bluuebunny/crossref_metadata_2025 huggingface dataset:
New Data Define the Molecular Phylogeny and Taxonomy of Four Freshwater Suctorian Ciliates With Redefinition of Two Families Heliophryidae and Cyclophryidae (Ciliophora, Phyllopharyngea, Suctoria)
Authors: Ma Mingzhen , Li Yuqing , Yuan Qingxiang , Zhao Xuetong , Al-Rasheid Khaled A. S. , Huang Jie , Ma Honggang , Chen Xiangrui
Published: December 2021

Four suctorian ciliates, Cyclophrya magna Gönnert, 1935, Peridiscophrya florea (Kormos & Kormos, 1958) Dovgal, 2002, Heliophrya rotunda (Hentschel, 1916) Matthes, 1954 and Dendrosoma radians Ehrenberg, 1838, were collected from a freshwater lake in Ningbo, China. The morphological redescription and molecular phylogenetic analyses of these ciliates were investigated. Phylogenetic analyses inferred from SSU rDNA sequences show that all three suctorian orders, Endogenida, Evaginogenida, and Exogenida, are monophyletic and that the latter two clusters as sister clades. The newly sequenced P. florea forms sister branches with C. magna, while sequences of D. radians group with those from H. rotunda within Endogenida. The family Heliophryidae, which is comprised of only two genera, Heliophrya and Cyclophrya, was previously assigned to Evaginogenida. There is now sufficient evidence, however, that the type genus Heliophrya reproduces by endogenous budding, which corresponds to the definitive feature of Endogenida. In line with this and with the support of molecular phylogenetic analyses, we therefore transfer the family Heliophryidae with the type genus Heliophrya to Endogenida. The other genus, Cyclophrya, still remains in Evaginogenida because of its evaginative budding. Therefore, combined with morphological and phylogenetic analysis, Cyclophyidae are reactivated, and it belongs to Evaginogenida.
Novel Insights Into the Neurobiology of the Antidepressant Response From Ketamine Research: A Mini Review
Authors: Colla Michael , Scheerer Hanne , Weidt Steffi , Seifritz Erich , Kronenberg Golo
Published: December 2021

The serendipitous discovery of ketamine’s antidepressant effects represents one of the major landmarks in neuropsychopharmacological research of the last 50 years. Ketamine provides an exciting challenge to traditional concepts of antidepressant drug therapy, producing rapid antidepressant effects seemingly without targeting monoaminergic pathways in the conventional way. In consequence, the advent of ketamine has spawned a plethora of neurobiological research into its putative mechanisms. Here, we provide a brief overview of current theories of antidepressant drug action including monoaminergic signaling, disinhibition of glutamatergic neurotransmission, neurotrophic and neuroplastic effects, and how these might relate to ketamine. Given that research into ketamine has not yet yielded new therapies beyond ketamine itself, current knowledge gaps and limitations of available studies are also discussed.
Nanocarriers for Inner Ear Disease Therapy
Authors: Xu Xiaoxiang , Zheng Jianwei , He Yanze , Lin Kun , Li Shuang , Zhang Ya , Song Peng , Zhou Yuye , Chen Xiong
Published: December 2021

Hearing loss is a common disease due to sensory loss caused by the diseases in the inner ear. The development of delivery systems for inner ear disease therapy is important to achieve high efficiency and reduce side effects. Currently, traditional drug delivery systems exhibit the potential to be used for inner ear disease therapy, but there are still some drawbacks. As nanotechnology is developing these years, one of the solutions is to develop nanoparticle-based delivery systems for inner ear disease therapy. Various nanoparticles, such as soft material and inorganic-based nanoparticles, have been designed, tested, and showed controlled delivery of drugs, improved targeting property to specific cells, and reduced systemic side effects. In this review, we summarized recent progress in nanocarriers for inner ear disease therapy. This review provides useful information on developing promising nanocarriers for the efficient treatment of inner ear diseases and for further clinical applications for inner ear disease therapy.
Interobserver and Intraobserver Reproducibility and Reliability of the Huashan Clinical Classification System for Hirayama Disease
Authors: Sun Chi , Xu Guangyu , Zhang Yuxuan , Cui Zhongyi , Liu Dayong , Yang Yong , Wang Xiandi , Ma Xiaosheng , Lu Feizhou , Jiang Jianyuan , Wang Hongli
Published: December 2021

Purpose: The Huashan clinical classification system for Hirayama disease has recently been proposed and has been found useful for diagnosis and treatment. So far, however, there has been little in-depth evaluation of its reliability. Thus, this study aimed to assess the reproducibility and reliability of the system.

Methods: Patients diagnosed with Hirayama disease between 2019 and 2020 were recruited. Seven spine surgeons from four different institutions, including an experienced group of three and an inexperienced group of four, were trained as observers of the Huashan clinical classification system for Hirayama disease, and these surgeons classified the recruited patients using the system. Then, 2 months later, they repeated the classification on the same patients in a different order. The interobserver and intraobserver agreement between the results was analyzed using percentage agreement and weighted kappa (κ) statistics.

Results: A total of 60 patients were included in the analysis. For all the observers, experienced observers, and inexperienced observers, the agreement percentages were, respectively, 78.5% (κ = 0.76), 80.0% (κ = 0.78), and 78.9% (κ = 0.77), indicating substantial interobserver reproducibility. For distinguishing typical (Types I and II) and atypical (Type III) Hirayama disease among the different groups of observers, the percentage agreement ranged from 95.6 to 98.9% (κ = 0.74–0.92), indicating substantial to nearly perfect reproducibility. For suggesting conservative treatment (Types I and III) or surgery (Type II), the percentage agreement ranged from 93.3 to 96.4% (κ = 0.81–0.90), indicating nearly perfect reproducibility. As for intraobserver agreement, the percentage agreement ranged from 68.3 to 81.7% (κ = 0.65–0.79), indicating substantial reliability.

