bluuebunny/crossref_metadata_2025 huggingface dataset:
Variation in Manduca sexta Pollination-Related Floral Traits and Reproduction in a Wild Tobacco Plant
Authors: Bing Julia , Li Xiang , Haverkamp Alexander , Baldwin Ian T. , Hansson Bill S. , Knaden Markus , Yon Felipe
Published: July 2021

Most flowering plants depend on animal pollination for successful sexual reproduction. Floral signals such as color, shape, and odor are crucial in establishing this (often mutualistic) interaction. Plant and pollinator phenotypes can vary temporally but also spatially, thus creating mosaic-like patterns of local adaptations. Here, we investigated natural variation in floral morphology, flower volatile emission, and phenology in four accessions of a self-compatible wild tobacco, Nicotiana attenuata, to assess how these traits match the sensory perception of a known pollinator, the hawkmoth Manduca sexta. These accessions differ in floral traits and also in their habitat altitudes. Based on habitat temperatures, the accession occurring at the highest altitude (California) is less likely to be visited by M. sexta, while the others (Arizona, Utah 1, and Utah 2) are known to receive M. sexta pollinations. The accessions varied significantly in flower morphologies, volatile emissions, flower opening, and phenology, traits likely important for M. sexta perception and floral handling. In wind tunnel assays, we assessed the seed set of emasculated flowers after M. sexta visitation and of natural selfed and hand-pollinated selfed flowers. After moth visitations, plants of two accessions (Arizona and Utah 2) produced more capsules than the other two, consistent with predictions that accessions co-occurring with M. sexta would benefit more from the pollination services of this moth. We quantified flower and capsule production in four accessions in a glasshouse assay without pollinators to assess the potential for self-pollination. The two Utah accessions set significantly more seeds after pollen supplementation compared with those of autonomous selfing flowers, suggesting a greater opportunistic benefit from efficient pollinators than the other two. Moreover, emasculated flowers of the accession with the most exposed stigma (Utah 2) produced the greatest seed set after M. sexta visitation. This study reveals intraspecific variation in pollination syndromes that illuminate the potential of a plant species to adapt to local pollinator communities, changing environments, and altered pollination networks.
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach
Authors: Bhai Pratibha , Levy Michael A. , Rooney Kathleen , Carere Deanna Alexis , Reilly Jack , Kerkhof Jennifer , Volodarsky Michael , Stuart Alan , Kadour Mike , Panabaker Karen , Schenkel Laila C. , Lin Hanxin , Ainsworth Peter , Sadikovic Bekim
Published: July 2021

Background

Hereditary cancer predisposition syndromes account for approximately 10% of cancer cases. Next generation sequencing (NGS) based multi-gene targeted panels is now a frontline approach to identify pathogenic mutations in cancer predisposition genes in high-risk families. Recent evolvement of NGS technologies have allowed simultaneous detection of sequence and copy number variants (CNVs) using a single platform. In this study, we have analyzed frequency and nature of sequence variants and CNVs, in a Canadian cohort of patients, suspected with hereditary cancer syndrome, referred for genetic testing following specific genetic testing guidelines based on patient’s personal and/or family history of cancer.

Methods

A 2870 patients were subjected to a single NGS based multi-gene targeted hereditary cancer panel testing algorithm to identify sequence variants and CNVs in cancer predisposition genes at our reference laboratory in Southwestern Ontario. CNVs identified by NGS were confirmed by alternative techniques like Multiplex ligation-dependent probe amplification (MLPA).

Results

A 15% (431/2870) patients had a pathogenic variant and 36% (1032/2870) had a variant of unknown significance (VUS), in a cancer susceptibility gene. A total of 287 unique pathogenic variant were identified, out of which 23 (8%) were novel. CNVs identified by NGS based approach accounted for 9.5% (27/287) of pathogenic variants, confirmed by alternate techniques with high accuracy.

Conclusion

This study emphasizes the utility of NGS based targeted testing approach to identify both sequence and CNVs in patients suspected with hereditary cancer syndromes in clinical setting and expands the mutational spectrum of high and moderate penetrance cancer predisposition genes.
PSGL-1 Is a T Cell Intrinsic Inhibitor That Regulates Effector and Memory Differentiation and Responses During Viral Infection
Authors: Tinoco Roberto , Neubert Emily N. , Stairiker Christopher J. , Henriquez Monique L. , Bradley Linda M.
Published: July 2021

Effective T cell differentiation during acute virus infections leads to the generation of effector T cells that mediate viral clearance, as well as memory T cells that confer protection against subsequent reinfection. While inhibitory immune checkpoints have been shown to promote T cell dysfunction during chronic virus infections and in tumors, their roles in fine tuning the differentiation and responses of effector and memory T cells are only just beginning to be appreciated. We previously identified PSGL-1 as a fundamental regulator of T cell exhaustion that sustains expression of several inhibitory receptors, including PD-1. We now show that PSGL-1 can restrict the magnitude of effector T cell responses and memory T cell development to acute LCMV virus infection by limiting survival, sustaining PD-1 expression, and reducing effector responses. After infection, PSGL-1-deficient effector T cells accumulated to a greater extent than wild type T cells, and preferentially generated memory precursor cells that displayed enhanced accumulation and functional capacity in response to TCR stimulation as persisting memory cells. Although, PSGL-1-deficient memory cells did not exhibit inherent greater sensitivity to cell death, they failed to respond to a homologous virus challenge after adoptive transfer into naïve hosts indicating an impaired capacity to generate memory effector T cell responses in the context of viral infection. These studies underscore the function of PSGL-1 as a key negative regulator of effector and memory T cell differentiation and suggest that PSGL-1 may limit excessive stimulation of memory T cells during acute viral infection.
Advanced HCC Patient Benefit From Neoantigen Reactive T Cells Based Immunotherapy: A Case Report
Authors: Liu Chenxi , Shao Jie , Dong Yanbing , Xu Qiuping , Zou Zhengyun , Chen Fangjun , Yan Jing , Liu Juan , Li Shuangshuang , Liu Baorui , Shen Jie
Published: July 2021

