bluuebunny/crossref_metadata_2025 huggingface dataset:
Aphananthe aspera (Thunb.) Planch.: An Unexploited Eastern Asian Species from the Center of Biodiversity
Authors: Momtaj Maliha , Alam Safaet , Sultana Arifa , Rashid Mohammad A
Published: August 2022

Aphananthe Aspera (Thunb.) Planch. is a towering woody deciduous tree and belongs to riparian forest territory. It is highly allocated to the Northern region of Eastern Asia especially Korea, China, Northern Vietnam, and Japan to be the richest countries with this species. The plants were assayed based on various types of methods including extraction. Based on folkloric usage it is important to treat acne, inflammation and cancer. Google Scholar, Web of Science, PubMed, Science Direct, and MEDLINE etc. are the electronic versions from which many bibliographic records were thoroughly explored to identify, collect, and analyze available information relevant to A. aspera. The extracted data were scrutinized in order to have a better understanding of the existing research on this species and to look into the plant's future potential in pharmaceutical research. This study aims to offer current knowledge on botany, distribution, ethnomedicinal applications, pharmacological actions, clinical study and reported phytochemicals of A. aspera. Finally, this plant is still recommended for extensive research to explore prospective novel sources of novel therapeutic agents as there are very little data available on this plant to the best of our knowledge. Extensive research on this plant can open a new horizon to discover novel therapeutics.
Bangladesh Pharmaceutical Journal 25(2): 218-228, 2022 (July)
Current Health News Vol. 25(2)
Authors: Rashid Md Abdur
Published: August 2022

Abstract not available
Bangladesh Pharmaceutical Journal 25(2): 235, 2022 (July)
Mevlit Kıraati Bağlamında Şiir-Müzik İlişkisi: Felsefi Bir Analiz
Authors: TATAR Burhanettin
Published: August 2022

Mevlid kıraati dediğimizde öncelikle şu üç temel hususu anlamaktayız: 1) Dini tecrübe geleneği; 2) Bir sözlü ve yazılı edebiyat formu olarak mevlid ya da şiir; 3) Bu şiirin müzikal makamlar içinde nadiren besteli ve genel olarak irticalen (doğaçlama) icrası. Bu üç temel unsur arasındaki ilişkilerin analiz edilmesi mevlid dediğimiz geleneğin anlaşılması için önemlidir. Mevlid geleneği derken, özel olarak Süleyman Çelebi’nin Vesiletü’n-Necât adlı mesnevi formundaki kitabında topladığı şiirlerin kıraat geleneğine atıf yapacağımızı belirtmeliyiz. Felsefi analizlerimiz söz konusu kitaptaki şiirler ve müzik arasındaki ilişkiler üzerinde odaklanacaktır. Mevlid kıraatinde söz (şiir)-müzik ilişkisi bazen sözün bazen müziğin daha etkinlik ve ağırlık kazandığı bir etkileşim alanı haline gelir. Mevlidin bestelenmiş hallerini de göz önünde tutarak, şiir-söz ilişkisinde bir diyalog ya da karşılıklı bir söyleşi etkinliğinin genel olarak ortaya çıktığını söyleyebiliriz.
Some considerations on the principles of the Cognitive Theory of Multimedia Learning for instructional video design for the elderly
Authors: Muñoz José Henrique Oliveira de , Letouze Patrick
Published: August 2022

The COVID-19 pandemic exposed that the field of education has been using indiscriminately instructional videos. The starting point is evident, a lack of careful design, and in that scenario, the Cognitive Theory of Multimedia Learning may play a significant role. The rationale of this study is that the elderly, as the targeted audience, might have cognitive decay, hearing loss, or eyesight decline, which might impact the principles of the Cognitive Theory of Multimedia Learning. This work is an analysis of the evidence that supports or not these cognitive processing principles based on previous literature, with an additional investigation of the literature for the Brazilian scientific journals market. Then, some processing principles of this theory are evaluated for instructional video design for the elderly. The main results summarize that only instructional material directly related to the key learning goal should be included, that important information should be highlighted to learners, that longer videos should be broken into meaningful parts, and that redundancy in instructional videos for the elderly should be investigated considering their specificities.
DNA-directed coimmobilization of multiple enzymes on organic−inorganic hybrid DNA flowers
Authors: Li Yali , Wang Jing , Huang Fenghong , Zhang Yufei , Zheng Mingming
Published: August 2022