Conclusion: The Huashan clinical classification system for Hirayama disease was easy to learn and apply in a clinical environment, showing excellent reproducibility and reliability. Therefore, it would be promising to apply and promote this system for the precise and individualized future treatment of Hirayama disease.
Revealing the Specific Regulations of Brassinolide on Tomato Fruit Chilling Injury by Integrated Multi-Omics
Authors: Bai Chunmei , Zheng Yanyan , Watkins Christopher B. , Fu Anzhen , Ma Lili , Gao HongWu , Yuan Shuzhi , Zheng Shufang , Gao Lipu , Wang Qing , Meng Demei , Zuo Jinhua
Published: December 2021

Tomato fruit is susceptible to chilling injury (CI) when stored at low temperatures, limiting its storage potential, and resulting in economic loss if inappropriate temperatures are used. Brassinolide (BR) is a plant growth regulator that is known to decrease the susceptibility of fruit to CI. In this study, transcriptome, metabolome, and proteome analysis revealed the regulation mechanism of BR treatment in alleviating tomato fruit CI. The results showed that the differentially expressed metabolites mainly included amino acids, organic acids, carbohydrates, and lipids. Differentially expressed genes (DEGs) were involved in plant cold stress response (HSFA3, SHSP, and TPR), fruit redox process (POD, PAL, and LOX), related to the fruit texture (CESA, β-Gal, and PAE), plant hormone signal transduction (ACS3, ARF, and ERF,), transcription factors (TCP, bHLH, GATA). Moreover, differentially expressed proteins were associated with fruit texture (CESA, PE, PL, and CHI), plant oxidation processes (LOX, GPX, CAT, and POD), plant cold stress response (HSF, HSP20, HSP70, and HSP90B), plant hormone signal transduction (BSK1 and JAR1) and transcription factors (WRKY and MYB). Our study showed that BR alleviates CI symptoms of tomato fruit by regulating LOX in the α-linolenic acid metabolism pathway, enhancing jasmonic acid-CoA (JA-CoA) synthesis, inhibiting cell wall and membrane lipid damage. The results provided a theoretical basis for further study on the CI mechanism of tomato fruit.
Antibody Drug Conjugates in Glioblastoma – Is There a Future for Them?
Authors: Parakh Sagun , Nicolazzo Joseph , Scott Andrew M , Gan Hui Kong
Published: December 2021

Glioblastoma (GBM) is an aggressive and fatal malignancy that despite decades of trials has limited therapeutic options. Antibody drug conjugates (ADCs) are composed of a monoclonal antibody which specifically recognizes a cellular surface antigen linked to a cytotoxic payload. ADCs have demonstrated superior efficacy and/or reduced toxicity in a range of haematological and solid tumors resulting in nine ADCs receiving regulatory approval. ADCs have also been explored in patients with brain tumours but with limited success to date. While earlier generations ADCs in glioma patients have had limited success and high toxicity, newer and improved ADCs characterised by low immunogenicity and more effective payloads have shown promise in a range of tumour types. These newer ADCs have also been tested in glioma patients, however, with mixed results. Factors affecting the effectiveness of ADCs to target the CNS include the blood brain barrier which acts as a physical and biochemical barrier, the pro-cancerogenic and immunosuppressive tumor microenvironment and tumour characteristics like tumour volume and antigen expression. In this paper we review the data regarding the ongoing the development of ADCs in glioma patients as well as potential strategies to overcome these barriers to maximise their therapeutic potential.
The Distinct Impact of TAM Infiltration on the Prognosis of Patients With Cardia and Non-Cardia Gastric Cancer and Its Association With H. pylori Infection
Authors: Liu Min , Zhang Li , Zhou Qiuru , Wang Yuejie , Sun Qian , Ren Xiubao
Published: December 2021

Background

In stage III gastric cancer (GC), the role of tumor-associated macrophages (TAMs) and Helicobacter pylori (H. pylori) infection impact tumor progression; however, the specific mechanisms remain controversial. We speculated whether this controversy is caused by differences in the location of TAM infiltration (in the core (CT) and invasive margin (MI) of primary tumors) and the topographical subsites of GC (cardia and non-cardia). Therefore, in this study, we investigated TAMs in different locations and H. pylori infection status as prognostic biomarkers for GC.

Methods

Immunohistochemical staining for CD68 (pan-macrophage), CD163 (M2-like macrophage), and H. pylori in 200 samples (100 cases of cardia-GC [CGC] and 100 cases of non-cardia GC [NCGC]) was performed. We compared the number of CD68+ and CD163+ macrophages that infiltrated the CT and MI in patients with the prognosis of CGC and NCGC, respectively. In addition, we analyzed the relationship between H. pylori status and the prognosis of patients with GC in different locations, as well as the correlation with TAM infiltration.

Results

The distribution of TAMs had distinct characteristics in CGC and NCGC, especially differences between CT and MI subtype. A Kaplan–Meier analysis showed that a high number of CD68+ macrophages that infiltrated the CT in CGC was associated with a better prognosis, whereas infiltration at the MI in NCGC indicated a poor prognosis. Furthermore, a high number of CD163+ macrophages infiltrating the MI resulted in a poor prognosis in CGC and NCGC cohorts. Considering the larger differences in the relationship between the infiltration of CD68+ macrophages at different locations and prognosis, we divided the GC cases into marginal and central GC, based on this difference. This resulted in an accurate estimation of the prognosis. Moreover, positive H. pylori status in central GC was significantly associated with a better prognosis and TAM infiltration.