Advanced hepatocellular carcinoma (HCC) is a highly lethal disease, mainly due to the late stage at diagnosis and its rapid progression. Although patients with advanced HCC can choose targeted therapy or chemotherapy, overall, the treatment response rate is extremely low and the average survival time is one year more or less. But the application of immunotherapy have led to a paradigm shift in the treatment of HCC,such as TILs (tumor infiltrating lymphocytes),Checkpoint blockade (immune Checkpoint blockade), CAR-T(chimeric antigen receptor T cells) and TCR-T (engineered t-cell receptor T cells). And recent data indicate neoantigens generated when tumors mutate are the main target of tumor-specific TILs, and they are also the main antigens mediating tumor regression in TILs treatment. Moreover, numerous evidences have revealed that radiotherapy lead to massive release of tumor antigens, which may increase the effectiveness of immunotherapy. Based on the above theory, we used neoantigen reactive T cells combined with tomotherapy to treat a patient with advanced HCC (Clinical Trial Study Registration Number: NCT03199807), who reached a long time progress free survival.
The Many Faces of JAKs and STATs Within the COVID-19 Storm
Authors: Grant Alice H. , Estrada Armando , Ayala-Marin Yoshira M. , Alvidrez-Camacho America Y. , Rodriguez Georgialina , Robles-Escajeda Elisa , Cadena-Medina Denisse A. , Rodriguez Alejandro C. , Kirken Robert A.
Published: July 2021

The positive-sense single stranded RNA virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), resulted in a global pandemic with horrendous health and economic consequences not seen in a century. At a finer scale, immunologically, many of these devastating effects by SARS-CoV-2 can be traced to a “cytokine storm” resulting in the simultaneous activation of Janus Kinases (JAKs) and Signal Transducers and Activators of Transcription (STAT) proteins downstream of the many cytokine receptor families triggered by elevated cytokines found in Coronavirus Disease 2019 (COVID-19). In this report, cytokines found in the storm are discussed in relation to the JAK-STAT pathway in response to SARS-CoV-2 and the lessons learned from RNA viruses and previous Coronaviruses (CoVs). Therapeutic strategies to counteract the SARS-CoV-2 mediated storm are discussed with an emphasis on cell signaling and JAK inhibition.
Contemporary Progresses in Ultrasonic Welding of Aluminum Metal Matrix Composites
Authors: Selvaraj Senthil Kumaran , Srinivasan Kathiravan , Chadha Utkarsh , Mishra Rajat , Arpit Kurane , Apurb Kumar , Hu Yuh-Chung
Published: July 2021

Graphical Abstract

A Brief Review of the Ultrasonic welding process flow and sequence for joining aluminium metal matrix composite.
The Resistance of Denti-Geogrid Reinforcement in a Sand Model Based on the Pullout Test
Authors: Wei Fang , Jingsheng Zhang , Lijun Shi , Xudong Zha
Published: July 2021

In order to investigate the pullout resistance of the Horizontal-Vertical reinforcement, a “denti-geogrid” was assembled by bonding a “denti-strip” with the geogrid and the pullout tests were carried out. Subsequently, the analytical approaches were investigated to calculate the pullout resistance on the basis of the surface sliding model, Perterson and Anderson’s model, Jewell’s model, Chai’s model, and the proposed stress summation model. Moreover, a new index named “scale factor” was suggested to reflect the proportion of bearing resistance provided by transversal members. The research showed that: 1) under the same test conditions, the pullout resistance of denti-geogrid was much higher than that of a common geogrid. All common geogrids showed linear strain softening in the later stage of pullout tests. Given the same normal stresses, due to the expansion of effective areas suffering lateral earth pressure, more denti-strips meant more significant resistance; 2) Among five theoretical approaches, the solutions of the proposed stress summation model made the best agreement with lab test results, with an average relative error of 2.82%. On the other hand, the stress summation model also showed a simplicity in calculation; and 3) Due to higher gradient of the fitting curve of scale factors under lower load, the bearing resistance would be more and more dominant, which means that the lateral resistance of denti-strips could play a decisive role in cases of low stress level.
Physicochemical Properties of Extracellular Polymeric Substances Produced by Three Bacterial Isolates From Biofouled Reverse Osmosis Membranes
Authors: Rehman Zahid Ur , Vrouwenvelder Johannes S. , Saikaly Pascal E.
Published: July 2021