The artificial multienzyme systems developed by mimicking nature has attracted much interest. However, precisely controlled compositions and ratios of multienzymatic co-immobilization systems are still limited by the indistinguishable nature of enzymes. Herein, a strategy for fabricating DNA-directed immobilization of horseradish peroxidase (HRP) and glucose oxidase (GOx) on hybrid DNA nanoflowers (GOx-HRP@hDFs) is presented. The preparation of micron-sized hybrid DNA flowers (hDFs) begins with the predetermined repeatable polymer-like DNA sequences which contained two strands. The hDFs structure is generated through one-pot rolling circle amplification (RCA) and self-assembly with magnesium pyrophosphate inorganic crystals. Based on the rigid-base pairing, GOx and HRP conjugated with sequences complementary to strands would be anchored to the predesigned locations, respectively. By adjusting the loading amount/ratio of enzymes properly, the maximal catalytic efficiency can be precisely regulated. The reaction activity of GOx-HRP@hDFs was 7.4 times higher than that of the free GOx-HRP under the optimal mole ratio (GOx/HRP 4:1). In addition, this multienzyme catalyst system exhibits excellent precision, specificity, reproducibility, and long-term storage stability when applied to real human blood samples. The preceding results validate that GOx-HRP@hDFs are promising candidates for personal diabetes detection.
Tannic acid assisted metal–chelate interphase toward highly stable Zn metal anodes in rechargeable aqueous zinc-ion batteries
Authors: Hu Nan , Qin Hongyu , Chen Xiangyou , Huang Yanping , Xu Jing , He Huibing
Published: August 2022

Aqueous zinc-ion batteries (AZIBs) have attracted extensive attention because of their eco-friendliness, intrinsic safety, and high theoretical capacity. Nevertheless, the long-standing Zn anode issues such as dendrite growth, hydrogen evolution, and passivation greatly restrict the further development of AZIBs. Herein, a metal–chelate interphase with high Zn affinity is constructed on the Zn metal surface (TA@Zn) via dipping metallic Zn into a tannic acid (TA) solution to address the aforementioned problems. Benefiting from the abundant hydrophilic and zincophilic phenolic hydroxyl groups of TA molecules, the metal–chelate interphase shows strong attraction for Zn2+ ions, guiding uniform zinc deposition as well as decreasing Zn2+ migration barrier. Therefore, the TA@Zn anode displays an extended lifespan of 850 h at 1 mA cm−2, 1 mAh cm−2 in the Zn|Zn symmetrical cell, and a high Coulombic efficiency of 96.8% in the Zn|Ti asymmetric cell. Furthermore, the Zn|V2O5 full cell using TA@Zn anode delivers an extremely high capacity retention of 95.9% after 750 cycles at 2 A g−1. This simple and effective strategy broadens the interfacial modification scope on Zn metal anodes for advanced rechargeable Zn metal batteries.
How concerning is a SARS-CoV-2 variant of concern? Computational predictions and the variants labeling system
Authors: Ashoor Dana , Marzouq Maryam , Trabelsi Khaled , Chlif Sadok , Abotalib Nasser , Khalaf Noureddine Ben , Ramadan Ahmed R. , Fathallah M-Dahmani
Published: August 2022

In this study, we evaluated the use of a predictive computational approach for SARS-CoV-2 genetic variations analysis in improving the current variant labeling system. First, we reviewed the basis of the system developed by the World Health Organization (WHO) for the labeling of SARS-CoV-2 genetic variants and the derivative adapted by the United States Centers for Disease Control and Prevention (CDC). Both labeling systems are based on the virus’ major attributes. However, we found that the labeling criteria of the SARS-CoV-2 variants derived from these attributes are not accurately defined and are used differently by the two agencies. Consequently, discrepancies exist between the labels given by WHO and the CDC to the same variants. Our observations suggest that giving the variant of concern (VOC) label to a new variant is premature and might not be appropriate. Therefore, we used a comparative computational approach to predict the effects of the mutations on the virus structure and functions of five VOCs. By linking these data to the criteria used by WHO/CDC for variant labeling, we ascertained that a predictive computational comparative approach of the genetic variations is a good way for rapid and more accurate labeling of SARS-CoV-2 variants. We propose to label all emergent variants, variant under monitoring or variant being monitored (VUM/VBM), and to carry out computational predictive studies with thorough comparison to existing variants, upon which more appropriate and informative labels can be attributed. Furthermore, harmonization of the variant labeling system would be globally beneficial to communicate about and fight the COVID-19 pandemic.
Gut microbiota remodeling: A promising therapeutic strategy to confront hyperuricemia and gout
Authors: Wang Zhilei , Li Yuchen , Liao Wenhao , Huang Ju , Liu Yanping , Li Zhiyong , Tang Jianyuan
Published: August 2022

