sites (CFSs) are specific regions of all individuals’ genome that are predisposed to DNA double strand breaks (DSBs) and undergo subsequent rearrangements. CFS formation can be induced in vitro by mild level of DNA replication stress, such as DNA polymerase inhibition or nucleotide pool disturbance. The mechanisms of CFS formation have been linked to DNA replication timing control, transcription activities, as well as chromatin organization. However, it is unclear what specific cis- or trans-factors regulate the interplay between replication and transcription that determine CFS formation. We recently reported genome-wide mapping of DNA DSBs under replication stress induced by aphidicolin in human lymphoblastoids for the first time. Here, we systematically compared these DSBs with regards to nearby epigenomic features mapped in the same cell line from published studies. We demonstrate that aphidicolin-induced DSBs are strongly correlated with histone 3 lysine 36 trimethylation, a marker for active transcription. We further demonstrate that this DSB signature is a composite effect by the dual treatment of aphidicolin and its solvent, dimethylsulfoxide, the latter of which potently induces transcription on its own. We also present complementing evidence for the association between DSBs and 3D chromosome architectural domains with high density gene cluster and active transcription. Additionally, we show that while DSBs were detected at all but one of the fourteen finely mapped CFSs, they were not enriched in the CFS core sequences and rather demarcated the CFS core region. Related to this point, DSB density was not higher in large genes of greater than 300 kb, contrary to reported enrichment of CFS sites at these large genes. Finally, replication timing analyses demonstrate that the CFS core region contain initiation events, suggesting that altered replication dynamics are responsible for CFS formation in relatively higher level of replication stress.
A one-year unisexual Schistosoma mansoni infection causes pathologic organ alterations and persistent non-polarized T cell-mediated inflammation in mice
Authors: Sombetzki Martina , Reinholdt Cindy , Winkelmann Franziska , Rabes Anne , Koslowski Nicole , Reisinger Emil C.
Published: November 2022

In exhibiting gonochorism and phenotypic sexual dimorphism,Schistosomaspp. are unique among trematodes. Only females mating with male schistosomes can produce the highly immunogenic parasite eggs which determine the clinical picture of the disease schistosomiasis. The strong immune-modulatory effect of the eggs masks the influence of the adult worms. To shed light on the complexity of the immune response triggered by adult worms ofSchistosoma mansoni, we performed a long-term unisexual infection experiment in mice. We were able to demonstrate that both male and female schistosomes can survive unpaired for one year in the murine host. Furthermore, unisexualS. mansoniinfection leads to pronounced inflammation of the liver characterized by a non-polarized Th1/Th2 immune response, regardless of worm sex.
Predictive value of CD3+ cells and interleukin 2 receptor in systemic inflammatory response syndrome after percutaneous nephrolithotomy
Authors: He Yu , Xia Ding , Tong Yonghua , Shang Haojie , Liu Xiao , Peng Ejun , Huang Qiu , Tang Kun , Chen Zhiqiang
Published: November 2022

Objective

The aim of the current study was to evaluate the risk factors that influence the development of postoperative systemic inflammatory response syndrome (SIRS) after percutaneous nephrolithotomy (PCNL), including cytokines and lymphocyte subsets.

Methods

A total of 154 patients who underwent PCNL at our hospital between October 2019 and January 2022 were retrospectively reviewed. The development of post-PCNL SIRS was the primary endpoint of the study. Univariable analysis and multivariable logistic regression analysis were performed to identify independent risk factors of post-PCNL SIRS. A nomogram was constructed using the independent risk factors, and receiver operating characteristic (ROC) curves were drawn.

Results

There were 50 patients (32.5%) who developed SIRS after PCNL. In multivariate analysis, positive urine culture (odds ratio [OR], 3.556; p = 0.048), long operation time (OR, 1.011; p = 0.027), high IL-2R (OR, 1.002; p = 0.018), low percentage of CD3+ cells (OR 0.931; p = 0.006), and high white blood cell (WBC) count (OR, 1.282; p = 0.044) were independent risk factors for post‐PCNL SIRS. These five significant variables were used to generate a nomogram that exhibited favorable fitting. The discrimination area under the ROC curves was 0.795.

Conclusions

Patients with long operation times, positive urine cultures, high interleukin 2 receptor, high white blood cell counts, and low percentages of CD3+ cells may be at a higher risk of developing SIRS after PCNL. In these patients, cautious and comprehensive preoperative evaluations and appropriate treatment strategies should be considered.
Crosstalk of angiogenesis-related subtypes, establishment of a prognostic signature and immune infiltration characteristics in colorectal adenocarcinoma
Authors: Cui Guoliang , Liu Jinhui , Wang Manli , Shon Kinyu , Wang Can , Wei Fei , Sun Zhiguang
Published: November 2022

Background

Colorectal adenocarcinoma (COAD) is one of the most common malignancies and angiogenesis is vital to the development of cancer. Here, we explored the roles of angiogenesis-related genes (ARGs) that affect the prognosis of COAD and constructed risk models to assess patient prognosis, immune characteristics, and treatment outcomes.

