bluuebunny/crossref_metadata_2025 huggingface dataset:
Splenic Transcriptional Responses in Severe Visceral Leishmaniasis: Impaired Leukocyte Chemotaxis and Cell Cycle Arrest
Authors: de Melo Caroline Vilas Boas , Guimarães Torres Felipe , Hermida Micely D’El-Rei , Fontes Jonathan L. M. , Mesquita Bianca Ramos , Brito Reginaldo , Ramos Pablo Ivan P. , Fernandes Gabriel R. , Freitas Luiz Antônio Rodrigues , Khouri Ricardo , Costa Carlos Henrique Nery , dos-Santos Washington L. C.
Published: November 2021

Structural changes in the spleen have been reported in several infectious diseases. In visceral leishmaniasis (VL), a severe parasitic disease caused byLeishmaniaspp., the loss of white pulp accompanies a severe clinical presentation. Hamster model reproduces aspects of human VL progression. In the early stages, a transcriptomic signature of leukocyte recruitment was associated with white pulp hyperplasia. Subsequently, impaired leukocyte chemotaxis with loss of T lymphocytes in the periarteriolar lymphoid sheath occurred. This differential gene expression was subsequently corroborated by transcriptomic profiling of spleens in severe human VL. At the latest stage, spleen disorganization was associated with increasing clinical signs of VL. White pulp disruption was accompanied by decreasedDLK1expression. The expression ofCXCL13, CCR5, CCL19, CCR6, CCR7andLTAdecreased, likely regulated byCDKN2Aoverexpression. Our findings enlighten a pathway implying cell cycle arrest and decreased gene expression involved in spleen organization.
Loss of Diacylglycerol Kinase α Enhances Macrophage Responsiveness
Authors: Manigat Laryssa C. , Granade Mitchell E. , Taori Suchet , Miller Charlotte Anne , Vass Luke R. , Zhong Xiao-Ping , Harris Thurl E. , Purow Benjamin W.
Published: November 2021

The diacylglycerol kinases (DGKs) are a family of enzymes responsible for the conversion of diacylglycerol (DAG) to phosphatidic acid (PA). In addition to their primary function in lipid metabolism, DGKs have recently been identified as potential therapeutic targets in multiple cancers, including glioblastoma (GBM) and melanoma. Aside from its tumorigenic properties, DGKα is also a known promoter of T-cell anergy, supporting a role as a recently-recognized T cell checkpoint. In fact, the only significant phenotype previously observed in Dgka knockout (KO) mice is the enhancement of T-cell activity. Herein we reveal a novel, macrophage-specific, immune-regulatory function of DGKα. In bone marrow-derived macrophages (BMDMs) cultured from wild-type (WT) and KO mice, we observed increased responsiveness of KO macrophages to diverse stimuli that yield different phenotypes, including LPS, IL-4, and the chemoattractant MCP-1. Knockdown (KD) of Dgka in a murine macrophage cell line resulted in similar increased responsiveness. Demonstrating in vivo relevance, we observed significantly smaller wounds in Dgka-/- mice with full-thickness cutaneous burns, a complex wound healing process in which macrophages play a key role. The burned area also demonstrated increased numbers of macrophages. In a cortical stab wound model, Dgka-/- brains show increased Iba1+ cell numbers at the needle track versus that in WT brains. Taken together, these findings identify a novel immune-regulatory checkpoint function of DGKα in macrophages with potential implications for wound healing, cancer therapy, and other settings.
HIVEP1 Is a Negative Regulator of NF-κB That Inhibits Systemic Inflammation in Sepsis
Authors: Matsumoto Hisatake , Scicluna Brendon P. , Jim Kin Ki , Falahi Fahimeh , Qin Wanhai , Gürkan Berke , Malmström Erik , Meijer Mariska T. , Butler Joe M. , Khan Hina N. , Takagi Tsuyoshi , Ishii Shunsuke , Schultz Marcus J. , van de Beek Diederik , de Vos Alex F. , van ‘t Veer Cornelis , van der Poll Tom
Published: November 2021

Our previous work identified human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) as a putative driver of LPS-induced NF-κB signaling in humans in vivo. While HIVEP1 is known to interact with NF-ĸB binding DNA motifs, its function in mammalian cells is unknown. We report increased HIVEP1 mRNA expression in monocytes from patients with sepsis and monocytes stimulated by Toll-like receptor agonists and bacteria. In complementary overexpression and gene deletion experiments HIVEP1 was shown to inhibit NF-ĸB activity and induction of NF-ĸB responsive genes. RNA sequencing demonstrated profound transcriptomic changes in HIVEP1 deficient monocytic cells and transcription factor binding site analysis showed enrichment for κB site regions. HIVEP1 bound to the promoter regions of NF-ĸB responsive genes. Inhibition of cytokine production by HIVEP1 was confirmed in LPS-stimulated murine Hivep1-/- macrophages and HIVEP1 knockdown zebrafish exposed to the common sepsis pathogen Streptococcus pneumoniae. These results identify HIVEP1 as a negative regulator of NF-κB in monocytes/macrophages that inhibits proinflammatory reactions in response to bacterial agonists in vitro and in vivo.
Interrelation Between Fibroblasts and T Cells in Fibrosing Interstitial Lung Diseases
Authors: Lai Yunxin , Wei Xinru , Ye Ting , Hang Lilin , Mou Ling , Su Jin
Published: November 2021

Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by varying degrees of inflammation and fibrosis of the pulmonary interstitium. The interrelations between multiple immune cells and stromal cells participate in the pathogenesis of ILDs. While fibroblasts contribute to the development of ILDs through secreting extracellular matrix and proinflammatory cytokines upon activation, T cells are major mediators of adaptive immunity, as well as inflammation and autoimmune tissue destruction in the lung of ILDs patients. Fibroblasts play important roles in modulating T cell recruitment, differentiation and function and conversely, T cells can balance fibrotic sequelae with protective immunity in the lung. A more precise understanding of the interrelation between fibroblasts and T cells will enable a better future therapeutic design by targeting this interrelationship. Here we highlight recent work on the interactions between fibroblasts and T cells in ILDs, and consider the implications of these interactions in the future development of therapies for ILDs.
Single-Cell RNA Sequencing Reveals the Heterogeneity of Tumor-Associated Macrophage in Non-Small Cell Lung Cancer and Differences Between Sexes
Authors: Yang Qi , Zhang Hongman , Wei Ting , Lin Anqi , Sun Yueqin , Luo Peng , Zhang Jian
Published: November 2021

Non-Small Cell Lung Cancer (NSCLC) is a disease with high morbidity and mortality, which has sex-related differences in prognosis and immunotherapy efficacy. However, the difference in the mechanisms remains unclear. Macrophages, characterized by high plasticity and heterogeneity, act as one of the key cells that exert anti-tumor effects in the tumor microenvironment (TME) and play a complicated role in the process of tumor progression. To elucidate the subtype composition and functional heterogeneity of tumor-associated macrophages (TAMs) in NSCLC and further compare the sex-mediated differences, we conducted a single-cell level analysis in early-stage smoking NSCLC patients, combined with ssGSEA analysis, pseudotime ordering, and SCENIC analysis. We found two universally presented immune-suppressive TAMs with different functional and metabolic characteristics in the TME of NSCLC. Specifically, CCL18+ macrophages exerted immune-suppressive effects by inhibiting the production of inflammatory factors and manifested high levels of fatty acid oxidative phosphorylation metabolism. Conversely, the main metabolism pathway for SPP1+ macrophage was glycolysis which contributed to tumor metastasis by promoting angiogenesis and matrix remodeling. In terms of the differentially expressed genes, the complement gene C1QC and the matrix remodeling relevant genes FN1 and SPP1 were differentially expressed in the TAMs between sexes, of which the male upregulated SPP1 showed the potential as an ideal target for adjuvant immunotherapy and improving the efficacy of immunotherapy. According to the early-stage TCGA-NSCLC cohort, high expression of the above three genes in immune cells were associated with poor prognosis and acted as independent prognostic factors. Moreover, through verification at the transcription factor, transcriptome, and protein levels, we found that TAMs from women showed stronger immunogenicity with higher interferon-producing and antigen-presenting ability, while men-derived TAMs upregulated the PPARs and matrix remodeling related pathways, thus were more inclined to be immunosuppressive. Deconstruction of the TAMs at the single-cell level deepens our understanding of the mechanism for tumor occurrence and progress, which could be helpful to achieve the precise sex-specific tumor treatment sooner.
Platelet-to-Lymphocyte Ratio as an Independent Factor Was Associated With the Severity of Ankylosing Spondylitis
Authors: Liang Tuo , Chen Jiarui , Xu Guoyong , Zhang Zide , Xue Jiang , Zeng Haopeng , Jiang Jie , Chen Tianyou , Qin Zhaojie , Li Hao , Ye Zhen , Nie Yunfeng , Zhan Xinli , Liu Chong
Published: November 2021

The study was aimed to determine the association of the platelet-lymphocyte ratio (PLR) with the disease activity of ankylosing spondylitis (AS). A total of 275 patients, including 180 AS patients and 95 non-AS patients, participated in the study. We assessed a full blood count for each participant. Platelet to monocyte ratio (PMR), monocytes to lymphocyte ratio (MLR), monocyte to neutrophil ratio (MNR), platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), and platelet to neutrophil ratio (PNR) were calculated. LASSO and logistic regression analyses were performed to establish the nomogram. Receiver operating characteristic (ROC) analysis was performed to evaluate the clinical value of the nomogram. We constructed a novel nomogram, which incorporated easily accessible clinical characteristics like sex, PLR, WBC, EOS, and ESR for AS diagnosis. The AUC value of this nomogram was 0.806; also, the calibration curves indicated a satisfactory agreement between nomogram prediction and actual probabilities. Furthermore, PLR was positively correlated with the severity of AS. PLR was identified as an independent factor for the diagnosis of AS and was associated with the severity of AS.
High Throughput Human T Cell Receptor Sequencing: A New Window Into Repertoire Establishment and Alloreactivity
Authors: Fu Jianing , Khosravi-Maharlooei Mohsen , Sykes Megan
Published: November 2021