This work describes the chemical composition of extracellular polymeric substances (EPS) produced by three bacteria (RO1, RO2, and RO3) isolated from a biofouled reverse osmosis (RO) membrane. We isolated pure cultures of three bacterial strains from a 7-year-old biofouled RO module that was used in a full-scale seawater treatment plant. All the bacterial strains showed similar growth rates, biofilm formation, and produced similar quantities of proteins and polysaccharides. The gel permeation chromatography showed that the EPS produced by all the strains has a high molecular weight; however, the EPS produced by strains RO1 and RO3 showed the highest molecular weight. Fourier Transform Infrared Spectroscopy (FTIR), Proton Nuclear Magnetic Resonance (1H NMR), and Carbon NMR (13C NMR) were used for a detailed characterization of the EPS. These physicochemical analyses allowed us to identify features of EPS that are important for biofilm formation. FTIR analysis indicated the presence of α-1,4 glycosidic linkages (920 cm–1) and amide II (1,550 cm–1) in the EPS, the presence of which has been correlated with the fouling potential of bacteria. The presence of α-glycoside linkages was further confirmed by13C NMR analysis. The13C NMR analysis also showed that the EPS produced by these bacteria is chemically similar to foulants obtained from biofouled RO membranes in previous studies. Therefore, our results support the hypothesis that the majority of substances that cause fouling on RO membranes originate from bacteria. Investigation using1H NMR showed that the EPS contained a high abundance of hydrophobic compounds, and these compounds can lead to flux decline in the membrane processes. Genome sequencing of the isolates showed that they represent novel species of bacteria belonging to the genusBacillus. Examination of genomes showed that these bacteria carry carbohydrates-active enzymes that play a role in the production of polysaccharides. Further genomic studies allowed us to identify proteins involved in the biosynthesis of EPS and flagella involved in biofilm formation. These analyses provide a glimpse into the physicochemical properties of EPS found on the RO membrane. This knowledge can be useful in the rational design of biofilm control treatments for the RO membrane.
Bacillus cereus in Packaging Material: Molecular and Phenotypical Diversity Revealed
Authors: Schmid Paul Jakob , Maitz Stephanie , Kittinger Clemens
Published: July 2021

The Bacillus cereus group has been isolated from soils, water, plants and numerous food products. These species can produce a variety of toxins including several enterotoxins [non-hemolytic enterotoxin (Nhe), hemolysin BL (Hbl), cytotoxin K, and enterotoxin FM], the emetic toxin cereulide and insecticidal Bt toxins. This is the first study evaluating the presence of B. cereus in packaging material. Among 75 different isolates, four phylogenetic groups were detected (II, III, IV, and VI), of which the groups III and IV were the most abundant with 46.7 and 41.3%, respectively. One isolate was affiliated to psychrotolerant group VI. Growth experiments showed a mesophilic predominance. Based on PCR analysis, nhe genes were detectable in 100% of the isolates, while hbl genes were only found in 50.7%. The cereulide encoding gene was found in four out of 75 isolates, no isolate carried a crystal toxin gene. In total, thirteen different toxin gene profiles were identified. We showed that a variety of B. cereus group strains can be found in packaging material. Here, this variety lies in the presence of four phylogenetic groups, thirteen toxin gene profiles, and different growth temperatures. The results suggest that packaging material does not contain significant amounts of highly virulent strains, and the low number of cereulide producing strains is in accordance with other results.
Immune-Related lncRNA Signature for Predicting the Immune Landscape of Head and Neck Squamous Cell Carcinoma
Authors: Yin Ji , Li Xiaohui , Lv Caifeng , He Xian , Luo Xiaoqin , Li Sen , Hu Wenjian
Published: July 2021

Background: Long non-coding RNA (lncRNA) plays a significant role in the development, establishment, and progression of head and neck squamous cell carcinoma (HNSCC). This article aims to develop an immune-related lncRNA (irlncRNA) model, regardless of expression levels, for risk assessment and prognosis prediction in HNSCC patients.

Methods: We obtained clinical data and corresponding full transcriptome expression of HNSCC patients from TCGA, downloaded GTF files to distinguish lncRNAs from Ensembl, discerned irlncRNAs based on co-expression analysis, distinguished differentially expressed irlncRNAs (DEirlncRNAs), and paired these DEirlncRNAs. Univariate Cox regression analysis, LASSO regression analysis, and stepwise multivariate Cox regression analysis were then performed to screen lncRNA pairs, calculate the risk coefficient, and establish a prognosis model. Finally, the predictive power of this model was validated through the AUC and the ROC curves, and the AIC values of each point on the five-year ROC curve were calculated to select the maximum inflection point, which was applied as a cut-off point to divide patients into low- or high-risk groups. Based on this methodology, we were able to more effectively differentiate between these groups in terms of survival, clinico-pathological characteristics, tumor immune infiltrating status, chemotherapeutics sensitivity, and immunosuppressive molecules.

Results: A 13-irlncRNA-pair signature was built, and the ROC analysis demonstrated high sensitivity and specificity of this signature for survival prediction. The Kaplan–Meier analysis indicated that the high-risk group had a significantly shorter survival rate than the low-risk group, and the chi-squared test certified that the signature was highly related to survival status, clinical stage, T stage, and N stage. Additionally, the signature was further proven to be an independent prognostic risk factor via the Cox regression analyses, and immune infiltrating analyses showed that the high-risk group had significant negative relationships with various immune infiltrations. Finally, the chemotherapeutics sensitivity and the expression level of molecular markers were also significantly different between high- and low-risk groups.