The incidence of hyperuricemia (HUA) and gout continuously increases and has become a major public health problem. The gut microbiota, which colonizes the human intestine, has a mutually beneficial and symbiotic relationship with the host and plays a vital role in the host’s metabolism and immune regulation. Structural changes or imbalance in the gut microbiota could cause metabolic disorders and participate in the synthesis of purine-metabolizing enzymes and the release of inflammatory cytokines, which is closely related to the occurrence and development of the metabolic immune disease HUA and gout. The gut microbiota as an entry point to explore the pathogenesis of HUA and gout has become a new research hotspot. This review summarizes the characteristics of the gut microbiota in patients with HUA and gout. Meanwhile, the influence of different dietary structures on the gut microbiota, the effect of the gut microbiota on purine and uric acid metabolism, and the internal relationship between the gut microbiota and metabolic endotoxemia/inflammatory factors are explored. Moreover, the intervention effects of probiotics, prebiotics, and fecal microbial transplantation on HUA and gout are also systematically reviewed to provide a gut flora solution for the prevention and treatment of related diseases.
Porcisia transmission by prediuresis of sand flies
Authors: Sadlova Jovana , Bacikova Dominika , Becvar Tomas , Vojtkova Barbora , England Marion , Shaw Jeffrey , Volf Petr
Published: August 2022

Parasites of the genus Porcisia, together with the genus Endotrypanum, form a sister clade to the species-rich and medically important genus Leishmania. Both Porcisia species, P. hertigi and P. deanei, are dixenous parasites of Neotropical porcupines. Almost 50 years after their first discovery, knowledge of their life cycle remains poor and their insect vectors are unknown. Because competent vectors of their closest phylogenetic relatives, genera Endotrypanum and Leishmania, are phlebotomine sand flies (Diptera: Psychodidae) and/or biting midges (Diptera: Ceratopogonidae), we examined here the potential of both sand flies and biting midges to transmit Porcisia parasites. The insects (Lutzomyia longipalpis, L. migonei and Culicoides sonorensis) were exposed to parasites through the chicken skin membrane and dissected at various time intervals post bloodmeal. Potentially infected females were also allowed to feed on the ears of anaesthetized BALB/c mice and the presence of parasite DNA was subsequently confirmed in the mice by PCR. Porcisia hertigi did not survive defecation in L. longipalpis or L. migonei, suggesting that these sand fly species are unlikely to serve as natural vectors of this parasite. Similarly, P. hertigi infections were lost in Culicoides midges. In contrast, mature P. deanei infections developed in 51-61% of L. longipalpis females, 7.3% of L. migonei females and 7.7% of Culicoides sonorensis females. In all three vector species, P. deanei colonized predominantly Malpighian tubules and produced metacyclic infective forms. Transmission of P. daenei to BALB/c mice was demonstrated via the prediuresis of L. longipalpis females. This mode of transmission, as well the colonization of Malpighian tubules as the dominant tissue of the vector, is unique among trypanosomatids. In conclusion, we demonstrated the vector competence of L. longipalpis for P. deanei but not for P. hertigi, and further studies are needed to evaluate competence of other Neotropical vectors for these neglected parasites.
The emotions effect on a virtual characters design–A student perspective analysis
Authors: del Valle-Canencia Marta , Moreno Martínez Carlos , Rodríguez-Jiménez Rosa-María , Corrales-Paredes Ana
Published: August 2022