Recent advances in high throughput sequencing (HTS) of T cell receptors (TCRs) and in transcriptomic analysis, particularly at the single cell level, have opened the door to a new level of understanding of human immunology and immune-related diseases. In this article, we discuss the use of HTS of TCRs to discern the factors controlling human T cell repertoire development and how this approach can be used in combination with human immune system (HIS) mouse models to understand human repertoire selection in an unprecedented manner. An exceptionally high proportion of human T cells has alloreactive potential, which can best be understood as a consequence of the processes governing thymic selection. High throughput TCR sequencing has allowed assessment of the development, magnitude and nature of the human alloresponse at a new level and has provided a tool for tracking the fate of pre-transplant-defined donor- and host-reactive TCRs following transplantation. New insights into human allograft rejection and tolerance obtained with this method in combination with single cell transcriptional analyses are reviewed here.
Interferons in Pain and Infections: Emerging Roles in Neuro-Immune and Neuro-Glial Interactions
Authors: Tan Ping-Heng , Ji Jasmine , Yeh Chun-Chang , Ji Ru-Rong
Published: November 2021

Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-β are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-β can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections.
Determination of Salmonella enterica Leaf Internalization Varies Substantially According to the Method and Conditions Used to Assess Bacterial Localization
Authors: Chahar Madhvi , Kroupitski Yulia , Gollop Rachel , Belausov Eduard , Melotto Maeli , Sela-Saldinger Shlomo
Published: November 2021

In a previous study, comparing the internalization of S. enterica serovar Typhimurium in various leaves by confocal microscopy, we have demonstrated that the pathogen failed to internalize tomato leaves. Numerous reasons may account for these findings, yet one such factor might be the methodology employed to quantify leaf internalization. To this end, we have systematically studied leaf localization of a Green-fluorescent protein-labeled Salmonella strain in tomato, lettuce, and Arabidopsis leaves by surface sterilization and enumeration of the surviving bacteria, side by side, with confocal microscopy observations. Leaf sterilization was performed using either sodium hypochlorite, silver nitrate, or ethanol for 1 to 7min. The level of internalization varied according to the type of disinfectant used for surface sterilization and the treatment time. Treatment of tomato leaves with 70% ethanol for up to 7min suggested possible internalization of Salmonella, while confocal microscopy showed no internalization. In the case of in lettuce and Arabidopsis leaves, both the plate-count technique and confocal microscopy demonstrated considerable Salmonella internalization thought different sterilization conditions resulted in variations in the internalization levels. Our findings highlighted the dependency of the internalization results on the specific disinfection protocol used to determine bacterial localization. The results underscore the importance of confocal microscopy in validating a particular surface sterilization protocol whenever a new pair of bacterial strain and plant cultivar is studied.
An Intranasal Vaccine Based on Outer Membrane Vesicles Against SARS-CoV-2
Authors: Thapa Himadri B. , Müller Anna M. , Camilli Andrew , Schild Stefan
Published: November 2021

The prevailing pandemic of SARS-CoV-2 highlights the desperate need of alternative vaccine-platforms, which are safe, effective, and can be modified to carry antigens of emerging pathogens. The current SARS-CoV-2 vaccines based on mRNA and adenoviral vector technology meet some of these criteria but still face limitations regarding administration route, mass production, stability, and storage. Herein, we introduce a novel SARS-CoV-2 vaccine candidate based on bacterial outer membrane vesicles (OMVs). Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC) have been genetically modified to produce increased amounts of detoxified OMVs decorated with the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein. Intranasal immunization with RBD-decorated OMVs induced not only a robust immune response against the bacterial outer membrane components but also detectable antibody titers against the Spike protein. Cell culture infection assays using a Spike-pseudotyped lentivirus confirmed the presence of SARS-CoV-2 neutralizing antibodies. Highest titers against the SARS-CoV-2 Spike protein and most potent neutralization activity were observed for an alternating immunization regimen using RBD-decorated OMVs from ETEC and V. cholerae in turn. These results highlight the versatile vaccine applications offered by OMVs via expression of heterologous antigens in the donor bacterium.
Application of a 360-Degree Radiation Thermosonication Technology for the Inactivation of Staphylococcus aureus in Milk
Authors: Zhou Jianwei , Sheng Lele , Lv Ruiling , Liu Donghong , Ding Tian , Liao Xinyu
Published: November 2021

Milk is easy to be contaminated by microorganisms due to its abundant nutrients. In this study, a 360-degree radiation thermosonication (TS) system was developed and utilized for the inactivation of Staphylococcus aureus in milk. The 360-degree radiation TS system-induced inactivation kinetics of S. aureus was fitted best by the Weibull model compared with biphasic and linear models. The treatment time, the exposure temperature, and the applied ultrasound power was found to affect the bactericidal efficacy of the 360-degree radiation TS system. Additionally, the TS condition of 200 W and 63°C for 7.5 min was successfully applied to achieve complete microbial inactivation (under the limit of detection value) in raw milk. The treatment of 360-degree radiation TS can enhance the zeta potential and decrease the average particle size of milk. It also exhibited better retainment of the proteins in milk compared with the ultrahigh temperature and conventional pasteurization processing. Therefore, the 360-degree radiation TS system developed in this study can be used as an alternative technology to assure the microbiological safety and retain the quality of milk, and the Weibull model could be applied for the prediction of the inactivation levels after exposure to this technology.
Social Factors Influence Behavior in the Novel Object Recognition Task in a Mouse Model of Down Syndrome
Authors: Sierra Cesar , De Toma Ilario , Cascio Lorenzo Lo , Vegas Esteban , Dierssen Mara
Published: November 2021