Conclusion: The signature established by paring irlncRNAs, with regard to specific expression levels, can be utilized for survival prediction and to guide clinical therapy in HNSCC.
Acute TBK1/IKK-ε Inhibition Enhances the Generation of Disease-Associated Microglia-Like Phenotype Upon Cortical Stab-Wound Injury
Authors: Rehman Rida , Tar Lilla , Olamide Adeyemi Jubril , Li Zhenghui , Kassubek Jan , Böckers Tobias , Weishaupt Jochen , Ludolph Albert , Wiesner Diana , Roselli Francesco
Published: July 2021

Traumatic brain injury has a poorer prognosis in elderly patients, possibly because of the enhanced inflammatory response characteristic of advanced age, known as “inflammaging.” Recently, reduced activation of the TANK-Binding-Kinase 1 (Tbk1) pathway has been linked to age-associated neurodegeneration and neuroinflammation. Here we investigated how the blockade of Tbk1 and of the closely related IKK-ε by the small molecule Amlexanox could modify the microglial and immune response to cortical stab-wound injury in mice. We demonstrated that Tbk1/IKK-ε inhibition resulted in a massive expansion of microglial cells characterized by the TMEM119+/CD11c+ phenotype, expressing high levels of CD68 and CD317, and with the upregulation of Cst7a, Prgn and Ccl4 and the decrease in the expression levels of Tmem119 itself and P2yr12, thus a profile close to Disease-Associated Microglia (DAM, a subset of reactive microglia abundant in Alzheimer’s Disease and other neurodegenerative conditions). Furthermore, Tbk1/IKK-ε inhibition increased the infiltration of CD3+ lymphocytes, CD169+ macrophages and CD11c+/CD169+ cells. The enhanced immune response was associated with increased expression of Il-33, Ifn-g, Il-17, and Il-19. This upsurge in the response to the stab wound was associated with the expanded astroglial scars and increased deposition of chondroitin-sulfate proteoglycans at 7 days post injury. Thus, Tbk1/IKK-ε blockade results in a massive expansion of microglial cells with a phenotype resembling DAM and with the substantial enhancement of neuroinflammatory responses. In this context, the induction of DAM is associated with a detrimental outcome such as larger injury-related glial scars. Thus, the Tbk1/IKK-ε pathway is critical to repress neuroinflammation upon stab-wound injury and Tbk1/IKK-ε inhibitors may provide an innovative approach to investigate the consequences of DAM induction.
Neuroimaging Markers of Cerebral Small Vessel Disease on Hemorrhagic Transformation and Functional Outcome After Intravenous Thrombolysis in Patients With Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
Authors: Wang Yiqiao , Yan Xiaoting , Zhan Jie , Zhang Peiming , Zhang Guangming , Ge Shuqi , Wen Hao , Wang Lin , Xu Nenggui , Lu Liming
Published: July 2021

Objective: The aim of this study was to perform a systematic review and meta-analysis to assess whether cerebral small vessel disease (CSVD) on neuroimaging of patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis (IVT) is associated with an increased risk of hemorrhagic transformation (HT), symptomatic intracranial hemorrhage (sICH), and poor functional outcome (PFO).

Methods: A thorough search of several databases was carried out to identify relevant studies up to December 2020. We included studies of patients with AIS and neuroimaging markers of CSVD treated with IVT. The primary outcome was HT, and the secondary outcomes were sICH and 3-month PFO. The quality of the studies involved was evaluated using the Newcastle–Ottawa Scale (NOS). The meta-analysis with the fixed effects model was performed.

Results: Twenty-four eligible studies (n = 9,419) were pooled in the meta-analysis. All included studies were regarded as high quality with the NOS scores of at least 6 points. The meta-analysis revealed associations between the presence of CSVD and HT, sICH, and the 3-month PFO after IVT. Compared with no CSVD, the presence of CSVD was associated with an increased risk of HT (OR: 1.81, 95% CI: 1.52–2.16), sICH (OR: 2.42, 95% CI: 1.76–3.33), and 3-month PFO (OR: 2.15, 95% CI: 1.89–2.44). For patients with AIS complicated with CSVD, compared with a CSVD score of 0–1, a CSVD score of 2–4 was associated with an increased risk of HT (OR: 3.10, 95% CI: 1.67–5.77), sICH (OR: 2.86, 95% CI: 1.26–6.49), and 3-month PFO (OR: 4.58, 95% CI: 2.97–7.06).

Conclusion: Patients with AIS complicated with neuroimaging markers of CSVD are at increased risk of HT and 3-month PFO after IVT. However, it is still necessary to clarify the exact role of CSVD in the occurrence, development, and prognosis of AIS.

Systematic Review Registration:www.ClinicalTrials.gov, identifier CRD4202123 3900.
Long Non-coding RNA Uc.48+ Small Interfering RNA Alleviates Neuroinflammatory Hyperalgesia in Gp120-Treated Rats via the P2Y12 Receptor
Authors: Peng Lichao , Wu Bing , Shi Liran , Zou Lifang , Li Lin , Yang Runan , Xu Xiumei , Li Guilin , Liu Shuangmei , Zhang Chunping , Liang Shangdong
Published: July 2021

Human immunodeficiency virus envelope glycoprotein 120 (gp120) leads to hyperalgesia. Long non-coding RNAs are characterized by the lack of a protein-coding sequence and may contribute to the development and maintenance of inflammatory and neuroinflammatory pain. Rats with neuroinflammatory pain were established by gp120 treatment, which is featured by intensified pain behaviors. Long non-coding RNA uc.48+ was increased in the dorsal root ganglia of gp120-treated rats, and small interfering RNA that targets uc.48+ markedly alleviated hyperalgesia in gp120-treated rats. Notably, uc.48+ overexpression increased P2Y12 expression in control rats dorsal root ganglia and induced hyperalgesia. Uc.48+ small interfering RNA inhibited P2Y12 expression in gp120-treated rats. Uc.48+ potentiated P2Y12 receptor functions in the neurons and heterologous cells. Therefore, uc.48+ siRNA treatment reduced the upregulation of P2Y12 expression and function in DRG neurons, and, hence, alleviated hyperalgesia in gp120-treated rats.
LncRNA FENDRR in Carcinoma-Associated Fibroblasts Regulates the Angiogenesis of Oral Squamous Cell Carcinoma Through the PI3K/AKT Pathway
Authors: Xu Yuming , Jiang Erhui , Shao Zhe , Shang Zhengjun
Published: July 2021