Interaction between people and virtual characters through digital and electronic devices is a reality. In this context, the design of virtual characters must incorporate emotional expression at a nonverbal level looking for effective communication with the user. This exploratory study investigates the design features of an avatar functioning as a virtual assistant in educational contexts. From a multidisciplinary approach, the user's research was elaborated by a semi-open questionnaire of self-perception of emotional characteristics: likeability, attractiveness, and applicability of a set of six 2D and 3D characters. The results extracted from a sample of 69 university students provide a relevant information on design features and open new lines for future research. Aspects such as Ekman's basic emotion discrimination and the design of facial expression are analyzed. The incorporation of other body parts, their spatial orientation and contextual elements, seems to contribute to effective emotional communication. The results also highlight how the design of a virtual character should take into consideration the complexity involved in facial gestures and changes in relation to the vertical axis and planes of movement. Finally, this article discusses the complexity involved in expressing a given emotion in a virtual character.
Myocardial disturbances of intermediary metabolism in Barth syndrome
Authors: Greenwell Amanda A. , Tabatabaei Dakhili Seyed Amirhossein , Ussher John R.
Published: August 2022

Barth Syndrome (BTHS) is a rare X-linked mitochondrial disorder due to mutations in the gene TAFAZZIN, which leads to immature cardiolipin (CL) remodeling and is characterized by the development of cardiomyopathy. The immature CL remodeling in BTHS results in electron transport chain respiratory defects and destabilization of supercomplexes, thereby impairing ATP production. Thus, BTHS-related cardiomyopathy appears to share metabolic characteristics of the failing heart being an “engine out of fuel.” As CL associates with numerous mitochondrial enzymes involved in ATP production, BTHS is also characterized by several defects in intermediary energy metabolism. Herein we will describe the primary disturbances in intermediary energy metabolism relating to the heart's major fuel sources, fatty acids, carbohydrates, ketones, and amino acids. In addition, we will interrogate whether these disturbances represent potential metabolic targets for alleviating BTHS-related cardiomyopathy.
Quantifying spatiotemporal dynamics of urban building and material metabolism by combining a random forest model and GIS-based material flow analysis
Authors: Mao Ting , Liu Yupeng , Chen Wei-Qiang , Li Nan , Dong Nan , Shi Yao
Published: August 2022

Understanding building metabolism is critical for guiding urban resource management and addressing challenges in urban sustainable development. Key attributes of buildings, including geolocation, footprint, height, and vintage, are crucial to characterizing spatiotemporal patterns of building metabolism. However, these attributes are usually challenging to obtain broadly and automatically, which obscures a comprehensive understanding and accurate assessment of urban metabolism. Moreover, the lack of a finer spatial pattern of these attributes shadows a spatially explicit characterization of material stock and flow in cities. In this study, we took Shenzhen—whose urbanization over the past three decades has been unprecedented in China and even around the world— has been taken as an example to develop a city-level building dataset based on a random-forest model and quantify the spatiotemporal patterns of material metabolism at relatively high spatial resolution (in 500 m × 500 m grids) by combing material flow analysis (MFA) with geographic information system (GIS). The results show that Shenzhen grew from a small town with 281.02 × 106 m3 of buildings in the 1990s to a mega-city with 3585.5 × 106 m3 of buildings in 2018 and expanded both outward and upward from downtown to suburban areas. The urban “weight” (material stock) increased from 92.69 Mt in the 1990s to 1667.8 Mt in 2018 and tended to be saturated, with an average growth rate of 9.5% per year. Spatially, the south-central areas were the largest container of material stocks and generated the most demolition waste. The spatially explicit maps of building three-dimensional (3-D) form and vintage provide detailed information for architectural conservation and could support the decision-making for urban renewal planning. The spatiotemporal patterns of in-use material stocks and potential generation of construction and demolition waste (CDW) provide a benchmark of environmental risk assessment and potential secondary resources to reduce “original” material consumption, which could help alter urban renewal to an environmental-friendly and sustainable trajectory.
Hydrogen sulfide: A new therapeutic target in vascular diseases
Authors: Zhu Cuilin , Liu Qing , Li Xin , Wei Ran , Ge Tongtong , Zheng Xiufen , Li Bingjin , Liu Kexiang , Cui Ranji
Published: August 2022

Hydrogen sulfide (H2S) is one of most important gas transmitters. H2S modulates many physiological and pathological processes such as inflammation, oxidative stress and cell apoptosis that play a critical role in vascular function. Recently, solid evidence show that H2S is closely associated to various vascular diseases. However, specific function of H2S remains unclear. Therefore, in this review we systemically summarized the role of H2S in vascular diseases, including hypertension, atherosclerosis, inflammation and angiogenesis. In addition, this review also outlined a novel therapeutic perspective comprising crosstalk between H2S and smooth muscle cell function. Therefore, this review may provide new insight inH2S application clinically.
The prevalence of hypothyroxinemia in premature newborns
Authors: Stawerska Renata , Nowak-Bednarek Marzena , Talar Tomasz , Kolasa-Kicińska Marzena , Łupińska Anna , Hilczer Maciej , Gulczyńska Ewa , Lewiński Andrzej
Published: August 2022