Methods

We comprehensively characterized the transcriptional and genetic modifications of 48 ARGs in COAD and evaluated the expression patterns. We identified two ARG subgroups using the consensus clustering algorithm. Based on the differentially expressed genes (DEGs) of two ARG subtypes, we calculated risk score, namely ARG_scores, and calssified COAD patients into different risk groups. To investigate the expression of ARG_score-related genes, qRT-PCR was performed. Subsequently, we mapped the nomogram to visually and accurately describe the value of the application of ARG_score. Finally, the correlation between ARG_score and clinical features, immune infiltration along with drug sensitivity were explored.

Results

We identified two ARG related subgroups and there were great differences in overall survival (OS) and tumor microenvironment. Then, we created an ARG_score for predicting overall survival based on eight DEGs and confirmed its reliable predictive power in COAD patients, with higher ARG_score associated with worse prognosis. Furthermore, eight ARG_score-related genes expression was investigated by qRT-PCR. To make the ARG_score clinically feasible, we created a highly reliable nomogram. We also found a higher proportion of microsatellite instability-high (MSI-H) and higher tumor mutational burden (TMB) in the high-risk group. In addition, ARG_score was notably correlated with cancer stem cell indices and drug sensitivity.

Conclusion

This scoring model has potential clinical application value in the prognosis, immune microenvironment and therapeutic drug sensitivity of COAD, which provides new insights for personalized treatment.
Glucocorticoid receptor hypersensitivity enhances inflammatory signaling and inhibits cell cycle progression in porcine PBMCs
Authors: Li Zhiwei , Hadlich Frieder , Wimmers Klaus , Murani Eduard
Published: November 2022

The consequences of glucocorticoid receptor (GR) hypersensitivity during infection have so far received little attention. We previously discovered that a natural gain-of-function Ala610Val substitution in the porcine GR aggravates response of pigs to lipopolysaccharide (LPS)-induced endotoxemia, which can be alleviated by dexamethasone (DEX) pretreatment. In this work, we investigated the relevant molecular basis of these phenotypes by transcriptomic profiling of porcine peripheral blood mononuclear cells (PBMCs) carrying different GR genotypes, in unstimulated conditions or in response to DEX and/or LPS in vitro. The Val allele differentially regulated abunda+nt genes in an additive-genetic manner. A subset of more than 200 genes was consistently affected by the substitution across treatments. This was associated with upregulation of genes related i.a. to endo-lysosomal system, lipid and protein catabolism, and immune terms including platelet activation, and antigen presentation, while downregulated genes were mainly involved in cell cycle regulation. Most importantly, the set of genes constitutively upregulated by Val includes members of the TLR4/LPS signaling pathway, such as LY96. Consequently, when exposing PBMCs to LPS treatment, the Val variant upregulated a panel of additional genes related to TLR4 and several other pattern recognition receptors, as well as cell death and lymphocyte signaling, ultimately amplifying the inflammatory responses. In contrast, when stimulated by DEX treatment, the Val allele orchestrated several genes involved in anti-inflammatory responses during infection. This study provides novel insights into the impact of GR hypersensitivity on the fate and function of immune cells, which may be useful for endotoxemia therapy.
The impact of soluble HLA-G in IVF/ICSI embryo culture medium on implantation success
Authors: Radwan Paweł , Tarnowska Agnieszka , Piekarska Karolina , Wiśniewski Andrzej , Krasiński Rafał , Radwan Michał , Nowak Izabela
Published: November 2022

The HLA-G molecule is widely accepted as an important factor for pregnancy success. Its expression has been detected in the extravillous trophoblasts. Soluble HLA-G (sHLA-G) was found in the genital tract, pre-implanted embryos as well as in seminal fluid. In this study, we investigated the concentration of sHLA-G (sHLA-G1 and sHLA-G5) in media from 344 single cultured embryos following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). The level of sHLA-G (U/ml) was tested with a sandwich enzyme-linked immunosorbent assay (ELISA) kit. We correlated sHLA-G secretion with ovarian stimulation protocols, the type of embryo transfer (fresh or frozen cycle) and the quality of the embryos. The ovarian stimulation protocol affects the secretion of sHLA-G by the embryo. Embryos obtained from the long agonist protocol secreted more sHLA-G than those originating from the short antagonist protocol (p = 0.0001). Embryos whose transfer resulted in a clinical pregnancy and/or live birth secreted more sHLA-G compared to those whose transfer ended without pregnancy. This was particularly observable in embryos following the long ovarian stimulation protocol and from a frozen embryo cycle. In conclusion, sHLA-G secreted by the embryo has an impact on implantation and live birth and could be a developmental potential marker of the embryo. Its concentration depends on the ovarian stimulation protocol used.
The G protein subunit α1, CaGα1, mediates ethylene sensing of mango anthracnose pathogen Colletotrichum asianum to regulate fungal development and virulence and mediates surface sensing for spore germination
Authors: Kao Chao-Yang , Wu Chun-Ta , Lin Hsien-Che , Hsieh Dai-Keng , Lin Huey-Ling , Lee Miin-Huey
Published: November 2022