Conclusion

TAMs in different locations and H. pylori status were identified as independent prognostic markers, with an obvious correlation between them. Therefore, it is important to clarify the impact of TAM location on the prognosis of patients with GC, which contributes to the development of potential therapeutic strategies.
Plasmatic Levels of HSP90α at Diagnosis: A Novel Prognostic Indicator of Clinical Outcome in Advanced Lung Cancer Patients Treated With PD-1/PD-L1 Inhibitors Plus Chemotherapy
Authors: Chen Shubin , Yu Qitao , Zhou Shaozhang
Published: December 2021

Background

The purpose of this study was set to investigate the prognostic role of plasmatic levels of heat shock protein 90 alpha (HSP90α) at diagnosis in advanced lung cancer patients treated with Programmed cell death protein 1 (PD-1)/Programmed cell death-Ligand protein 1 (PD-L1) inhibitors plus chemotherapy.

Methods

A total of 137 advanced lung cancer patients treated with PD-1/PD-L1 inhibitors plus chemotherapy admitted to the Guangxi Medical University Cancer Hospital were enrolled in this study. Smooth curve fitting was conducted to address the nonlinearity of HSP90α and progression-free survival (PFS) and overall survival (OS). We calculated the inflection point using a recursive algorithm. Kaplan–Meier survival analysis and Cox proportional hazards regression model were used to assess the prognostic value of HSP90α for PFS and OS. Subgroup analysis was performed to evaluate the relationship between high HSP90α and disease progression and death risk.

Results

The average age of patients was 58.6 ± 9.8 years, and 73.7% of them were men. We divided patients according to their plasmatic levels of HSP90α into low (HSP90α <52.7 ng/ml) group and high (HSP90α ≥52.7 ng/ml) group. Kaplan–Meier analysis showed a shorter PFS and OS for the high group with log-rank P < 0.05. Univariate and multivariate analyses indicated that high HSP90α was associated with an increased risk of disease progression and death after fully adjusting potential confounders with hazard ratio (HR) 1.8 (95% CI = 1.0–3.2) and HR 2.4 (95% CI = 1.1–5.1), respectively (P < 0.05). After stratification by subgroup analysis, the relationship between high HSP90α and the risk of disease progression and death was consistent across all patient subgroups.

Conclusion

Plasmatic levels of HSP90α at diagnosis can be considered a potential independent prognostic marker of advanced lung cancer patients treated with PD-1/PD-L1 inhibitors plus chemotherapy. A further large-scale prospective validation study is needed to determine whether these results are widely applicable.
Preclinical Evaluation of the HDAC Inhibitor Chidamide in Transformed Follicular Lymphoma
Authors: Zhong Mengya , Tan Jinshui , Pan Guangchao , Jiang Yuelong , Zhou Hui , Lai Qian , Chen Qinwei , Fan Liyuan , Deng Manman , Xu Bing , Zha Jie
Published: December 2021

The key factors leading to transformed follicular lymphoma (t-FL) include the aberrations of epigenetic modifiers as early and driving events, especially mutations in the gene encoding for histone acetyltransferase. Therefore, reversal of this phenomenon by histone deacetylase (HDAC) inhibitors is essential for the development of new treatment strategies in t-FL. Several t-FL cell lines were treated with various doses of chidamide and subjected to cell proliferation, apoptosis and cell cycle analyses with CCK-8 assay, Annexin V/PI assay and flow cytometry, respectively. Chidamide dose-dependently inhibited cell proliferation, caused G0/G1 cycle arrest and triggered apoptosis in t-FL cells. In addition, the effects of chidamide on tumor growth were evaluated in vivo in xenograft models. RNA-seq analysis revealed gene expression alterations involving the PI3K-AKT signaling pathway might account for the mechanism underlying the antitumor activity of chidamide as a single agent in t-FL. These findings provide a basis for further clinical exploration of chidamide as a promising treatment for FL.
Efficacy and Safety of Central Memory T Cells Combined With Adjuvant Therapy to Prevent Recurrence of Hepatocellular Carcinoma With Microvascular Invasion: A Pilot Study
Authors: Cai Jianqiang , Zhao Jianjun , Liu Defang , Xie Huangfan , Qi Hailong , Ma Junfan , Sun Zhongjie , Zhao Hong
Published: December 2021

Background

Postoperative adjuvant transcatheter arterial chemoembolization (TACE) following curative hepatectomy has been reported to improve the clinical outcomes of hepatocellular carcinoma (HCC) patients with microvascular invasion (MVI), but more endeavors are required to achieve greater clinical benefit. Central memory T-cell (Tcm) self-transfusion has shown superior antitumor activity in several preclinical studies; however, clinical studies are rare. The aim of this study was to evaluate the clinical benefit and safety of combination treatment with Tcm self-transfusion and TACE as adjuvant treatment in HCC patients with MVI after curative hepatectomy.

Methods

From October 2016 to September 2018, primary HCC patients with histologically confirmed MVI who underwent curative hepatectomy at the Cancer Hospital of the Chinese Academy of Medical Sciences were recruited for this study. The patients were divided into a Tcm group (combined Tcm self-transfusion with TACE treatment) or a control group (TACE treatment alone) according to their willingness. The recurrence-free survival (RFS), quality-of-life (QOL) score, and adverse events of each patient were recorded within 2 years.