The use of mouse models has revolutionized the field of Down syndrome (DS), increasing our knowledge about neuropathology and helping to propose new therapies for cognitive impairment. However, concerns about the reproducibility of results in mice and their translatability to humans have become a major issue, and controlling for moderators of behavior is essential. Social and environmental factors, the experience of the researcher, and the sex and strain of the animals can all have effects on behavior, and their impact on DS mouse models has not been explored. Here we analyzed the influence of a number of social and environmental factors, usually not taken into consideration, on the behavior of male and female wild-type and trisomic mice (the Ts65Dn model) in one of the most used tests for proving drug effects on memory, the novel object recognition (NOR) test. Using principal component analysis and correlation matrices, we show that the ratio of trisomic mice in the cage, the experience of the experimenter, and the timing of the test have a differential impact on male and female and on wild-type and trisomic behavior. We conclude that although the NOR test is quite robust and less susceptible to environmental influences than expected, to obtain useful results, the phenotype expression must be contrasted against the influences of social and environmental factors.
The Chinese Adolescent Cohort Study: Design, Implementation, and Major Findings
Authors: Duan Ruonan , Wang Xiaoyu , Shan Shufang , Zhao Li , Xiong Jingyuan , Libuda Lars , Cheng Guo
Published: November 2021

The importance of diet quality on children's growth is being increasingly recognized. The Chinese Adolescent Cohort (CAC) is a longitudinal cohort study to comprehensively investigate the health impacts of nutritional factors on child growth. From 2013 to 2018, 6,967 children aged 6–8 years have been recruited from 23 primary schools in Sichuan, Guizhou, and Chongqing, which have been planned to be followed up annually until their age of 15 years. Regular assessments included the measurement of height, weight, waist circumference, and skinfold thicknesses; pubertal development was examined by trained investigators according to Tanner stages; dietary intake was obtained by three 24-h recalls and food frequency questionnaire; validated questionnaires were used to estimate socio-demographic characteristics, physical activity, and sedentary behaviors. Findings from the CAC baseline and the first follow-up data suggested that higher protein intake among girls and unhealthy eating habits among children might increase the risk for childhood obesity. Also, higher intakes of grain and meat and lower overall diet quality and intakes of dietary fiber and tuber might be associated with advanced pubertal development. Those results indicated that the CAC study could contribute to the development of strategies for optimizing Chinese children's health.
Dietary Folic Acid Alters Metabolism of Multiple Vitamins in a CerS6- and Sex-Dependent Manner
Authors: Barron Keri , Ogretmen Besim , Krupenko Natalia
Published: November 2021

Folic acid, an oxidized synthetic pro-vitamin B9, is widely used in vitamin supplement formulations and food fortification to maintain optimal folate status in humans. Studies on folic acid (FA) efficiency in improving folate status and correcting folate deficiency pathologies are abundant, but precise knowledge of FA effects on human and animal tissues is not available. In our recent study, 10-week-old wild-type and CerS6 knockout (KO) mice were placed on FA-deficient, control, or FA over-supplemented diet for 4 weeks. Untargeted metabolomics characterization of mouse liver, brain, and testes tissues after the dietary treatment revealed profound effects of FA on the liver metabolome. Here, we present the analysis of dietary FA effects on tissue concentrations of other vitamins in mice. Despite the expectation that identical dietary supply of the vitamins (excluding FA) to each group should support similar tissue vitamins concentrations, metabolomics data demonstrate significant alterations of tissue concentrations of multiple vitamins by different levels of FA supplementation that were sex- and genotype-dependent. Moreover, we found significant differences in the liver concentration of retinol, thiamin diphosphate, pantetheine, pyridoxal, and pyridoxamine between males and females. While the liver had more changes in vitamins and vitamin derivative levels, the brain tissue and testes also showed changes linked to FA supplementation. Over-supplementation with FA had negative effects on concentrations of vitamins A, B1, B2, and B6, or their metabolites in the liver, but increased intermediates in coenzyme A (CoA) biosynthesis, as well as gamma/beta-tocopherol and phosphorylated forms of B6 in the CerS6 KO brain. Overall, our data demonstrate that dietary FA supplementation significantly affects the metabolism of other vitamins, and that these effects depend on the CerS6 status and sex of the animal. Further research is required to determine whether the observed effects are specific to FA, and the mechanisms that are involved.
Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia
Authors: Edwards Donna M. , Mitchell Dana K. , Abdul-Sater Zahi , Chan Ka-Kui , Sun Zejin , Sheth Aditya , He Ying , Jiang Li , Yuan Jin , Sharma Richa , Czader Magdalena , Chin Pei-Ju , Liu Yie , de Cárcer Guillermo , Nalepa Grzegorz , Broxmeyer Hal E. , Clapp D. Wade , Sierra Potchanant Elizabeth A.
Published: November 2021

Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.
A Novel Hydroxamic Acid-Based Curcumin Derivative as Potent Histone Deacetylase Inhibitor for the Treatment of Glioblastoma
Authors: Wang Hao , Shi Lei , Wang Zhimin
Published: November 2021