Mango is an important tropic fruit, but its production is highly restricted by anthracnose diseases. Mango anthracnose development is related to the fruit-ripening hormone ethylene, but how the pathogen senses ethylene and affects the infection remains largely unknown. In this study, mango pathogen Colletotrichum asianum strain TYC-2 was shown to sense ethylene to enhance spore germination, appressorium formation and virulence. Upon further analysis of ethylene sensing signaling, three histidine kinase genes (CaHKs) and a G-protein gene (CaGα1) were functionally characterized. Ethylene upregulated the expression of the three CaHKs but had no influence on CaGα1 expression. No function in ethylene sensing was identified for the three CaHKs. Ethylene enhanced spore germination and multiple appressorium formation of the wild-type TYC-2 but not CaGα1 mutants. TYC-2 has extremely low germination in water, where self-inhibition may play a role in ethylene sensing via CaGα1 signaling. Self-inhibitors extracted from TYC-2 inhibited spore germination of TYC-2 and CaGα1 mutants, but ethylene could not rescue the inhibition, indicating that the self-inhibition was not mediated by CaGα1 and had no interactions with ethylene. Interestingly, spore germination of CaGα1 mutants was significantly enhanced in water on hydrophobic but not hydrophilic surfaces, suggesting that CaGα1 is involved in surface sensing. In the pathogenicity assay, CaGα1 mutants showed less virulence with delayed germination and little appressorium formation at early infection on mango leaves and fruit. Transcriptome and qRT–PCR analyses identified several pathogenicity-related genes regulated by ethylene, indicating that ethylene may regulate TYC-2 virulence partially by regulating the expression of these genes.
Rcs phosphorelay affects the sensitivity of Escherichia coli to plantaricin BM-1 by regulating biofilm formation
Authors: Bian Zheng , Liu Wenbo , Jin Junhua , Hao Yanling , Jiang Linshu , Xie Yuanhong , Zhang Hongxing
Published: November 2022

Introduction: Plantaricin BM-1 is a class IIa bacteriocin produced by Lactobacillus plantarum BM-1 that exerts significant antibacterial activity against many foodborne bacteria. Studies have shown that class IIa bacteriocins inhibit Gram-positive bacteria via the mannose phosphotransferase system; however, their mechanism of action against Gram-negative bacteria remains unknown. In this study, we explored the mechanism through which the Rcs phosphorelay affects the sensitivity of Escherichia coli K12 cells to plantaricin BM-1.

Methods and Results: The minimum inhibitory concentrations of plantaricin BM-1 against E. coli K12, E. coli JW5917 (rcsC mutant), E. coli JW2204 (rcsD mutant), and E. coli JW2205 (rcsB mutant) were 1.25, 0.59, 1.31, and 1.22 mg/ml, respectively. Growth curves showed that E. coli JW5917 sensitivity to plantaricin BM-1 increased to the same level as that of E. coli K12 after complementation. Meanwhile, scanning electron microscopy and transmission electron microscopy revealed that, under the action of plantaricin BM-1, the appearance of E. coli JW5917 cells did not significantly differ from that of E. coli K12 cells; however, cell contents were significantly reduced and plasmolysis and shrinkage were observed at both ends. Crystal violet staining and laser scanning confocal microscopy showed that biofilm formation was significantly reduced after rcsC mutation, while proteomic analysis identified 382 upregulated and 260 downregulated proteins in E. coli JW5917. In particular, rcsC mutation was found to affect the expression of proteins related to biofilm formation, with growth curve assays showing that the deletion of these proteins increased E. coli sensitivity to plantaricin BM-1.

Discussion: Consequently, we speculated that the Rcs phosphorelay may regulate the sensitivity of E. coli to plantaricin BM-1 by affecting biofilm formation. This finding of class IIa bacteriocin against Gram-negative bacteria mechanism provides new insights.
The anterior cingulate cortex contributes to the analgesic rather than the anxiolytic effects of duloxetine in chronic pain-induced anxiety
Authors: Li Chenglin , Ni Kaiji , Qi Meiru , Li Jie , Yang Kexin , Luo Yanli
Published: November 2022

Mood disorders, such as anxiety and depression, are commonly found in people suffering from chronic pain. Serotonin–norepinephrine reuptake inhibitors (SNRIs) are potential in alleviating chronic pain and are the first-line option for anxiety disorder. The anterior cingulate cortex (ACC) plays a vital role in chronic pain-induced anxiety, but its role in the therapeutic effects of SNRIs remains largely unclear. We used complete Freund’s adjuvant (CFA) in this current study to induce chronic inflammatory pain. Von Frey test was used to measure the mechanical withdrawal threshold. The elevated plus maze test (EPM) and the novelty-suppressed feeding test (NSF) were used to measure anxiety-like behaviors. Twenty-one days after the modeling, anxiety-like behaviors were successfully induced in CFA mice, and a 3-day intraperitoneal injection of duloxetine attenuated such behaviors. While, mechanical hyperalgesia was also improved. Then, we locally infused duloxetine in ACC for 3 days only to find out its analgesic effect in CFA mice. Furthermore, we used fiber photometry to discover decreased glutamatergic excitability and enhanced serotonin concentration in ACC after intraperitoneal injection of duloxetine. Overall, this study proposed a potential mechanism for the analgesic effect of duloxetine and shed light on further studies on the mechanism of its anxiolytic effect in chronic pain-induced anxiety.
Anti-CD19 chimeric antigen receptor T-cell followed by interferon−α therapy induces durable complete remission in donor cell-derived acute lymphoblastic leukemia: A case report
Authors: Ni Jing , Zhou Junjie , Long Zhangbiao , Chen Xin , Chen Xiaowen , Hong Jian , Liang Xinglin , Li Qingsheng , Xia Ruixiang , Ge Jian
Published: November 2022