Angiogenesis is essential for the development of tumors. Studies have shown that carcinoma-associated fibroblasts (CAFs) are involved in regulating tumor angiogenesis, but the mechanism remains unclear. Recently, long noncoding RNAs (lncRNAs) have been proved to play an important role in the angiogenesis of various tumors. However, there is currently no research involving the regulation of CAFs on the angiogenesis of oral squamous cell carcinoma (OSCC) mediated by lncRNAs. By analyzing microarray data, we identified that the expression of lncRNA FOXF1 adjacent noncoding developmental regulatory RNA (FENDRR) in OSCC patients is downregulated, compared to that in normal tissues. Quantitative polymerase chain reaction (qPCR) results demonstrated that FENDRR expression is lower in CAFs compared to normal fibroblasts (NFs) of OSCC patients. KEGG pathway analysis revealed that some genes differentially expressed between CAFs and NFs of HNSCC patients are enriched to the PI3K/AKT pathway. Further experiments confirmed that the downregulation of FENDRR can activate the PI3K/AKT pathway in NFs and enhances the expression of matrix metalloproteinase 9 (MMP9). The overexpression of FENDRR had the opposite effect. Besides, we co-cultured human umbilical vein endothelial cells (HUVECs) with CAFs, and the tube-forming ability of HUVECs co-cultured with CAFs overexpressing FENDRR decreased significantly. However, activation of the AKT pathway of CAFs overexpressing FENDRR can weaken the inhibitory effect of FENDRR on angiogenesis. In summary, our experiments are focused on the influence of lncRNAs in CAFs on OSCC angiogenesis for the first time and prove that FENDRR mediates CAFs’ regulation of OSCC angiogenesis through the PI3K/AKT pathway.
Suppressing ERK Pathway Impairs Glycochenodeoxycholate-Mediated Survival and Drug-Resistance in Hepatocellular Carcinoma Cells
Authors: Li Bingxin , Zhou Maojun , Wang Jue , Xu Hongjuan , Yang Manyi
Published: July 2021

Glycochenodeoxycholate (GCDA), a toxic component in bile salts, is involved in carcinogenesis of gastrointestinal tumors. The objective of this research was to study the function of ERK1/2 in the GCDA-mediated survival and drug-resistance in hepatocellular carcinoma cells (HCCs). Firstly, extracellular signal-regulated kinase 1/2 (ERK1/2) was detected extensively expressed in liver cancer cells, and silencing ERK1/2 by RNA interference could suppress GCDA-stimulated survival and promote apoptosis. Furthermore, phosphorylation of endogenous ERK1/2 could be potently stimulated by GCDA in combination with enhanced chemoresistance in QGY-7703 hepatocellular carcinoma cells. The GCDA-mediated proliferation and chemoresistance could be impaired by PD98059, which acted as an inhibitor to block the phosphorylation of ERK1/2. Mechanistically, PD98059 was able to potently suppress GCDA-stimulated nuclear aggregation of ERK1/2 and p-ERK1/2, upregulate pro-survival protein Mcl-1 and downregulate pro-apoptotic protein Bim. The results of this study indicated that disruption of ERK1/2 by blocking phosphorylation or nuclear translocation may put forward new methods for solving the problem of GCDA-related proliferation and drug-resistance in liver cancer treatment.
Clinical Activity and Safety of Penpulimab (Anti-PD-1) With Anlotinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: An Open-Label, Multicenter, Phase Ib/II Trial (AK105-203)
Authors: Han Chun , Ye Sisi , Hu Chunhong , Shen Liangfang , Qin Qun , Bai Yuxian , Yang Shizhong , Bai Chunmei , Zang Aimin , Jiao Shunchang , Bai Li
Published: July 2021

Objective

This study aims to assess the efficacy and safety of penpulimab (a humanized anti-PD-1 IgG1 antibody) with anlotinib in the first-line treatment of Chinese patients with uHCC.

Methods

In this open-label multicenter phase Ib/II trial, patients with histologically or cytologically confirmed uHCC, without previous systemic treatment, aged 18–75 years old, classified as BCLC stage B (not amenable for locoregional therapy) or C, with Child–Pugh score ≤7 and ECOG performance status ≤1 were enrolled. Patients received penpulimab [200 mg intravenous (i.v.) Q3W] and oral anlotinib (8 mg/day, 2 weeks on/1 week off). The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), duration of response (DoR), and overall survival (OS). This trial is registered with ClinicalTrials.gov (NCT04172571).

Results

At the data cutoff (December 30, 2020), 31 eligible patients had been enrolled and treated with a median follow-up of 14.7 months (range, 1.4–22.1). The ORR was 31.0% (95% CI, 15.3–50.8%), and the DCR was 82.8% (95% CI, 64.2–94.2%). The median PFS and TTP for 31 patients were 8.8 months (95% CI, 4.0–12.3) and 8.8 months (95% CI, 4.0–12.9) respectively. The median OS was not reached; the 12-month OS rate was 69.0% (95% CI, 48.9–82.5%). Only 19.4% (6/31) of patients had grade 3/4 treatment-related adverse events (TRAEs).