Congenital hypothyroidism diagnosed by TSH assessment in bloodspot screening may be overlooked in preterm newborns due to immaturity of the hypothalamus-pituitary-thyroid axis in them. The purpose of the study was to determine the prevalence and causes of hypothyroxinemia in preterm newborns, determined by TSH and FT4 serum concentration measurement, performed on the 3-5th day of life. We assessed TSH, FT4 and FT3 serum concentration on the 3-5th day of life in preterm children born at our centre within three consecutive years. We assessed the incidence of hypothyroxinemia, and its cause: primary hypothyroidism, secondary hypothyroidism or low FT4 syndrome - with normal TSH concentration, its dependence - among others - on gestational age (GA), birth body weight (BBW) and being SGA. A total of 525 preterm children were examined. FT4 concentration was decreased in 14.9% of preterm newborns. The most frequent cause of hypothyroxinemia was low FT4 syndrome (79.5%). More than 92% cases of hypothyroxinemia occurred in children born before the 32nd week and/or with BBW below 1500 g. Thus, every fourth child in these groups had a reduced FT4 concentration. Neonates with hypothyroxinemia were significantly lighter than those with normal FT4. In older and heavier neonates with hypothyroxinemia, serious congenital defects were observed. Neither IVH nor SGA nor twin pregnancies predispose children to hypothyroxinemia. Among newborns with untreated hypothyroxinemia in whom TSH and FT4 assessment was repeated within 2-5 weeks, a decreased FT4 concentration was confirmed in 56.1% of cases. As hypothyroxinemia affects 25% of newborns born before the 32nd week of gestation and those in whom BBW is less than 1500g, it seems that in this group of children the newborn screening should be extended to measure serum TSH and FT4 concentration between the 3-5th day of life. In older and heavier neonates, additional serum TSH and FT4 assessment should be limited to children with severe congenital abnormalities but not to all SGA or twins. Despite the fact that the most common form of preterm hypothyroxinemia is low FT4 syndrome, it should be emphasized that FT4 remains lowered on subsequent testing in more them 50% of cases.
The analysis of Modified Qing’ E Formula on the differential expression of exosomal miRNAs in the femoral head bone tissue of mice with steroid-induced ischemic necrosis of femoral head
Authors: Zhu Wei , Zhang Faxue , Lu Junjie , Ma Chen , Shen Lin , Hu Desheng , Xu Xiaojuan , Shuai Bo
Published: August 2022

Objective

To investigate the differential expression of exosomal miRNAs in the bone marrow tissue of Modified Qing’ E Formula (MQEF) on steroid-induced ischemic necrosis of the femoral head (INFH) model.

Methods

Steroid hormones were used to establish the INFH model and treated with MQEF. After successful modeling, femoral tissue exosomes were isolated for miRNA sequencing to obtain femoral tissue exosomal differential miRNAs. By GO analysis and KEGG analysis of the differential genes in both groups, the major exosomal miRNAs of MQEF exerting anti-INFH as well as the major signaling pathways were identified. Next, a quantitative metabolomic validation of MQEF with broad targeting was performed to obtain the main active components of MQEF and to perform biological analysis and signaling pathway prediction of the active components by network pharmacology. Finally, the sequencing results were validated by using RT-qPCR. The results of miRNA sequencing were verified by double examination of network pharmacology and RT-qPCR, and the exosomal miRNAs regulated by the anti-INFH effect of MQEF and the specific signaling pathway of the effect were clarified.