Donor cell-derived leukemia (DCL) is a special type of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with DCL generally have a poor prognosis due to resistance to conventional chemotherapy. Here, we report a case of donor cell-derived acute lymphoblastic leukemia after umbilical cord blood transplantation. The patient didn’t respond to induction chemotherapy. She then received anti-CD19 CAR-T cell therapy and achieved MRD-negative complete remission (CR). However, MRD levels rose from negative to 0.05% at 5 months after CAR-T cell therapy. Higher MRD levels were significantly associated with an increased risk of leukemia recurrence. Afterward, preemptive interferon-α treatment was administrated to prevent disease recurrence. To date, the patient has maintained MRD-negative CR for 41 months. Our results suggested that anti-CD19 CAR-T cells followed by interferon-α therapy are effective in treating donor cell-derived acute lymphoblastic leukemia. This report provides a novel strategy for the treatment of DCL.
NSCLC patients with rare EGFR Ex19del/G724S mutation showed good response to afatinib combined with chemotherapy treatment: A two-case report
Authors: Wang Huilin , Yu Qitao , Shi Lina , Hou Qinhan , Dan Liang , Liang Chuqiao , Hong Xiaoyu , Zhao Yun , Ning Ruiling
Published: November 2022

EGFR G724S mutation in exon 18 has been shown to be resistant to both first- and third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). However, we found a rare mutation of EGFR Ex19del/G724S in two patients with lung cancer who demonstrated a favorable response to the combination of afatinib and chemotherapy. Identified by next-generation sequencing (NGS), EGFR G724S was found from a primary and a secondary tumor biopsy, respectively. Treated with afatinib combined with chemotherapy, both patients responded well and achieved progression-free survival. Analysis of acquired mutations developed during treatment using afatinib revealed that the emergence of EGFR T790M or ALK fusion was the potential mechanism of afatinib resistance. Our study lends credence to treatment using afatinib combined with chemotherapy as a viable option for patients with Ex19del/G724S.
Delivery of intensity-modulated electron therapy by mechanical scanning: An algorithm study
Authors: Ma Pan , Tian Yuan , Li Minghui , Niu Chuanmeng , Song Yuchun , Dai Jianrong
Published: November 2022

Purpose

In principle, intensity-modulated electron therapy (IMET) can be delivered through mechanical scanning, with a robotic arm mounting a linac.

Materials and methods

Here is a scanning algorithm to identify the back-and-forth, top-to-bottom (zigzag) pattern scan sequence. The algorithm includes generating beam positions with a uniform resolution according to the applicator size; adopting discrete energies to achieve the depth of 90% dose by compositing energies; selecting energy by locating the target’s distal edge; and employing the energy-by-energy scan strategy for step-and-shoot discrete scanning. After a zigzag scan sequence is obtained, the delivery order of the scan spots is optimized by fast simulated annealing (FSA) to minimize the path length. For algorithm evaluation, scan sequences were generated using the computed tomography data of 10 patients with pancreatic cancer undergoing intraoperative radiotherapy, and the results were compared between the zigzag path and an optimized path. A simple calculation of the treatment delivery time, which comprises the irradiation time, the total robotic arm moving time, the time for energy switch, and the time to stop and restart the beam, was also made.

Results

In these clinical cases, FSA optimization shortened the path lengths by 12%–43%. Assuming the prescribed dose was 15 Gy, machine dose rate was 15 Gy/s, energy switch time was 2 s, stop and restart beam time was 20 ms, and robotic arm move speed was 50 mm/s, the average delivery time was 124±38 s. The largest reduction in path length yielded an approximately 10% reduction in the delivery time, which can be further reduced by increasing the machine dose rate and the robotic arm speed, decreasing the time for energy switch, and/or developing more efficient algorithms.

Conclusion

Mechanically scanning IMET is potentially feasible and worthy of further exploration.
Machine learning-based analysis of a semi-automated PI-RADS v2.1 scoring for prostate cancer
Authors: Singh Dharmesh , Kumar Virendra , Das Chandan J. , Singh Anup , Mehndiratta Amit
Published: November 2022

Background

Prostate Imaging-Reporting and Data System version 2.1 (PI-RADS v2.1) was developed to standardize the interpretation of multiparametric MRI (mpMRI) for prostate cancer (PCa) detection. However, a significant inter-reader variability among radiologists has been found in the PI-RADS assessment. The purpose of this study was to evaluate the diagnostic performance of an in-house developed semi-automated model for PI-RADS v2.1 scoring using machine learning methods.

Methods

The study cohort included an MRI dataset of 59 patients (PI-RADS v2.1 score 2 = 18, score 3 = 10, score 4 = 16, and score 5 = 15). The proposed semi-automated model involved prostate gland and zonal segmentation, 3D co-registration, lesion region of interest marking, and lesion measurement. PI-RADS v2.1 scores were assessed based on lesion measurements and compared with the radiologist PI-RADS assessment. Machine learning methods were used to evaluate the diagnostic accuracy of the proposed model by classification of PI-RADS v2.1 scores.