Glioblastoma (GBM) is one of the most common primary and deadliest malignant brain tumor with chemoresistance and poor prognosis. There is a lack of effective chemotherapeutic drug for the treatment of GBM. In this work, we reported the preparation of a histone deacetylase (HDAC) inhibitor, DMC-HA, from the structural modification of natural product curcumin. DMC-HAs were tested in an HDAC inhibition assay and an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay for cytotoxicity. It showed potent inhibition of HDAC1–2 and HDAC6 with IC50 values in the submicromolar concentration range. DMC-HA significantly inhibited the proliferation of human glioblastoma U87 cells and mediated apoptosis of U87 cells in a dose- and time-dependent manner. In addition, DMC-HA elevated the acetylation level of histone H3 in U87 cells. Pharmacokinetic studies showed that DMC-HA possessed acceptable pharmacokinetic profiles, accompanied with certain brain permeability. Lastly, we showed that DMC-HA suppressed the growth of tumor in U87 tumor xenograft model in vivo with no obvious toxicity. These results demonstrate that DMC-HA has the potential to be developed as a chemotherapeutic drug for GBM patients.
The Combination of T Stage and the Number of Pathologic Lymph Nodes Provides Better Prognostic Discrimination in Early-Stage Cervical Cancer With Lymph Node Involvement
Authors: Bai Yongrui , Rong Ling , Hu Bin , Ma Xiumei , Wang Jiahui , Chen Haiyan
Published: November 2021

Objective

Stage I and II cervical cancer with pelvic and/or para-aortic lymph node (LN) metastases are upstaged to stage IIIC under the new FIGO 2018 staging system, and radical chemoradiotherapy was recommended. But heterogeneity in outcome existed in this group of patients. We conducted this retrospective analysis to evaluate the heterogeneity of these patients and tried to provide a more detailed classification to reflect the prognosis and guide the treatment. We also evaluated the efficacy and toxicity of surgery followed by sequential chemoradiotherapy in this cohort.

Methods

Early-stage cervical cancer with LN involvement that had radical hysterectomy followed by sequential chemoradiotherapy were retrospectively analyzed. Survival analyses were conducted to identify the prognostic factors.

Results

A total of 242 patients were included in the study; 64 (26.4%) patients had treatment failure, and 51 (21.1%) died. Pathology, T stage, the number of pathologic LN (pLN), and neoadjuvant chemotherapy or not were independent prognostic factors for disease-free survival and overall survival (OS). Patients with T1N < 3 pLN had significantly better survival than T2N < 3 pLN/T1-2 N≥ 3 pLN, with failure rates of 11.6% and 35.8% in each group; and 5 year OS was 92% and 62%, respectively (P = 0.000). About 1.5% of the patients discontinued radiotherapy, and 14.1% had G3-4 hematological toxic effects during radiotherapy; 1.7% developed G2-3 lower limb edema, and 2.9% developed severe urinary toxicity.

Conclusion

Nodal involvement alone is inadequate as the sole pathologic factor to predict survival in early-stage cervical cancer. The combination of tumor and node subcategory provides better prognostic discrimination.
Continuous Renal Replacement Therapy for Two Neonates With Hyperammonemia
Authors: Markham Christopher , Williams Caroline , Miller Cory , Grange Dorothy K. , Davis T. Keefe , Remy Kenneth E.
Published: November 2021

Objectives:This study aims to assess the feasibility of using hemofiltration for ammonia clearance in low body weight infants with an inborn error of metabolism.

Design:A study of two cases.

Setting:Quaternary pediatric hospital (Saint Louis Children's Hospital) NICU and PICU.

Patients:Infants <6 months of age with an ICD-9 diagnosis of 270.6 (hyperammonemia).

Interventions:Continuous renal replacement therapy (CRRT).

Measurements and Main Results:We measure serum ammonia levels over time and the rate of ammonia clearance over time. Continuous renal replacement therapy was more effective than scavenger therapy alone (Ammonul™) for rapid removal of ammonia in low weight infants (as low as 2.5 kg).

Conclusions:Continuous renal replacement therapy is technically feasible in low weight infants with severe hyperammonemia secondary to an inborn error of metabolism.
Circulating Natural Autoantibodies to HER2-Derived Peptides Performed Antitumor Effects on Oral Squamous Cell Carcinoma
Authors: Liu Xiu , He Ziyi , Qu Yi , Meng Qingyong , Qin Lizheng , Hu Ying
Published: November 2021