Results

A total of 65,389 target genes were predicted in the exosomes of two groups of mice, and 18 significant differentially expressed miRNAs were obtained, of which 14 were up-regulated and 4 down-regulated. GO enrichment analysis showed that these predicted target genes were enriched in 12371 biological processes, 1727 cell components, and 4112 molecular functions. KEGG analysis showed that the predicted miRNA target genes were annotated to 342 signal pathways, in which the highly enriched pathways closely related to bone metabolism were PI3K-Akt signal pathway, MAPK signal pathway, and Wnt signal pathway. The most significantly up-regulated miRNAs were miR-185-3p and miR-1b-5p and the most significantly down-regulated miRNAs were miR-129b-5p and miR-223-5p, of which the targeted genes were closely related to the PI3K-Akt signal pathway. MQEF aqueous decoction extract targeted metabolomics quantitatively combined with network pharmacology predicted targets also closely related to PI3K-Akt signaling pathway. Real-time quantitative PCR validation showed that miR-185-3p was up-regulated 7.2-fold and miR-129b-5p was down-regulated 2.2-fold in the treatment group, and the difference was significant (P < 0.05).

Conclusions

MQEF can regulate exosomal miRNA expression in steroid-induced INFH models, miR-185-3p or miR-129b-5p/PI3K-Akt signal axis may be part of the mechanism of MQEF against steroid-induced INFH.
Neuroendocrine regulation of female aggression
Authors: Oliveira Vinícius Elias de Moura , Bakker Julie
Published: August 2022

Classically the neurobiology of aggression has been studied exclusively in males. Thus, females have been considered mildly aggressive except during lactation. Interestingly, recent studies in rodents and humans have revealed that non-lactating females can show exacerbated and pathological aggression similarly to males. This review provides an overview of recent findings on the neuroendocrine mechanisms regulating aggressive behavior in females. In particular, the focus will be on novel rodent models of exaggerated aggression established in non-lactating females. Among the neuromodulatory systems influencing female aggression, special attention has been given to sex-steroids and sex-steroid-sensitive neuronal populations (i.e., the core nuclei of the neural pathway of aggression) as well as to the neuropeptides oxytocin and vasopressin which are major players in the regulation of social behaviors.
Dexamethasone-associated metabolic effects in male mice are partially caused by depletion of endogenous corticosterone
Authors: Koorneef Lisa L. , van der Meulen Merel , Kooijman Sander , Sánchez-López Elena , Scheerstra Jari F. , Voorhoeve Maaike C. , Ramesh Ajith N. Nadamuni , Rensen Patrick C. N. , Giera Martin , Kroon Jan , Meijer Onno C.
Published: August 2022

Synthetic glucocorticoids are clinically used to treat auto-immune and inflammatory disease. Despite the high efficacy, glucocorticoid treatments causes side effects such as obesity and insulin resistance in many patients. Via their pharmacological target, the glucocorticoid receptor (GR), glucocorticoids suppress endogenous glucocorticoid secretion. Endogenous, but not synthetic, glucocorticoids activate the mineralocorticoid receptor (MR) and side effects of synthetic glucocorticoids may thus not only result from GR hyperactivation but also from MR hypoactivation. Here, we tested the hypothesis that reactivation of MR with corticosterone add-on treatment can attenuate the metabolic effects of the synthetic glucocorticoid dexamethasone. Male 8-week-old C57Bl/6J mice received a high-fat diet supplemented with dexamethasone or vehicle, and were subcutaneously implanted with low-dose corticosterone- or vehicle-containing pellets. Dexamethasone strongly reduced body weight and fat mass gain, while corticosterone add-on partially normalized this. Dexamethasone-induced hyperglycemia and hyperinsulinemia were exacerbated by corticosterone add-on, which was prevented by MR antagonism. In subcutaneous white adipose tissue, corticosterone add-on prevented the dexamethasone-induced expression of intracellular lipolysis genes. In brown adipose tissue, dexamethasone also upregulated gene expression of brown adipose tissue identity markers, lipid transporters and lipolysis enzymes, which was prevented by corticosterone add-on. In conclusion, corticosterone add-on treatment prevents several, while exacerbating other metabolic effects of dexamethasone. While the exact role of MR remains elusive, this study suggests that corticosterone suppression by dexamethasone contributes to its effects in mice.
SETD2 regulates gene transcription patterns and is associated with radiosensitivity in lung adenocarcinoma
Authors: Zeng Zihang , Zhang Jianguo , Li Jiali , Li Yangyi , Huang Zhengrong , Han Linzhi , Xie Conghua , Gong Yan
Published: August 2022