Results

A total of 52 patients were enrolled, and 48 were eligible for the final data analysis. The median follow-up time was 20.5 months (95% CI: 17.05–22.55 months). The median RFS time was 9.5 months in the control group; the cutoff date was not reached in the Tcm group (when the follow-up duration was 12 months, p = 0.049, HR = 0.40; 95% CI: 0.16–0.99). Compared with the control group, 1- and 2-year RFS rates were higher in the Tcm group (72.0% vs. 46.4% and 58.18% vs. 39.14%, respectively). Multivariate analysis did not indicate that Tcm treatment was an independent prognostic factor associated with HCC recurrence (p = 0.107, HR = 2.312; 95% CI: 0.835–6.400), which might be due to the small sample size of this study. Nevertheless, Tcm treatment effectively improved a reduced QOL due to HCC and liver function injury. Finally, the safety profile of Tcm treatment in this study was good, without any serious adverse events.

Conclusions

This pilot study showed that Tcm self-transfusion combined with TACE treatment might be a beneficial adjuvant therapy with good safety for primary HCC patients with MVI after curative hepatectomy.

Trial registration number

NCT03575806
Effect of HIPEC on Peritoneal Recurrence in Peritoneal Metastasis Treated With Cytoreductive Surgery: A Systematic Review
Authors: Yap Daniel Ren Yi , Wong Jolene Si Min , Tan Qiu Xuan , Tan Joey Wee-Shan , Chia Claramae Shulyn , Ong Chin-Ann Johnny
Published: December 2021

Background

Peritoneal metastasis (PM) is a late-stage manifestation of intra-abdominal malignancies. The current standard of care indicates that cure can only be achieved with cytoreductive surgery (CRS) which is often indicated with concurrent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). However, the utility of HIPEC within subsets of PM is not fully understood. We seek to compare the effectiveness of HIPEC in improving peritoneal recurrence rates in PM of different origins.

Methods

We conducted a systematic review of trials on the PubMed, EMBASE, and Cochrane databases, last searched in August 2021. Biases were assessed using the Cochrane Collaboration’s tool for assessing the risk of bias in randomized trials as well as the Methodological Index for Non-Randomized Studies (MINORS) framework.

Results

7 gastric PM studies, 3 ovarian PM studies, and 3 colorectal PM studies were included. Recurrence-free survival was improved in the HIPEC + CRS cohort in 5 gastric trials but only 1 ovarian trial and none of colorectal origin.

Discussion

Our findings indicate decent effectiveness of HIPEC in gastric PM, but limited utility in ovarian and colorectal PM. Limitations in the current literature are attributed to the paucity of data available, a lack of homogeneity and consideration of novel and personalised treatment regimens. We implore for further studies to be conducted with a focus on patient selection and stratification, and suggest a reframing of approach towards modern molecular and targeted therapeutic options in future studies of HIPEC.

Systematic Review Registration

https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/60c1ffff0c1b78001e8efbe3/, identifier reviewregistry1166.
Feasibility and Effect of Physiological-Based CPAP in Preterm Infants at Birth
Authors: Martherus Tessa , Kuypers Kristel L. A. M. , Böhringer Stefan , Dekker Janneke , Witlox Ruben S. G. M. , Hooper Stuart B. , Pas Arjan B. te
Published: December 2021

Background: Preterm infants are commonly supported with 5–8 cmH2O CPAP. However, animal studies demonstrate that high initial CPAP levels (12–15 cmH2O) which are then reduced (termed physiological based (PB)-CPAP), improve lung aeration without adversely affecting cardiovascular function. We investigated the feasibility of PB-CPAP and the effect in preterm infants at birth.

Methods: Preterm infants (24–30 weeks gestation) were randomized to PB-CPAP or 5–8 cmH2O CPAP for the first 10 min after birth. PB-CPAP consisted of 15 cmH2O CPAP that was decreased when infants were stabilized (heart rate ≥100 bpm, SpO2 ≥85%, FiO2 ≤ 0.4, spontaneous breathing) to 8 cmH2O with steps of ~2/3 cmH2O/min. Primary outcomes were feasibility and SpO2 in the first 5 min after birth. Secondary outcomes included physiological and breathing parameters and short-term neonatal outcomes. Planned enrollment was 42 infants.

Results: The trial was stopped after enrolling 31 infants due to a low inclusion rate and recent changes in the local resuscitation guideline that conflict with the study protocol. Measurements were available for analysis in 28 infants (PB-CPAP n = 8, 5–8 cmH2O n = 20). Protocol deviations in the PB-CPAP group included one infant receiving 3 inflations with 15 cmH2O PEEP and two infants in which CPAP levels were decreased faster than described in the study protocol. In the 5–8 cmH2O CPAP group, three infants received 4, 10, and 12 cmH2O CPAP. During evaluations, caregivers indicated that the current PB-CPAP protocol was difficult to execute. The SpO2 in the first 5 min after birth was not different [61 (49–70) vs. 64 (47–74), p = 0.973]. However, infants receiving PB-CPAP achieved higher heart rates [121 (111–130) vs. 97 (82–119) bpm, p = 0.016] and duration of mask ventilation was shorter [0:42 (0:34–2:22) vs. 2:58 (1:36–6:03) min, p = 0.020]. Infants in the PB-CPAP group required 6:36 (5:49-11:03) min to stabilize, compared to 9:57 (6:58–15:06) min in the 5–8 cmH2O CPAP group (p = 0.256). There were no differences in short-term outcomes.