Natural autoantibodies play a crucial role in destruction of malignant tumors due to immune surveillance function. Epidermal growth factor receptor 2 (HER2) has been found to be highly expressed in a variety of epithelial tumors including oral squamous cell carcinoma (OSCC). The present study was thus undertaken to investigate the effect of anti-HER2 natural autoantibodies on OSCC. Compared with cancer-adjacent tissues, cancer tissues from OSCC patients exhibited higher HER2 expression especially in those with middle & advanced stage OSCC. Plasma anti-HER2 IgG levels examined with an enzyme-linked immunosorbent assay (ELISA) developed in-house showed differences between control subjects, individuals with oral benign tumor and patients with OSCC. In addition, anti-HER2 IgG-abundant plasma was screened from healthy donors to treat OSCC cells and to prepare for anti-HER2 intravenous immunoglobulin (IVIg). Both anti-HER2 IgG-abundant plasma and anti-HER2 IVIg could significantly inhibit proliferation and invasion of OSCC cells by inducing the apoptosis, and also regulate apoptosis-associated factors and epithelial-mesenchymal transition (EMT), respectively. Besides, the complement-dependent cytotoxicity (CDC) pathway was likely to contribute to the anti-HER2 IgG mediated inhibition of OSCC cells. After the HER2 gene was knocked down with HER2-specific siRNAs, the inhibitory effects on OSCC cell proliferation and apoptotic induction faded away. In conclusion, human plasma IgG, or IVIg against HER2 may be a promising agent for anti-OSCC therapy.
The Mechanism Actions of Astragaloside IV Prevents the Progression of Hypertensive Heart Disease Based on Network Pharmacology and Experimental Pharmacology
Authors: Jing Haoran , Xie Rongsheng , Bai Yu , Duan Yuchen , Sun Chongyang , Wang Ye , Cao Rongyi , Ling Zaisheng , Qu Xiufen
Published: November 2021

Astragaloside IV (AS-IV) has been used to treat cardiovascular disease. However, whether AS-IV exerts a protective effect against hypertensive heart disease has not been investigated. This study aimed to investigate the antihypertensive and cardioprotective effects of AS-IV on L-NAME-induced hypertensive rats via network pharmacology and experimental pharmacology. The network pharmacology and bioinformatics analyses were performed to obtain the potential targets of AS-IV and hypertensive heart disease. The rat hypertension model was established by administrated 50 mg/kg/day of L-NAME for 5 weeks. Meanwhile, hypertension rats were intragastrically administrated with vehicle or AS-IV or fosinopril for 5 weeks. Cardiovascular parameters (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rates, and body weight), cardiac function parameters (LVEDd, LVEDs, and fractional shortening), cardiac marker enzymes (creatine kinase, CK-MB, and lactate dehydrogenase), cardiac hypertrophy markers (atrial natriuretic peptide and brain natriuretic peptide), endothelial function biomarkers (nitric oxide and eNOS), inflammation biomarkers (IL-6 and TNF-α) and oxidative stress biomarkers (SOD, MDA, and GSH) were measured and cardiac tissue histology performed. Network pharmacological analysis screened the top 20 key genes in the treatment of hypertensive heart disease treated with AS-IV. Besides, AS-IV exerted a beneficial effect on cardiovascular and cardiac function parameters. Moreover, AS-IV alleviated cardiac hypertrophy via down-regulating the expression of ANP and BNP and improved histopathology changes of cardiac tissue. AS-IV improved endothelial function via the up-regulation of eNOS expression, alleviated oxidative stress via increasing antioxidant enzymes activities, and inhibited cardiac inflammation via down-regulating IL-6 and TNF-α expression. Our findings suggested that AS-IV is a potential therapeutic drug to improve L-NAME-induced hypertensive heart disease partly mediated via modulation of eNOS and oxidative stress.
Therapeutic Role of Sirtuins Targeting Unfolded Protein Response, Coagulation, and Inflammation in Hypoxia-Induced Thrombosis
Authors: Sadia Khan , Ashraf Mohammad Zahid , Mishra Aastha
Published: November 2021

Thrombosis remains one of the leading causes of morbidity and mortality across the world. Many pathological milieus in the body resulting from multiple risk factors escort thrombosis. Hypoxic condition is one such risk factor that disturbs the integrity of endothelial cells to cause an imbalance between anticoagulant and procoagulant proteins. Hypoxia generates reactive oxygen species (ROS) and triggers inflammatory pathways to augment the coagulation cascade. Hypoxia in cells also activates unfolded protein response (UPR) signaling pathways in the endoplasmic reticulum (ER), which tries to restore ER homeostasis and function. But the sustained UPR linked with inflammation, generation of ROS and apoptosis stimulates the severity of thrombosis in the body. Sirtuins, a group of seven proteins, play a vast role in bringing down inflammation, oxidative and ER stress and apoptosis. As a result, sirtuins might provide a therapeutic approach towards the treatment or prevention of hypoxia-induced thrombosis. Sirtuins modulate hypoxia-inducible factors (HIFs) and counteract ER stress-induced apoptosis by attenuating protein kinase RNA-like endoplasmic reticulum kinase (PERK)/Eukaryotic translation initiation factor 2α (eIF2α) pathway activation. It prevents ER-stress mediated inflammation by targeting X-Box Binding Protein 1 (XBP1) and inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling through deacetylation. Sirtuins also obstruct nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome activation to reduce the expression of several pro-inflammatory molecules. It protects cells against oxidative stress by targeting nuclear factor erythroid 2-related factor 2 (Nrf2), glutathione (GSH), forkhead box O3 (FOXO3), superoxide dismutase (SOD), catalase (CAT), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), glucose-6-phosphate dehydrogenase (G6PD), phosphoglucomutase-2 (PGAM2), and NF-κB, to name few. This review, thus, discusses the potential role of sirtuins as a new treatment for hypoxia-induced thrombosis that involves an intersection of UPR and inflammatory pathways in its pathological manifestation.
Lipid Interactions Between Flaviviruses and Mosquito Vectors
Authors: Vial Thomas , Marti Guillaume , Missé Dorothée , Pompon Julien
Published: November 2021