Results

The semi-automated PI-RADS assessment based on the proposed model correctly classified 50 out of 59 patients and showed a significant correlation (r = 0.94, p < 0.05) with the radiologist assessment. The proposed model achieved an accuracy of 88.00% ± 0.98% and an area under the receiver-operating characteristic curve (AUC) of 0.94 for score 2 vs. score 3 vs. score 4 vs. score 5 classification and accuracy of 93.20 ± 2.10% and AUC of 0.99 for low score vs. high score classification using fivefold cross-validation.

Conclusion

The proposed semi-automated PI-RADS v2.1 assessment system could minimize the inter-reader variability among radiologists and improve the objectivity of scoring.
Development of restrictive eating disorders in children and adolescents with long-COVID-associated smell and taste dysfunction
Authors: Brasseler Maire , Schönecker Anne , Steindor Mathis , Della Marina Adela , Bruns Nora , Dogan Burcin , Felderhoff-Müser Ursula , Hebebrand Johannes , Dohna-Schwake Christian , Goretzki Sarah C.
Published: November 2022

Background

Absent or abnormal senses of smell and taste have been frequently reported during both acute and long COVID in adult patients. In contrast, pediatric patients who test positive for SARS-CoV-2 are often asymptomatic and the loss of smell and/or taste has been infrequently reported. After observing several young patients with COVID-associated anosmia and ageusia at our clinic, we decided to investigate the incidence of subsequent eating disorders in these patients and in SARS-CoV-2 positive patients who did not experience anosmia and ageusia during the same period.

Material and methods

A single-site retrospective cohort study of 84 pediatric patients with suspected long COVID who were treated in the Pediatric Infectious Diseases Outpatient Clinic at the University Hospital Essen were evaluated for persistent symptoms of COVID-19. Smell and taste dysfunction as well as eating behaviors were among the signs and symptoms analyzed in this study.

Results

24 out of 84 children and adolescents described smell and taste dysfunction after confirmed or suspected SARS-CoV-2 infections. A large number of these patients (6 out of 24) demonstrated increased fixation on their eating behavior post-COVID and over time these patients developed anorexia nervosa.

Discussion/Conclusion

In this study we saw a possible association of long-lasting post-COVID smell and taste dysfunction with subsequent development of eating disorders. This observation is worrisome and merits further investigation by healthcare providers at multiple clinical sites.
Alpiniae oxyphylla fructus extract promotes longevity and stress resistance of C. elegans via DAF-16 and SKN-1
Authors: Xiao Man , Chen Bocen , Niu Kun , Long Ziyu , Yang Fan , Xie Yiqiang
Published: November 2022

Background:Alpiniae Oxyphylla Fructus (AOF) is Traditional Chinese medicine and a dietary supplements for centuries, which posseses cardiotonic, neuroprotective, antioxidant, warming the kidney and nourish the spleen, these biological fuction is related to potential anti-aging properties. However, little is known about their effects on aging. This work aimed to investigate the effects of extracts of AOF on longevity and stress resistance in Caenorhabditis elegans (C. elegans) and the mechanisms that underlie its effects.

Methods: Wild-type (WT) strand of C.elegans (N2)worms were cultured in growth medium with or without AOF. First, we examined the effects of AOF on lifespan, reproduction and healthspan assay, stress resistance and oxidative analysis, lipofuscin levels. Second, The levels of ROS and MDA, the antioxidant enzyme activities were examined to explore the underlying mechanism of AOF. Finally, the expression of the longevity-related genes were investigated to further understand the AOF’s underlying mechanism.

Results: The lifespan of C. elegans was prolonged by 23.44% after treatment with high-dose AOF (100 ug/ml). AOF alleviated aging-related declines in C. elegans health and enhanced resistance to heat shock. Furthermore, AOF decreased reactive oxygen species and malondialdehyde, increased the activities of superoxide dismutase and catalase, and reduced accumulation of fat. AOF upregulated the expression of sod-3, gst-4, daf-16, and skn-1 but downregulated the expression of daf-2 and age-1 and accelerated the translocation of DAF-16 into the nucleus. The extended lifespan induced by AOF was reversed in daf-16(mu86) and skn-1(zu135) mutants, indicating that this gene is involved in AOF-regulated longevity.