Conclusion: Stabilization of preterm infants with PB-CPAP is feasible but tailoring CPAP appeared challenging. PB-CPAP did not lead to higher SpO2 but increased heart rate and shortened the duration of mask ventilation, which may reflect faster lung aeration.
Antiproliferative, Antiangiogenic, and Antimetastatic Therapy Response by Mangiferin in a Syngeneic Immunocompetent Colorectal Cancer Mouse Model Involves Changes in Mitochondrial Energy Metabolism
Authors: Rodriguez-Gonzalez Julio César , Hernández-Balmaseda Ivones , Declerck Ken , Pérez-Novo Claudina , Logie Emilie , Theys Claudia , Jakubek Patrycja , Quiñones-Maza Olga Luisa , Dantas-Cassali Geovanni , Carlos dos Reis Diego , Van Camp Guy , Lopes Paz Miriam Teresa , Rodeiro-Guerra Idania , Delgado-Hernández René , Vanden Berghe Wim
Published: December 2021

In spite of the current advances and achievements in cancer treatments, colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. Drug resistance, adverse side effects and high rate of angiogenesis, metastasis and tumor relapse remain one of the greatest challenges in long-term management of CRC and urges need for new leads of anticancer drugs. We demonstrate that CRC treatment with the phytopharmaceutical mangiferin (MGF), a glucosylxanthone present in Mango tree stem bark and leaves (Mangifera Indica L.), induces dose-dependent tumor regression and decreases lung metastasis in a syngeneic immunocompetent allograft mouse model of murine CT26 colon carcinoma, which increases overall survival of mice. Antimetastatic and antiangiogenic MGF effects could be further validated in a wound healing in vitro model in human HT29 cells and in a matrigel plug implant mouse model. Interestingly, transcriptome pathway enrichment analysis demonstrates that MGF inhibits tumor growth, metastasis and angiogenesis by multi-targeting of mitochondrial oxidoreductase and fatty acid β-oxidation metabolism, PPAR, SIRT, NFκB, Stat3, HIF, Wnt and GP6 signaling pathways. MGF effects on fatty acid β-oxidation metabolism and carnitine palmitoyltransferase 1 (CPT1) protein expression could be further confirmed in vitro in human HT29 colon cells. In conclusion, antitumor, antiangiogenic and antimetastatic effects of MGF treatment hold promise to reduce adverse toxicity and to mitigate therapeutic outcome of colorectal cancer treatment by targeting mitochondrial energy metabolism in the tumor microenvironment.
Rational Designed Hybrid Peptides Show up to a 6-Fold Increase in Antimicrobial Activity and Demonstrate Different Ultrastructural Changes as the Parental Peptides Measured by BioSAXS
Authors: Hilpert Kai , Gani Jurnorain , Rumancev Christoph , Simpson Nathan , Lopez-Perez Paula Matilde , Garamus Vasil M. , von Gundlach Andreas Robert , Markov Petar , Scocchi Marco , Mikut Ralf , Rosenhahn Axel
Published: December 2021

Antimicrobial peptides (AMPs) are a promising class of compounds being developed against multi-drug resistant bacteria. Hybridization has been reported to increase antimicrobial activity. Here, two proline-rich peptides (consP1: VRKPPYLPRPRPRPL-CONH2 and Bac5-v291: RWRRPIRRRPIRPPFWR-CONH2) were combined with two arginine-isoleucine-rich peptides (optP1: KIILRIRWR-CONH2 and optP7: KRRVRWIIW-CONH2). Proline-rich antimicrobial peptides (PrAMPs) are known to inhibit the bacterial ribosome, shown also for Bac5-v291, whereas it is hypothesized a “dirty drug” model for the arginine-isoleucine-rich peptides. That hypothesis was underpinned by transmission electron microscopy and biological small-angle X-ray scattering (BioSAXS). The strength of BioSAXS is the power to detect ultrastructural changes in millions of cells in a short time (seconds) in a high-throughput manner. This information can be used to classify antimicrobial compounds into groups according to the ultrastructural changes they inflict on bacteria and how the bacteria react towards that assault. Based on previous studies, this correlates very well with different modes of action. Due to the novelty of this approach direct identification of the target of the antimicrobial compound is not yet fully established, more research is needed. More research is needed to address this limitation. The hybrid peptides showed a stronger antimicrobial activity compared to the proline-rich peptides, except when compared to Bac5-v291 against E. coli. The increase in activity compared to the arginine-isoleucine-rich peptides was up to 6-fold, however, it was not a general increase but was dependent on the combination of peptides and bacteria. BioSAXS experiments revealed that proline-rich peptides and arginine-isoleucine-rich peptides induce very different ultrastructural changes in E. coli, whereas a hybrid peptide (hyP7B5GK) shows changes, different to both parental peptides and the untreated control. These different ultrastructural changes indicated that the mode of action of the parental peptides might be different from each other as well as from the hybrid peptide hyP7B5GK. All peptides showed very low haemolytic activity, some of them showed a 100-fold or larger therapeutic window, demonstrating the potential for further drug development.
Euphorbia Factor L2 ameliorates the Progression of K/BxN Serum-Induced Arthritis by Blocking TLR7 Mediated IRAK4/IKKβ/IRF5 and NF-kB Signaling Pathways
Authors: Tang Jing , Cheng Xiaolan , Yi Shiyu , Zhang Yuanyuan , Tang Zhigang , Zhong Yutong , Zhang Qiuping , Pan Bin , Luo Yubin
Published: December 2021