Mosquito-borne flaviviruses, such as dengue (DENV), Zika (ZIKV), yellow fever (YFV), West Nile (WNV), and Japanese encephalitis (JEV) viruses, threaten a large part of the human populations. In absence of therapeutics and effective vaccines against each flaviviruses, targeting viral metabolic requirements in mosquitoes may hold the key to new intervention strategies. Development of metabolomics in the last decade opened a new field of research: mosquito metabolomics. It is now clear that flaviviruses rely on mosquito lipids, especially phospholipids, for their cellular cycle and propagation. Here, we review the biosyntheses of, biochemical properties of and flaviviral interactions with mosquito phospholipids. Phospholipids are structural lipids with a polar headgroup and apolar acyl chains, enabling the formation of lipid bilayer that form plasma- and endomembranes. Phospholipids are mostly synthesized through the de novo pathway and remodeling cycle. Variations in headgroup and acyl chains influence phospholipid physicochemical properties and consequently the membrane behavior. Flaviviruses interact with cellular membranes at every step of their cellular cycle. Recent evidence demonstrates that flaviviruses reconfigure the phospholipidome in mosquitoes by regulating phospholipid syntheses to increase virus multiplication. Identifying the phospholipids involved and understanding how flaviviruses regulate these in mosquitoes is required to design new interventions.
Doxycycline Changes the Transcriptome Profile of mIMCD3 Renal Epithelial Cells
Authors: Jung Hyun Jun , Coleman Richard , Woodward Owen M. , Welling Paul A.
Published: November 2021

Tetracycline-inducible gene expression systems have been used successfully to study gene function in vivo and in vitro renal epithelial models but the effects of the common inducing agent, doxycycline (DOX), on gene expression are not well appreciated. Here, we evaluated the DOX effects on the transcriptome of a widely used renal epithelial cell model, mIMCD3 cells, to establish a reference. Cells were grown on permeable filter supports in the absence and presence of DOX (3 or 6 days), and genome-wide transcriptome profiles were assessed using RNA-Seq. We found DOX significantly altered the transcriptome profile, changing the abundance of 1,549 transcripts at 3 days and 2,643 transcripts at 6 days. Within 3 days of treatment, DOX significantly decreased the expression of multiple signaling pathways (ERK, cAMP, and Notch) that are associated with cell proliferation and differentiation. Genes associated with cell cycle progression were subsequently downregulated in cells treated with DOX for 6 days, as were genes involved in cellular immune response processes and several cytokines and chemokines, correlating with a remarkable repression of genes encoding cell proliferation markers. The results provide new insight into responses of renal epithelial cells to DOX and a establish a resource for DOX-mediated gene expression systems.
Multi-Modal Deep Learning for Weeds Detection in Wheat Field Based on RGB-D Images
Authors: Xu Ke , Zhu Yan , Cao Weixing , Jiang Xiaoping , Jiang Zhijian , Li Shuailong , Ni Jun
Published: November 2021

Single-modal images carry limited information for features representation, and RGB images fail to detect grass weeds in wheat fields because of their similarity to wheat in shape. We propose a framework based on multi-modal information fusion for accurate detection of weeds in wheat fields in a natural environment, overcoming the limitation of single modality in weeds detection. Firstly, we recode the single-channel depth image into a new three-channel image like the structure of RGB image, which is suitable for feature extraction of convolutional neural network (CNN). Secondly, the multi-scale object detection is realized by fusing the feature maps output by different convolutional layers. The three-channel network structure is designed to take into account the independence of RGB and depth information, respectively, and the complementarity of multi-modal information, and the integrated learning is carried out by weight allocation at the decision level to realize the effective fusion of multi-modal information. The experimental results show that compared with the weed detection method based on RGB image, the accuracy of our method is significantly improved. Experiments with integrated learning shows that mean average precision (mAP) of 36.1% for grass weeds and 42.9% for broad-leaf weeds, and the overall detection precision, as indicated by intersection over ground truth (IoG), is 89.3%, with weights of RGB and depth images at α = 0.4 and β = 0.3. The results suggest that our methods can accurately detect the dominant species of weeds in wheat fields, and that multi-modal fusion can effectively improve object detection performance.
Fertilization Following Pollination Predominantly Decreases Phytocannabinoids Accumulation and Alters the Accumulation of Terpenoids in Cannabis Inflorescences
Authors: Lipson Feder Carni , Cohen Oded , Shapira Anna , Katzir Itay , Peer Reut , Guberman Ohad , Procaccia Shiri , Berman Paula , Flaishman Moshe , Meiri David
Published: November 2021