Conclusion: Our findings demonstrated that AOF extends lifespan and healthspan and enhances stress via boosting the activity of the antioxidant enzyme and controlling the expression of genes associated with insulin/IGF signaling and SKN-1 pathways. As a result, this work suggested AOF as a possible candidate to reduce the signs of aging by activating and inhibiting target genes.
Challenges in evaluating treatments for COVID-19: The case of in-hospital anticoagulant use and the risk of adverse outcomes
Authors: Yu Ya-Hui , Oh In-Sun , Jeong Han Eol , Platt Robert W. , Douros Antonios , Shin Ju-Young , Filion Kristian B.
Published: November 2022

Anticoagulants are a potential treatment for the thrombotic complications resulting from COVID-19. We aimed to determine the association between anticoagulant use and adverse outcomes among hospitalized patients with COVID-19. We used data from the COVID-19 International Collaborative Research Project in South Korea from January to June 2020. We defined exposure using an intention-to-treat approach, with person-time classified as use or non-use of anticoagulants at cohort entry, and a time-varying approach. The primary outcome was all-cause, in-hospital mortality; the secondary outcome was a composite including respiratory outcomes, cardiovascular outcomes, venous thromboembolism, major bleeding, and intensive care unit admission. Cox proportional hazards models estimated adjusted hazard ratios (HRs) of the outcomes comparing use versus non-use of anticoagulants. Our cohort included 2,677 hospitalized COVID-19 patients, of whom 24 received anticoagulants at cohort entry. Users were older and had more comorbidities. The crude incidence rate (per 1,000 person-days) of mortality was 5.83 (95% CI: 2.80, 10.72) among anticoagulant users and 1.36 (95% CI: 1.14, 1.59) for non-users. Crude rates of the composite outcome were 3.20 (95% CI: 1.04, 7.47) and 1.80 (95% CI: 1.54, 2.08), respectively. Adjusted HRs for mortality (HR: 1.12, 95% CI: 0.48, 2.64) and the composite outcome (HR: 0.79, 95% CI: 0.28, 2.18) were inconclusive. Although our study was not able to draw conclusions on anticoagulant effectiveness for COVID-19 outcomes, these results can contribute to future knowledge syntheses of this important question. Our study demonstrated that the dynamic pandemic environment may have important implications for observational studies of COVID-19 treatment effectiveness.
Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS
Authors: Feng Zhen , Li Xiaoye , Tong Wai Kei , He Qingfeng , Zhu Xiao , Xiang Xiaoqiang , Tang Zhijia
Published: November 2022

Objective: We aimed to evaluate alirocumab- and evolocumab-related adverse events (AEs) in real-world compared with all other drugs, overall and by gender and age subgroups; we also aimed to compare their risks of cognitive impairment, musculoskeletal disorders and diabetes with various statins and ezetimibe.

Methods: We retrospectively extracted AE reports from the FDA Adverse Event Reporting System (FAERS) database during July 2015-June 2021. Disproportionality analyses were performed using reporting odds ratios (RORs) to detect AE signals of alirocumab and evolocumab in the overall population and in different age and gender subgroups, respectively.

Results: Compared with all other drugs, both alirocumab and evolocumab had a significant signal in “musculoskeletal and connective tissue disorders” (ROR1 = 2.626, 95% CI 2.552–2.702; ROR2 = 2.575, 95% CI 2.538–2.613). The highest ROR value of 2.311 (95% CI 2.272–2.351) was for “injury, poisoning and procedural complications” and was found in patients aged ≥65 years on evolocumab. The most frequent AEs were “general disorders and administration site conditions” and “musculoskeletal and connective tissue disorders” for all subpopulations. At the preferred term level, the most frequent AE signal was myalgia for alirocumab and injection site pain for evolocumab, overall and by subgroups. Compared with statins/ezetimibe, PCSK9 inhibitors exhibited lower ROR values for adverse events associated with SOC “nervous system disorders”, “psychiatric disorders” and “metabolism and nutrition disorders” (all RORs < 1), but mixed results for musculoskeletal disorders. Compared with all other drugs, undocumented AEs, such as acute cardiac event (ROR = 30.0, 95% CI 9.4–95.3) and xanthoma (ROR = 9.3, 95% CI 3.4–25.5), were also reported.

Conclusion: Real-world evidence showed that PCSK9 inhibitors were associated with an increased risk of musculoskeletal and connective tissue disorders and general disorders and administration site conditions, overall and by subgroups. Muscle toxicity, injection site reactions, and influenza-like illness were significant AE signals. Compared with various statins and ezetimibe, PCSK9 inhibitors have shown a favorable safety profile in muscle-related events, cognitive impairment and diabetes. Some undocumented AE signals were also reported. Due to the limitations of spontaneous reporting databases, further studies are still needed to establish causality and validate our results.
Adverse drug events in the prevention and treatment of COVID-19: A data mining study on the FDA adverse event reporting system
Authors: Guo Qiang , Duan Shaojun , Liu Yaxi , Yuan Yinxia
Published: November 2022

Background: In the emergent situation of COVID-19, off-label therapies and newly developed vaccines may bring the patients more adverse drug event (ADE) risks. Data mining based on spontaneous reporting systems (SRSs) is a promising and efficient way to detect potential ADEs to help health professionals and patients get rid of the risk.

Objective: This pharmacovigilance study aimed to investigate the ADEs of some attractive drugs (i.e., “hot drugs” in this study) in COVID-19 prevention and treatment based on the data from the US Food and Drug Administration (FDA) adverse event reporting system (FAERS).

Methods: The FAERS ADE reports associated with COVID-19 from the 2nd quarter of 2020 to the 2nd quarter of 2022 were retrieved with hot drugs and frequent ADEs were recognized. A combination of support, lower bound of 95% confidence interval (CI) of the proportional reporting ratio (PRR) was applied to detect significant hot drug and ADE signals by the Python programming language on the Jupyter notebook.