Toll like receptor (TLR)s have a central role in regulating innate immunity and their activation have been highlighted in the pathogenesis of rheumatoid arthritis (RA). EFL2, one of diterpenoids derived fromEuphorbiaseeds, is nearly unknown expect for its improving effect on acute lung injury. Our present study aimed to investigate EFL2’s pharmacokinetic features, its therapeutic effect on rheumatoid arthritis, and explored the potential anti-arthritic mechanisms. K/BxN serum transfer arthritis (STA) murine model was used to assess EFL2’s anti-arthritic effects. We also applied UPLC-MS method to measure the concentrations of EFL2 in plasma. The inhibitory effects of this compound on inflammatory cells infiltration and activation were determined by flow cytometry analysis and quantitative real-time polymerase chain reaction (qRT-PCR)in vivo, and immunochemistry staining and ELISA in murine macrophages and human PBMCsin vitro, respectively. The mechanism of EFL2 on TLRs mediated signaling pathway was evaluated by PCR array, Western blot, plasmid transfection and confocal observation. Intraperitoneal (i.p.) injection of EFL2, instead of oral administration, could effectively ameliorate arthritis severity of STA mice. The inflammatory cells migration and infiltration into ankles were also significantly blocked by EFL2, accompanied with dramatically reduction of chemokines mRNA expression and pro-inflammatory cytokines production.In vivoPCR microarray indicated that EFL2 exerted anti-arthritis bioactivity by suppressing TLR7 mediated signaling pathway.In vitrostudy confirmed the inhibitory effects of EFL2 on TLR7 or TLR3/7 synergistically induced inflammatory cytokines secretion in murine macrophages and human PBMCs. In terms of molecular mechanism, we further verified that EFL2 robustly downregulated TLR7 mediated IRAK4-IKKβ-IRF5 and NF-κB signaling pathways activation, and blocked IRF5 and p65 phosphorylation and translocation activity. Taken together, our data indicate EFL2’s therapeutic potential as a candidate for rheumatoid arthritis and other TLR7-dependent diseases.
Cognitive Performance During Night Work in the Cold
Authors: Færevik Hilde , Hansen Jakob Hønborg , Wiggen Øystein , Sandsund Mariann
Published: December 2021

Objective: The objective of this study was to investigate how night work at low ambient temperatures affects cognitive performance (short-term memory and reaction time), skin- and core temperature, thermal comfort, sleepiness, and cortisol. We hypothesized that cognitive performance is reduced at night compared with daytime and worsened when exposed to low ambient temperatures.

Method: Eleven male subjects were recruited to perform three tests in a climatic chamber at night and daytime: Night –2°C, Night 23°C and Day 23°C. Each test lasted 6 h. Cognitive performance (short-term memory and reaction time), skin- and core temperature, thermal sensation and comfort, cortisol levels and sleepiness were measured during the tests.

Results: A lower mean skin temperature and corresponding lower thermal sensation were observed at Night –2°C compared to Day 23°C and Night 23°C. Night work caused increased sleepiness and lower cortisol levels, but was not affected by changes in ambient temperatures, thermal comfort, or skin temperatures. There was no effect of either day/night work nor ambient temperature on the short-term memory or reaction time test.

Conclusion: Lower skin- and core temperature were observed at night when exposed to low ambient temperature (–2°C), but there was no effect on short-term memory or reaction time. Increased sleepiness and lower cortisol levels were observed at night compared to daytime and was not influenced by low ambient temperature at night. The result from this study suggests that cognitive performance (short-term memory and reaction time) is not adversely affected by night work when exposed to low ambient temperatures if adequate protective clothing is worn.
A Universal New Definition of Heart Failure With Improved Ejection Fraction for Patients With Coronary Artery Disease
Authors: Huang Haozhang , Liu Jin , Lei Min , Yang Zhou , Bao Kunming , Li Qiang , Lai Wenguang , Wang Bo , He Yibo , Chen Shiqun , Ou Chun-Quan , Abudukerimu Maimaitiaili , Hu Yuying , Tan Ning , Chen Jiyan , Liu Yong
Published: December 2021

Aims: The aims of this study were to describe the characteristics and outcomes of the universal new definition of heart failure with improved ejection fraction (HFimpEF) and to identify predictors for HFimpEF among patients with coronary artery disease (CAD).

Methods: CAD subjects with heart failure with reduced ejection fraction (HFrEF) (EF ≤ 40%) at baseline were enrolled from the real-world registry of the Cardiorenal ImprovemeNt study from January 2007 to December 2018. The new definition of HFimpEF was defined as left ventricular EF (LVEF) of≤40% at baseline and with improvement of up to 40% and at least a ≥ 10% increase during 1 month to 1 year after discharge.

Results: Of the 747 CAD patients with HFrEF (86.7% males, mean age: 61.4 ± 11 years), 267 (35.7%) patients conformed to the new HFimpEF definition. Patients with HFimpEF were younger (adjusted odds ratio [aOR]: 0.98 [0.97–0.99]) and had a higher rate of hypertension (aOR:1.43 [1.04–1.98]), lower rate of percutaneous coronary intervention (PCI) treatment at the time of detection of HFrEF (aOR: 0.48 [0.34–0.69]), history of PCI (aOR: 0.51 [0.28–0.88]), history of acute myocardial infarction (aOR: 0.40 [0.21–0.70]), and lower left ventricular end diastolic diameter (aOR: 0.92 [0.90–0.95]). During 3.3-year follow-up, patients with HFimpEF demonstrated lower rates of long-term all-cause mortality (13.1% vs. 20.8%, aHR: 0.61[0.41–0.90]).