Conclusion

Penpulimab plus anlotinib showed promising anti-tumor activity and a favorable safety profile as first-line treatment of patients with uHCC.
Patient-Derived Xenograft Models for Intrahepatic Cholangiocarcinoma and Their Application in Guiding Personalized Medicine
Authors: Gao Yang , Zhou Rong , Huang Jun-Feng , Hu Bo , Cheng Jian-Wen , Huang Xiao-Wu , Wang Peng-Xiang , Peng Hai-Xiang , Guo Wei , Zhou Jian , Fan Jia , Yang Xin-Rong
Published: July 2021

Background

Intrahepatic cholangiocarcinoma (ICC) remains one of the most intractable malignancies. The development of effective drug treatments for ICC is seriously hampered by the lack of reliable tumor models. At present, patient derived xenograft (PDX) models prove to accurately reflect the genetic and biological diversity required to decipher tumor biology and therapeutic vulnerabilities. This study was designed to investigate the establishment and potential application of PDX models for guiding personalized medicine and identifying potential biomarker for lenvatinib resistance.

Methods

We generated PDX models from 89 patients with ICC and compared the morphological and molecular similarities of parental tumors and passaged PDXs. The clinicopathologic features affecting PDX engraftment and the prognostic significance of PDX engraftment were analyzed. Drug treatment responses were analyzed in IMF-138, IMF-114 PDX models and corresponding patients. Finally, lenvatinib treatment response was examined in PDX models and potential drug resistance mechanism was revealed.

Results

Forty-nine PDX models were established (take rate: 55.1%). Successful PDX engraftment was associated with negative HbsAg (P = 0.031), presence of mVI (P = 0.001), poorer tumor differentiation (P = 0.023), multiple tumor number (P = 0.003), presence of lymph node metastasis (P = 0.001), and later TNM stage (P = 0.039). Moreover, patients with tumor engraftment had significantly shorter time to recurrence (TTR) (P < 0.001) and worse overall survival (OS) (P < 0.001). Multivariate analysis indicated that PDX engraftment was an independent risk factor for shortened TTR (HR = 1.84; 95% CI, 1.05–3.23; P = 0.034) and OS (HR = 2.13; 95% CI, 1.11–4.11; P = 0.024). PDXs were histologically and genetically similar to their parental tumors. We also applied IMF-138 and IMF-114 PDX drug testing results to guide clinical treatment for patients with ICC and found similar treatment responses. PDX models also facilitated personalized medicine for patients with ICC based on drug screening results using whole exome sequencing data. Additionally, PDX models reflected the heterogeneous sensitivity to lenvatinib treatment and CDH1 might be vital to lenvatinib-resistance.

Conclusion

PDX models provide a powerful platform for preclinical drug discovery, and potentially facilitate the implementation of personalized medicine and improvement of survival of ICC cancer patient.
Danggui-Shaoyao-San Improves Gut Microbia Dysbiosis and Hepatic Lipid Homeostasis in Fructose-Fed Rats
Authors: Yin Jing , Lu Jiaxi , Lei Peng , He Mingshuai , Huang Shengjie , Lv Jialin , Zhu Yan , Liu Zhidong , Jiang Miaomiao
Published: July 2021

Metabolic syndrome (MetS) is a pathological state of many abnormal metabolic sections. These abnormalities are closely related to diabetes, heart pathologies and other vascular diseases. Danggui-Shaoyao-San (DSS) is a traditional Chinese medicine formula that has been used as a therapy for Alzheimer’s disease. DSS has rarely been reported in the application of MetS and its mechanism of how it improves gut microbia dysbiosis and hepatic lipid homeostasis. In this study, three extracts of DSS were obtained using water, 50% methanol in water and methanol as extracting solvents. Their chemical substances were analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass (UPLC-Q/TOF-MS). Pharmacodynamic effect of the extracts were evaluated by comparison of biochemical factors, 16S rRNA sequencing test for gut microbiota analysis, as well as metabonomic and transcriptomic assessments on liver tissues from fructose-fed rats. This study aimed at investigating DSS’s mechanism of regulating blood lipid, anti-inflammation and reducing blood glucose. The results showed that the 50% methanol extract (HME) was more effective. It was worth noting that hydroxysteroid 17β-dehydrogenase 13 (HSD17β13) as a critical element of increasing blood lipid biomarker-triglyceride (TG), was decreased markedly by DSS. The influence from upgraded hydroxysteroid 17β-dehydrogenase 7 (HSD17β7) may be stronger than that from downgraded Lactobacillus in the aspect of regulating back blood lipid biomarker-total cholesterol (TC). The differential down-regulation of tumornecrosis factor alpha (TNF-α) and the significant up-regulation of Akkermansia showed the effective effect of anti-inflammation by DSS. The declining glycine and alanine induced the lowering glucose and lactate. It demonstrated that DSS slowed down the reaction of gluconeogenesis to reduce the blood glucose. The results demonstrated that DSS improved pathological symptoms of MetS and some special biochemical factors in three aspects by better regulating intestinal floras and improving hepatic gene expressions and metabolites.
Skeletal Muscle O-GlcNAc Transferase Action on Global Metabolism Is Partially Mediated Through Interleukin-15
Authors: Zumbaugh Morgan D. , Yen Con-Ning , Bodmer Jocelyn S. , Shi Hao , Gerrard David E.
Published: July 2021