In the last decades, growing evidence showed the therapeutic capabilities of Cannabis plants. These capabilities were attributed to the specialized secondary metabolites stored in the glandular trichomes of female inflorescences, mainly phytocannabinoids and terpenoids. The accumulation of the metabolites in the flower is versatile and influenced by a largely unknown regulation system, attributed to genetic, developmental and environmental factors. As Cannabis is a dioecious plant, one main factor is fertilization after successful pollination. Fertilized flowers are considerably less potent, likely due to changes in the contents of phytocannabinoids and terpenoids; therefore, this study examined the effect of fertilization on metabolite composition by crossbreeding (-)-Δ9-trans-tetrahydrocannabinol (THC)- or cannabidiol (CBD)-rich female plants with different male plants: THC-rich, CBD-rich, or the original female plant induced to develop male pollen sacs. We used advanced analytical methods to assess the phytocannabinoids and terpenoids content, including a newly developed semi-quantitative analysis for terpenoids without analytical standards. We found that fertilization significantly decreased phytocannabinoids content. For terpenoids, the subgroup of monoterpenoids had similar trends to the phytocannabinoids, proposing both are commonly regulated in the plant. The sesquiterpenoids remained unchanged in the THC-rich female and had a trend of decrease in the CBD-rich female. Additionally, specific phytocannabinoids and terpenoids showed an uncommon increase in concentration followed by fertilization with particular male plants. Our results demonstrate that although the profile of phytocannabinoids and their relative ratios were kept, fertilization substantially decreased the concentration of nearly all phytocannabinoids in the plant regardless of the type of fertilizing male. Our findings may point to the functional roles of secondary metabolites in Cannabis.
TbMYC4A Is a Candidate Gene Controlling the Blue Aleurone Trait in a Wheat-Triticum boeoticum Substitution Line
Authors: Liu Xin , Zhang Minghu , Jiang Xiaomei , Li Hui , Jia Zhenjiao , Hao Ming , Jiang Bo , Huang Lin , Ning Shunzong , Yuan Zhongwei , Chen Xuejiao , Chen Xue , Liu Dengcai , Liu Baolong , Zhang Lianquan
Published: November 2021

Triticum boeoticum Boiss (AbAb, 2n = 2x = 14) is one of the sources of the blue grain trait controlled by blue aleurone layer 2 (Ba2). However, the underlying genes have not been cloned. In this study, a transcriptomic comparison between a blue-grained wheat-T. boeoticum substitution line and its wheat parent identified 41 unigenes related to anthocyanin biosynthesis and 29 unigenes related to transport. The bHLH transcription factor gene TbMYC4A showed a higher expression level in the blue-grained substitution line. TbMYC4A contained the three characteristic bHLH transcription factor domains (bHLH-MYC_N, HLH and ACT-like) and clustered with genes identified from other wheat lines with the blue grain trait derived from other Triticeae species. TbMYC4A overexpression confirmed that it was a functional bHLH transcription factor. The analysis of a TbMYC4A-specific marker showed that the gene was also present in T. boeoticum and T. monococcum with blue aleurone but absent in other Triticeae materials with white aleurone. These results indicate that TbMYC4A is a candidate gene of Ba2 controlling the blue aleurone trait. The isolation of TbMYC4A is helpful for further clarifying the genetic mechanism of the blue aleurone trait and is of great significance for breeding blue-grained wheat varieties.
Reversed-Phase HPLC Characterization and Quantification and Antioxidant Capacity of the Phenolic Acids and Flavonoids Extracted From Eight Varieties of Sorghum Grown in Austria
Authors: Speranza Sofia , Knechtl Rebecca , Witlaczil Ragnar , Schönlechner Regine
Published: November 2021

Sorghum is raising great interest as a grain for the future, for its agricultural advantages in times of climate change, and for the positive impact of its bioactive compounds on human health. These compounds comprise phenolic acids, in a free, conjugated, and bound form, and flavonoids. The most commonly used extraction methods require high volumes of chemicals and are non-practical when handling many samples at a time. The main aim of this study was to develop a microscale extraction procedure for both phenolic acids and flavonoids to improve yield and diversity, labor time, and chemicals usage. The improved protocols allowed to perform the extraction in 2-ml safe-lock tubes using around 60 times less chemical volume for phenolic acids and 6 times less for flavonoids. In addition, compared to the macroscale method, the microscale approach was effective in extracting a comparable amount of phenolic acids (between 0.99 and 1.57 mg ferulic acid/g) and even a higher quantity of flavonoids (between 1.10 and 2.24 mg ferulic acid/g). With the established methods, phenolic compounds were extracted from eight varieties of sorghum grown in Austria, previously shown to be promising for food processing. In all sorghum varieties, protocatechuic, vanillic, caffeic, syringic, P-coumaric, and ferulic acids were detected in free, conjugated and bound form, with the last being the most abundant. Arsky and Icebergg varieties presented the lowest (922.65 μg/g) and the highest (1,269.28 μg/g) levels of total phenolic acids, respectively, recorded using high-performance liquid chromatography (HPLC). Flavonoids, comprising luteolinidin, apigenidin, naringenin, apigenin, 5-methoxy-luteolinidin (5-MetO-Lut), and 7-methoxy-apigeninidin (7-MetO-Api), were detected in amounts between 27.03 (Kalatur variety) and 87.52 μg/g (Huggo variety). The red varieties, Huggo, Armorik, and Arsky, had the highest antioxidant activity measured as 2,2-Diphenyl-1-picrylhydrazyl (DPPH) [around 5.00 μg Trolox equivalent (TE)/g] and Azino-bis(3-ehtylbenzthiazoline-6-sulfonic acid) (ABTS) (around 3.00 μg TE/g) scavenging capacity for both phenolic acids and flavonoids. Ferric reducing antioxidant power (FRAP) was the highest for the phenolic acids extracted from a white Ggolden variety.