Conclusion: In our study, CAD patients with HFimpEF achieved a better prognosis compared to those with persistent HFrEF. Patients with CAD meeting the criteria for the universal definition of HFimpEF tended to be younger, presented fewer clinical comorbidities, and had lower left ventricular end diastolic diameter.
Symbiosis of Electrical and Metabolic Oscillations in Pancreatic β-Cells
Authors: Marinelli Isabella , Fletcher Patrick A. , Sherman Arthur S. , Satin Leslie S. , Bertram Richard
Published: December 2021

Insulin is secreted in a pulsatile pattern, with important physiological ramifications. In pancreatic β-cells, which are the cells that synthesize insulin, insulin exocytosis is elicited by pulses of elevated intracellular Ca2+ initiated by bursts of electrical activity. In parallel with these electrical and Ca2+ oscillations are oscillations in metabolism, and the periods of all of these oscillatory processes are similar. A key question that remains unresolved is whether the electrical oscillations are responsible for the metabolic oscillations via the effects of Ca2+, or whether the metabolic oscillations are responsible for the electrical oscillations due to the effects of ATP on ATP-sensitive ion channels? Mathematical modeling is a useful tool for addressing this and related questions as modeling can aid in the design of well-focused experiments that can test the predictions of particular models and subsequently be used to improve the models in an iterative fashion. In this article, we discuss a recent mathematical model, the Integrated Oscillator Model (IOM), that was the product of many years of development. We use the model to demonstrate that the relationship between calcium and metabolism in beta cells is symbiotic: in some contexts, the electrical oscillations drive the metabolic oscillations, while in other contexts it is the opposite. We provide new insights regarding these results and illustrate that what might at first appear to be contradictory data are actually compatible when viewed holistically with the IOM.
Comprehensive Transcriptome and Metabolic Profiling of Petal Color Development in Lycoris sprengeri
Authors: Yang Feng , Li Chao-han , Das Debatosh , Zheng Yu-hong , Song Tao , Wang Lan-xiang , Chen Mo-Xian , Li Qing-zhu , Zhang Jianhua
Published: December 2021

Lycoris sprengeri (L. sprengeri) is an important ornamental bulbous plant, and its numerous varieties in different color forms are widely planted. Multiple color types of petals in L. sprengeri provide us with possibilities to delineate the complicated metabolic networks underlying the biochemical traits behind color formation in this plant species, especially petal color. In this study, we sequenced and annotated a reference transcriptome of pink and white petals of L. sprengeri and analyzed the metabolic role of anthocyanin biosynthesis in regulating color pigment metabolism. Briefly, white and pink petal samples were sequenced with an Illumina platform, to obtain the reads that could be assembled into 100,778 unique sequences. Sequences expressed differentially between white vs. pink petals were further annotated with the terms of Gene Ontology (GO), Clusters of Orthologous Groups (COG), Kyoto Encyclopedia of Genes and Genomes (KEGG), and eggNOG. Gene expression analyses revealed the repression of anthocyanin and steroid biosynthesis enzymes and R2R3 MYB transcription factor (TF) genes in white petals compared to pink petals. Furthermore, the targeted metabolic profiling of anthocyanins revealed that color-related delphinidin (Del) and cyanidin (Cy) pigments are lower in white petals, which correlate well with the reduced gene expression levels of anthocyanin biosynthesis genes. Taken together, it is hypothesized that anthocyanin biosynthesis, steroid biosynthesis, and R2R3 MYB TFs may play vital regulatory roles in petal color development in L. sprengeri. This work provides a valuable genomic resource for flower breeding and metabolic engineering in horticulture and markers for studying the flower trait evolution of L. sprengeri.
Imaging of the Entry Pathway of a Cell-Penetrating Peptide–DNA Complex From the Extracellular Space to Chloroplast Nucleoids Across Multiple Membranes in Arabidopsis Leaves
Authors: Oikawa Kazusato , Tateishi Ayaka , Odahara Masaki , Kodama Yutaka , Numata Keiji
Published: December 2021

Each plant cell has hundreds of copies of the chloroplast genome and chloroplast transgenes do not undergo silencing. Therefore, chloroplast transformation has many powerful potential agricultural and industrial applications. We previously succeeded in integrating exogenous genes into the chloroplast genome using peptide–DNA complexes composed of plasmid DNA and a fusion peptide consisting of a cell-penetrating peptide (CPP) and a chloroplast transit peptide (cpPD complex). However, how cpPD complexes are transported into the chloroplast from outside the cell remains unclear. Here, to characterize the route by which these cpPD complexes move into chloroplasts, we tracked their movement from the extracellular space to the chloroplast stroma using a fluorescent label and confocal laser scanning microscopy (CLSM). Upon infiltration of cpPD complexes into the extracellular space of Arabidopsis thaliana leaves, the complexes reached the chloroplast surface within 6h. The cpPD complexes reached were engulfed by the chloroplast outer envelope membrane and gradually integrated into the chloroplast. We detected several cpPD complexes localized around chloroplast nucleoids and observed the release of DNA from the cpPD. Our results thus define the route taken by the cpPD complexes for gene delivery from the extracellular space to the chloroplast stroma.
Integrative Proteomic and Phosphoproteomic Analyses of Pattern- and Effector-Triggered Immunity in Tomato
Authors: Yu Juanjuan , Gonzalez Juan M. , Dong Zhiping , Shan Qianru , Tan Bowen , Koh Jin , Zhang Tong , Zhu Ning , Dufresne Craig , Martin Gregory B. , Chen Sixue
Published: December 2021