Besides its roles in locomotion and thermogenesis, skeletal muscle plays a significant role in global glucose metabolism and insulin sensitivity through complex nutrient sensing networks. Our previous work showed that the muscle-specific ablation of O-GlcNAc transferase (OGT) led to a lean phenotype through enhanced interleukin-15 (IL-15) expression. We also showed OGT epigenetically modified and repressed the Il15 promoter. However, whether there is a causal relationship between OGT ablation-induced IL-15 secretion and the lean phenotype remains unknown. To address this question, we generated muscle specific OGT and interleukin-15 receptor alpha subunit (IL-15rα) double knockout mice (mDKO). Deletion of IL-15rα in skeletal muscle impaired IL-15 secretion. When fed with a high-fat diet, mDKO mice were no longer protected against HFD-induced obesity compared to wild-type mice. After 22 weeks of HFD feeding, mDKO mice had an intermediate body weight and glucose sensitivity compared to wild-type and OGT knockout mice. Taken together, these data suggest that OGT action is partially mediated by muscle IL-15 production and provides some clarity into how disrupting the O-GlcNAc nutrient signaling pathway leads to a lean phenotype. Further, our work suggests that interfering with the OGT-IL15 nutrient sensing axis may provide a new avenue for combating obesity and metabolic disorders.
Influence of Isometric Exercise Combined With Electromyostimulation on Inflammatory Cytokine Levels, Muscle Strength, and Knee Joint Function in Elderly Women With Early Knee Osteoarthritis
Authors: Park Sunhee , Min Sukyung , Park Si-Hwa , Yoo Jaehyun , Jee Yong-Seok
Published: July 2021

Background and Objectives: Muscle strengthening exercise is suggested to beneficial for patients with knee osteoarthritis (OA) and electrical muscular stimulation is reported to be effective in improvement of muscle strength. This study examined whether isometric exercise combined with whole body-electromyostimulation (WB-EMS) can improve serum cytokine levels, muscle strength, and knee function in elderly women with early knee OA.

Materials and Methods: This randomized controlled study included 75 participants assigned into three groups: the control group (CON), isometric exercise group (ISOM), and isometric exercise and electromyostimulation group (ISOM + EMS). The two exercise groups performed their respective programs for 8 weeks, 3 days a week, 30 min a day. The main exercises for both groups were performed continuously during the 20 min in an alternation of a 6-s contraction with a 4-s break. At pre- and post-intervention, anthropometric variables, muscle strength, Knee Injury and Osteoarthritis Outcome Score (KOOS), and blood sampling for biomarkers including interleukin-6, tumor necrosis factor-α, C-reactive protein, and resistin were performed.

Results: All variables at pre-intervention showed no significant differences among the three groups. However, there were significant differences between groups for body composition, muscle strength, KOOS subscale scores, and biomarkers. ISOM + EMS group resulted in a significant reduction in body weight, fat mass, fat percentage, inflammatory cytokine levels, and increased muscle strength. An ISOM + EMS group had the best KOOS score among all groups.

Conclusion: Isometric exercise combined with WB-EMS resulted in the best overall improvements in knee function and alleviating the pain and symptoms of patients with early knee OA. Further, reduced levels of inflammatory cytokines were observed. These non-pharmacologic, non-invasive interventions should be considered by healthcare specialists for elderly patients with early knee OA.
Coordination of Respiration, Swallowing, and Chewing in Healthy Young Adults
Authors: Hao Naohito , Sasa Anna , Kulvanich Sirima , Nakajima Yuta , Nagoya Kouta , Magara Jin , Tsujimura Takanori , Inoue Makoto
Published: July 2021

Examining the coordination of respiration and swallowing is important for elucidating the mechanisms underlying these functions and assessing how respiration is linked to swallowing impairment in dysphagic patients. In this study, we assessed the coordination of respiration and swallowing to clarify how voluntary swallowing is coordinated with respiration and how mastication modulates the coordination of respiration and swallowing in healthy humans. Twenty-one healthy volunteers participated in three experiments. The participants were asked to swallow 3 ml of water with or without a cue, to drink 100 ml of water using a cup without breathing between swallows, and to eat a 4-g portion of corned beef. The major coordination pattern of respiration and swallowing was expiration–swallow–expiration (EE type) while swallowing 3 ml of water either with or without a cue, swallowing 100 ml of water, and chewing. Although cueing did not affect swallowing movements, the expiratory time was lengthened with the cue. During 100-ml water swallowing, the respiratory cycle time and expiratory time immediately before swallowing were significantly shorter compared with during and after swallowing, whereas the inspiratory time did not differ throughout the recording period. During chewing, the respiratory cycle time was decreased in a time-dependent manner, probably because of metabolic demand. The coordination of the two functions is maintained not only in voluntary swallowing but also in involuntary swallowing during chewing. Understanding the mechanisms underlying respiration and swallowing is important for evaluating how coordination affects physiological swallowing in dysphagic patients.
Modeling of Individual Fruit-Bearing Capacity of Trees Is Aimed at Optimizing Fruit Quality of Malus x domestica Borkh. ‘Gala’
Authors: Penzel Martin , Herppich Werner B. , Weltzien Cornelia , Tsoulias Nikos , Zude-Sasse Manuela
Published: July 2021