Results: A total of 66,879 COVID-19 associated cases were retrieved with 22 hot drugs and 1,109 frequent ADEs on the “preferred term” (PT) level. The algorithm finally produced 992 significant ADE signals on the PT level among which unexpected signals such as “hypofibrinogenemia” of tocilizumab and “disease recurrence” of nirmatrelvir\ritonavir stood out. A picture of signals on the “system organ class” (SOC) level was also provided for a comprehensive understanding of these ADEs.

Conclusion: Data mining is a promising and efficient way to assist pharmacovigilance work, and the result of this study could help timely recognize ADEs in the prevention and treatment of COVID-19.
Application of herbal traditional Chinese medicine in the treatment of lupus nephritis
Authors: Liu Liu , Zhang Lei , Li Ming
Published: November 2022

Lupus nephritis (LN) is a secondary renal disease caused by systemic lupus erythematosus affecting the kidneys. It is one of the main causes of end-stage renal disease and a serious risk factor for early mortality and disability of systemic lupus erythematosus patients. Existing LN treatment is mainly based on hormones, cytotoxic drugs, and biological agents. Nevertheless, the prognosis of LN patients remains poor because of frequent recurrence and exacerbation of adverse drug reactions. Hence, LN is still the most important cause of end-stage renal disease. In recent years, traditional Chinese medicine (TCM) has attracted increasing attention because of encouraging evidence that it alleviates LN and the well-described mechanisms underlying renal injury. TCM has therapeutic benefits for treating LN patients. This review article elucidates TCM preparations, TCM monomers, and herbal or natural extraction for LN treatment to provide effective supplementary evidence for promoting the development of TCM treatment for LN and reference for future research and clinical practice.
Dysfunctional intercellular communication and metabolic signaling pathways in thin endometrium
Authors: Xu Liang , Fan Yingying , Wang Jianjun , Shi Rui
Published: November 2022

Background: The endometrial thickness is a key factor for successful implantation. Thin endometrium is associated with lower implantation rate and pregnancy rate. Lacking of a better understanding for the cellular and molecular mechanisms of thin endometrium, managing patients with thin endometrium still represents a major challenge for clinicians.

Methods: In this study, we combined four single-cell RNA sequencing (scRNA-seq) and one bulk sequencing (bulk-seq) data for thin endometrium to perform an integrated analysis for endometrial cells in proliferating phase. Cell proportion and differentially expressed genes (DEGs) were analyzed to determine the disease-specific cell type and signaling pathways. The cell-cell communication among cell types were inferred by “CellChat” to illustrate the differential intercellular communication under normal and thin endometrium conditions. GSEA and GSVA were applied to identify dysfunctional signals and metabolic pathways before and after thin endometrium.

Results: Integration of scRNA-seq identified eight cell types. The proportion of stromal cells showed a significant difference between normal and thin endometrial tissue. The DEGs in diverse cell types revealed enriched pathways in a cell-specific manner. Aberrant cell-cell signaling transduction was found in almost all cell types, especially in immune cells and epithelial cells. Furthermore, dysfunctional metabolic signaling pathways were induced in a cell-type dependent way. The down-regulation of carbohydrate metabolism and nucleotide metabolism was observed and the energy metabolism switch was indicated.

Conclusion: Conclusively, we discover dysfunctional signals and metabolic pathways in thin endometrium, providing insight into mechanisms and therapeutic strategies for the atrophic endometrium.
Responses of tree seedlings to understory filtering by the recalcitrant fern layer in a subtropical forest
Authors: Liu Heming , Liang Mengfang , Yang Qingsong , Zhang Jian , Shen Guochun , Zhang Zhenzhen , Wang Xihua
Published: November 2022

The recalcitrant understory fern layer is an important ecological filter for seedling regeneration, yet how the fern layer influences seedling regeneration dynamics remains unclear. Here we transplanted 576 seedlings of four dominant tree species, Castanopsis fargesii, Lithocarpus glaber, Schima superba and Hovenia acerba, to the treatments of Diplopterygium glaucum retention and removal under an evergreen broad-leaved forest in eastern China. We monitored the survival, growth and biomass data of these seedlings for 28 months, and then used generalized linear mixed models to evaluate the treatment effects on seedling survival, growth, biomass and root-shoot ratio. Our results showed that fern retention significantly inhibited the seedling establishment of all four species. During the seedling development stage, the seedling relative growth rate of L. glaber decreased under fern retention, which was not the case for the other three species. Root-shoot ratio of C. fargesii and L. glaber increased significantly under fern retention. Our findings provide new evidence of the filtering effect of a recalcitrant fern understory. Notably, we observed that the response of tree seedlings to the recalcitrant fern understory was more sensitive in the establishment stage. Finally, our work highlights that the filtering effect of the recalcitrant fern understory changes depending on the regeneration stages, and that shade-tolerant species, C. fargesii and L. glaber were even more affected by fern disturbed habitats, suggesting that effective management should attempt to curb forest fern outbreaks, thus unblocking forest recruitment.
Perspectives on the metabolism of strigolactone rhizospheric signals
Authors: Wang Jian You , Braguy Justine , Chen Guan-Ting Erica , Jamil Muhammad , Balakrishna Aparna , Berqdar Lamis , Al-Babili Salim
Published: November 2022