Plants have evolved a two-layered immune system consisting of pattern-triggered immunity (PTI) and effector-triggered immunity (ETI). PTI and ETI are functionally linked, but also have distinct characteristics. Unraveling how these immune systems coordinate plant responses against pathogens is crucial for understanding the regulatory mechanisms underlying plant defense. Here we report integrative proteomic and phosphoproteomic analyses of the tomato-Pseudomonas syringae (Pst) pathosystem with different Pst mutants that allow the dissection of PTI and ETI. A total of 225 proteins and 79 phosphopeptides differentially accumulated in tomato leaves during Pst infection. The abundances of many proteins and phosphoproteins changed during PTI or ETI, and some responses were triggered by both PTI and ETI. For most proteins, the ETI response was more robust than the PTI response. The patterns of protein abundance and phosphorylation changes revealed key regulators involved in Ca2+ signaling, mitogen-activated protein kinase cascades, reversible protein phosphorylation, reactive oxygen species (ROS) and redox homeostasis, transcription and protein turnover, transport and trafficking, cell wall remodeling, hormone biosynthesis and signaling, suggesting their common or specific roles in PTI and/or ETI. A NAC (NAM, ATAF, and CUC family) domain protein and lipid particle serine esterase, two PTI-specific genes identified from previous transcriptomic work, were not detected as differentially regulated at the protein level and were not induced by PTI. Based on integrative transcriptomics and proteomics data, as well as qRT-PCR analysis, several potential PTI and ETI-specific markers are proposed. These results provide insights into the regulatory mechanisms underlying PTI and ETI in the tomato-Pst pathosystem, and will promote future validation and application of the disease biomarkers in plant defense.
γ-Aminobutyric Acid (GABA) Priming Improves Seed Germination and Seedling Stress Tolerance Associated With Enhanced Antioxidant Metabolism, DREB Expression, and Dehydrin Accumulation in White Clover Under Water Stress
Authors: Zhou Min , Hassan Muhammad Jawad , Peng Yan , Liu Lin , Liu Wei , Zhang Yan , Li Zhou
Published: December 2021

As an important plant growth regulator, the role of γ-aminobutyric acid (GABA) in regulating seeds germination was less well elucidated under water stress. The present study was conducted to investigate the impact of GABA pretreatment on seeds germination of white clover (Trifolium repens) under water deficient condition. Results demonstrated that seeds pretreated with 2μmol/l GABA significantly alleviated decreases in endogenous GABA content, germination percentage, germination potential, germination index, root length, and fresh weight along with marked reduction in mean germination time after 7days of germination under drought stress. In addition, seeds priming with GABA significantly increased the accumulation of soluble sugars, non-enzymatic antioxidants [reduced ascorbate, dehydroascorbic acid, oxidized glutathione (GSSG), and reduced glutathione (GSH)], and enzymes [superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX), dehydroascorbate reductase (DHAR), glutathioe reductase, and monodehydroasorbate reductase (MDHR)] activities involved in antioxidant metabolism, which could be associated with significant reduction in osmotic potential and the accumulation of superoxide anion, hydrogen peroxide, electrical leakage, and malondialdehyde in seeds under drought stress. The GABA-pretreated seeds exhibited significantly higher abundance of dehydrin (DHN, 56 KDa) and expression levels of DHNs encoding genes (SK2,Y2K,Y2SK, andDehydrin b) and transcription factors (DREB2,DREB3,DREB4, andDREB5) than the untreated seeds during germination under water-limited condition. These results indicated that the GABA regulated improvement in seeds germination associated with enhancement in osmotic adjustment, antioxidant metabolism, andDREB-relatedDHNsexpression. Current study will provide a better insight about the GABA-regulated defense mechanism during seeds germination under water-limited condition.
Hillslope Processes Affect Vessel Lumen Area and Tree Dimensions
Authors: Kašpar Jakub , Šamonil Pavel , Krůček Martin , Vašíčková Ivana , Daněk Pavel
Published: December 2021

The height growth of the trees depends on sufficient mechanical support given by the stem and an effective hydraulic system. On unstable slopes, tree growth is affected by soil pressure from above and potential soil erosion from below the position of tree. The necessary stabilization is then provided by the production of mechanically stronger wood of reduced hydraulic conductivity. Unfortunately, the interaction between tree growth (both radial and axial) and stabilization in the soil is still insufficiently understood. Therefore, in this study, we aimed to quantify the impact of hillslope dynamics on the degree of tree growth and hydraulic limitation, and the potential effect on tree height growth and growth plasticity. To evaluate this effect, we took four cores from 80 individuals of Quercus robur and Fraxinus excelsior and measured tree-ring widths (TRWs) and vessel lumen areas (VLAs). The tree heights were evaluated using a terrestrial laser scanner, and local soil depth was measured by a soil auger. Our data showed a significant limitation of the tree hydraulic system related with the formation of eccentric tree-rings. The stem eccentricity decreased with increasing stem diameter, but at the same time, the negative effect of stem eccentricity on conduit size increased with the increasing stem diameter. Even though this anatomical adaptation associated with the effect of stem eccentricity differed between the tree species (mainly in the different degree of limitations in conduit size), the trees showed an increase in the proportion of hydraulically inactive wood elements and a lowered effectiveness of their hydraulic system. In addition, we observed a larger negative effect of stem eccentricity on VLA in Quercus. We conclude that the stabilization of a tree in unstable soil is accompanied by an inability to create sufficiently effective hydraulic system, resulting in severe height-growth limitation. This affects the accumulation of aboveground biomass and carbon sequestration.
A Multilevel Analysis of the Impact of Unit Tightness vs. Looseness Culture on Attitudes and Behaviors in the Workplace
Authors: Di Santo Daniela , Talamo Alessandra , Bonaiuto Flavia , Cabras Cristina , Pierro Antonio
Published: December 2021

This study examines the impact of work unit-level perceived Tightness vs. Looseness (T-L) culture on individual-level perceived stress, intention to leave, organizational deviance, job satisfaction, effort investment, and organizational commitment. Using quantitative cross-sectional data (N=417) collected from preexisting work units (N=57) in different organizations in Italy, multilevel analysis results revealed that a perceived cultural tightness at the unit level was significantly and positively related to individual-level job satisfaction, effort investment, and organizational commitment and significantly and negatively related to individual-level stress, intention to leave, and organizational deviance. The findings suggest that organizations should promote a culture of tightness to positively influence employee attitudes and behaviors. Limitations and recommendations for future research are discussed.