The capacity of apple trees to produce fruit of a desired diameter, i.e., fruit-bearing capacity (FBC), was investigated by considering the inter-tree variability of leaf area (LA). The LA of 996 trees in a commercial apple orchard was measured by using a terrestrial two-dimensional (2D) light detection and ranging (LiDAR) laser scanner for two consecutive years. The FBC of the trees was simulated in a carbon balance model by utilizing the LiDAR-scanned total LA of the trees, seasonal records of fruit and leaf gas exchanges, fruit growth rates, and weather data. The FBC was compared to the actual fruit size measured in a sorting line on each individual tree. The variance of FBC was similar in both years, whereas each individual tree showed different FBC in both seasons as indicated in the spatially resolved data of FBC. Considering a target mean fruit diameter of 65 mm, FBC ranged from 84 to 168 fruit per tree in 2018 and from 55 to 179 fruit per tree in 2019 depending on the total LA of the trees. The simulated FBC to produce the mean harvest fruit diameter of 65 mm and the actual number of the harvested fruit >65 mm per tree were in good agreement. Fruit quality, indicated by fruit's size and soluble solids content (SSC), showed enhanced percentages of the desired fruit quality according to the seasonally total absorbed photosynthetic energy (TAPE) of the tree per fruit. To achieve a target fruit diameter and reduce the variance in SSC at harvest, the FBC should be considered in crop load management practices. However, achieving this purpose requires annual spatial monitoring of the individual FBC of trees.
Compensation of Wild Plants Weakens the Effects of Crop-Wild Gene Flow on Wild Rice Populations
Authors: Ouyang Dongxin , Dong Shanshan , Xiao Manqiu , You Jianling , Zhao Yao , Wang Yuguo , Zhang Wenju , Yang Ji , Song Zhiping
Published: July 2021

Crop-wild gene flow may alter the fitness of the recipient i.e., crop-wild hybrids, then potentially impact wild populations, especially for the gene flow carrying selective advantageous crop alleles, such as transgenes conferring insect resistance. Given the continuous crop-wild gene flow since crop domestication and the occasionally stressful environments, the extant wild populations of most crops are still “wild.” One interpretation for this phenomenon is that wild populations have the mechanism buffered for the effects of crop alleles. However, solid evidence for this has been scarce. We used wild rice (Oryza rufipogon) and transgenic (Bt/CpTI) rice (O. sativa) as a crop-wild gene flow model and established cultivated, wild, and F7 hybrid rice populations under four levels of insect (Chilo suppressalis) pressure. Then, we measured the trait performance of the plants and estimated fitness to test the compensatory response of relatively high fitness compared to the level of insect damage. The performance of all plants varied with the insect pressure level; wild plants had higher insect-tolerance that was expressed as over- or equal-compensatory responses to insect damage, whereas crop and hybrids exhibited under-compensatory responses. The higher compensation resulted in a better performance of wild rice under insect pressure where transgenes conferring insect resistance had a somewhat beneficial effect. Remarkable hybrid vigour and the benefit effect of transgenes increased the fitness of hybrids together, but this joint effect was weakened by the compensation of wild plants. These results suggest that compensation to environmental stress may reduce the potential impacts of crop alleles on wild plants, thereby it is a mechanism maintaining the “wild” characteristics of wild populations under the scenario of continuous crop-wild gene flow.
The ROCK Tool: A Novel Method for the Structural Exploration of Schemata
Authors: Shi Bohao , Jiang Zhenhui , Zhou Jifan , Chen Hui
Published: July 2021

Information stored in the human memory is organized in the form of mental schemata. In this paper we report on the Reproduction of Categorical Knowledge (ROCK) tool, a novel method for uncovering the structure of mental schemata of memorized information. The tool applies serial reproduction and hierarchical clustering to magnify memory bias and uncover inner configurations of fragmented information, using strength of association. We conducted behavioral experiments to test the validity of the tool. Experiment 1a demonstrated that the schematic structure of personality traits uncovered by the ROCK tool highly matched those described by the Big Five theory. This finding was replicated in Experiment 1b, focusing on a lower-level personality dimension extroversion with results aligned with personality theories. Experiment 2 assessed the ROCK tool using artificial stimuli with a pre-defined structure, created using a Markov chain model. Participants acquired the structure of the stimuli through an implicit learning procedure, and the ROCK tool was used to assess their level of recall. The results showed that the learned structure was identical to the designed structure of the stimuli. The results from both studies suggest that the ROCK tool could effectively reveal the structure of mental schemata.
Decreasing Psychiatric Emergency Visits, but Stable Addiction Emergency Visits, During COVID-19—A Time Series Analysis 10 Months Into the Pandemic
Authors: Håkansson Anders , Grudet Cécile
Published: July 2021

Background: The COVID-19 pandemic has been suspected to increase mental health problems, but also to possibly lead to a decreased treatment seeking, for example due to fear of attending hospital. Early findings demonstrate decreased treatment seeking for mental health, which may differ across diagnostic groups. This study aimed to examine treatment uptake at a general psychiatry emergency unit and at an addiction psychiatry emergency unit in Malmö, Sweden, separately. In addition, the study aimed to investigate treatment uptake for different diagnostic groups—during and prior to the COVID-19 pandemic.

Methods: Monthly data for number of unique patients and number of contacts were extracted for the three-year period of January 2018 through December 2020. Data from each facility were analyzed separately for women, men and patients with psychotic, affective, anxiety and substance use-related disorders. Interrupted time series were used to demonstrate possible effects of COVID-19.

Results: COVID-19 was associated with a marked decrease in treatment contacts, both for women and men, in the general psychiatry emergency unit—driven by a significant decrease in anxiety-related disorders (p < 0.001) and affective disorders (p < 0.01)—but not in psychotic or substance use disorders (SUDs). Also, in the addiction psychiatry emergency unit, no significant impact of COVID-19 was seen.

Conclusions: COVID-19 may decrease treatment uptake for acute affective and anxiety-related disorders. Given the hypothesized increase in the population regarding these conditions, societal efforts are needed to facilitate adequate treatment for these patients during the COVID-19 pandemic. Society should also remain vigilant with respect to SUDs during the pandemic.