Strigolactones (SLs) are a plant hormone regulating different processes in plant development and adjusting plant’s architecture to nutrition availability. Moreover, SLs are released by plants to communicate with beneficial fungi in the rhizosphere where they are, however, abused as chemical cues inducing seed germination of root parasitic weeds, e.g. Striga spp., and guiding them towards host plants in their vicinity. Based on their structure, SLs are divided into canonical and non-canonical SLs. In this perspective, we describe the metabolism of root-released SLs and SL pattern in rice max1-900 mutants, which are affected in the biosynthesis of canonical SLs, and show the accumulation of two putative non-canonical SLs, CL+30 and CL+14. Using max1-900 and SL-deficient d17 rice mutants, we further investigated the metabolism of non-canonical SLs and their possible biological roles. Our results show that the presence and further metabolism of canonical and non-canonical SLs are particularly important for their role in rhizospheric interactions, such as that with root parasitic plants. Hence, we proposed that the root-released SLs are mainly responsible for rhizospheric communications and have low impact on plant architecture, which makes targeted manipulation of root-released SLs an option for rhizospheric engineering.
Untying the Gordian knot of plastid phylogenomic conflict: A case from ferns
Authors: Wang Ting , Li Ting-Zhang , Chen Si-Si , Yang Tuo , Shu Jiang-Ping , Mu Yu-Nong , Wang Kang-Lin , Chen Jian-Bing , Xiang Jian-Ying , Yan Yue-Hong
Published: November 2022

Phylogenomic studies based on plastid genome have resolved recalcitrant relationships among various plants, yet the phylogeny of Dennstaedtiaceae at the level of family and genera remains unresolved due to conflicting plastid genes, limited molecular data and incomplete taxon sampling of previous studies. The present study generated 30 new plastid genomes of Dennstaedtiaceae (9 genera, 29 species), which were combined with 42 publicly available plastid genomes (including 24 families, 27 genera, 42 species) to explore the evolution of Dennstaedtiaceae. In order to minimize the impact of systematic errors on the resolution of phylogenetic inference, we applied six strategies to generate 30 datasets based on CDS, intergenic spacers, and whole plastome, and two tree inference methods (maximum-likelihood, ML; and multispecies coalescent, MSC) to comprehensively analyze the plastome-scale data. Besides, the phylogenetic signal among all loci was quantified for controversial nodes using ML framework, and different topologies hypotheses among all datasets were tested. The species trees based on different datasets and methods revealed obvious conflicts at the base of the polypody ferns. The topology of the “CDS-codon-align-rm3” (CDS with the removal of the third codon) matrix was selected as the primary reference or summary tree. The final phylogenetic tree supported Dennstaedtiaceae as the sister group to eupolypods, andDennstaedtioideaewas divided into four clades with full support. This robust reconstructed phylogenetic backbone establishes a framework for future studies on Dennstaedtiaceae classification, evolution and diversification. The present study suggests considering plastid phylogenomic conflict when using plastid genomes. From our results, reducing saturated genes or sites can effectively mitigate tree conflicts for distantly related taxa. Moreover, phylogenetic trees based on amino acid sequences can be used as a comparison to verify the confidence of nucleotide-based trees.
Investigating the effect of synchronized movement on toddlers’ word learning
Authors: Bazhydai Marina , Ke Han , Thomas Hannah , Wong Malcolm K. Y. , Westermann Gert
Published: November 2022

The effect of interpersonal behavioral synchrony on children’s behavior is an emerging field rich with research potential. While studies demonstrate its effect on affiliative and prosocial outcomes, the role of synchronized movement on children’s specific learning outcomes has not yet been investigated experimentally. One possibility is that synchrony, as a coordinated social activity, encourages perceived social bonds, leading to heightened attention, and better information retention. Equally likely is that physiological, rather than social learning, mechanisms mediate the effect, given the previously demonstrated role of autonomic arousal in attentional fluctuations, cognitive engagement, problem solving, exploration, and curiosity. The present study investigated the behavioral and physiological effects of synchrony conceptualized as induced, interpersonal, behavioral, movement-based interaction, on word learning in 2.5-year-old children. In a laboratory experiment, toddlers engaged in either a synchronous or an asynchronous movement-based interaction with an adult experimenter while listening to an upbeat children’s song. After the (a)synchronous movement episode, the same experimenter engaged children in a word learning task. During the (a)synchrony and learning phases, children’s physiological arousal was continuously recorded, resulting in heart rate and skin conductance response measures. Following a caregiver-child free play break, children were tested on their novel word retention. The results indicated that children learned novel labels at equal rates during the learning phase in both conditions, and their retention at test did not differ between conditions: although above chance retention of novel labels was found only following the synchronous, but not the asynchronous episode, the cross-episode comparisons did not reach statistical significance. Physiological arousal indices following the (a)synchrony episode did not differ between conditions and did not predict better word learning, although skin conductance response was higher during the learning than the movement episode. This study contributes to our understanding of the underlying cognitive and physiological mechanisms of interpersonal behavioral synchrony in the knowledge acquisition domain and paves the way to future investigations.