Lung adenocarcinoma (LUAD) has high morbidity and mortality worldwide, and its prognosis remains unsatisfactory. Identification of epigenetic biomarkers associated with radiosensitivity is beneficial for precision medicine in LUAD patients. SETD2 is important in repairing DNA double-strand breaks and maintaining chromatin integrity. Our studies established a comprehensive analysis pipeline, which identified SETD2 as a radiosensitivity signature. Multi-omics analysis revealed enhanced chromatin accessibility and gene transcription by SETD2. In both LUAD bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq), we found that SETD2-associated positive transcription patterns were associated with DNA damage responses. SETD2 knockdown significantly upregulated tumor cell apoptosis, attenuated proliferation and migration of LUAD tumor cells, and enhanced radiosensitivity in vitro. Moreover, SETD2 was a favorably prognostic factor whose effects were antagonized by the m6A-related genes RBM15 and YTHDF3 in LUAD. In brief, SETD2 was a promising epigenetic biomarker in LUAD patients.
m6A regulator-based methylation modification patterns and characterization of tumor microenvironment in acute myeloid leukemia
Authors: Xu Zi-Jun , Wen Xiang-Mei , Zhang Yuan-Cui , Jin Ye , Ma Ji-Chun , Gu Yu , Chen Xin-Yi , Xia Pei-Hui , Qian Wei , Lin Jiang , Qian Jun
Published: August 2022

RNA N6-methyladenosine (m6A) is the most common and intensively studied RNA modification that critically regulates RNA metabolism, cell signaling, cell survival, and differentiation. However, the overall role of multiple m6A regulators in the tumor microenvironment (TME) has not yet been fully elucidated in acute myeloid leukemia (AML). In our study, we explored the genetic and transcriptional alterations of 23 m6A regulators in AML patients. Three distinct molecular subtypes were identified and associated with prognosis, patient clinicopathological features, as well as TME characteristics. The TME characterization revealed that m6A patterns were highly connected with metabolic pathways such as biosynthesis of unsaturated fatty acids, cysteine and methionine metabolism, and citrate cycle TCA cycle. Then, based on the differentially expressed genes (DEGs) related to m6A molecular subtypes, our study categorized the entire cohort into three m6A gene clusters. Furthermore, we constructed the m6Ascore for quantification of the m6A modification pattern of individual AML patients. It was found that the tumor-infiltrating lymphocyte cells (TILs) closely correlated with the three m6A clusters, three m6A gene clusters, and m6Ascore. And many biological processes were involved, including glycogen degradation, drug metabolism by cytochrome P450, pyruvate metabolism, and so on. Our comprehensive analysis of m6A regulators in AML demonstrated their potential roles in the clinicopathological features, prognosis, tumor microenvironment, and particularly metabolic pathways. These findings may improve our understanding of m6A regulators in AML and offer new perspectives on the assessment of prognosis and the development of anticancer strategy.
Analysis of the Prognostic Significance and Immune Infiltration of the Amino Acid Metabolism-Related Genes in Colon Adenocarcinoma
Authors: Wang Zhenling , Huang Changzhi , Wu Jingyu , Zhang Hongqiang , Shao Yu , Fu Zan
Published: August 2022

Amino acid metabolization is verified to be a part in the progression of cancer. However, genes related to the amino acid metabolism have not been identified in colon adenocarcinoma (COAD). A systematic prognostic model of COAD becomes a pressing need. Among genes related to the amino acid metabolism, RIMKLB, ASPG, TH, MTAP, AZIN2, PSMB2, HDC, ACMSD, and PSMA8 were identified to construct a risk model. Kaplan–Meier (K–M) analyses demonstrated that the high-risk group achieved a poor prognosis. Area under the respective ROC (AUC) values indicated the robustness of the model. To highlight its clinical value, multivariate Cox was used to obtain the optimal variables to construct a nomogram. A higher tumor mutation burden was observed in the high-risk group. However, the low-risk group had a stronger immune infiltration. Seven molecular subtypes were found by consensus cluster. Twenty-two hub genes were identified related to the ESTIMATE score using WGCNA. In brief, our research constructed a stable prognostic model related to the amino acid metabolism in COAD, revealing its connection to the immune microenvironment. The model guided the outcome of COAD and the direction of immunotherapy.
m7G-Associated subtypes, tumor microenvironment, and validation of prognostic signature in lung adenocarcinoma
Authors: Wang Guangyao , Zhao Mei , Li Jiao , Li Guosheng , Zheng Fukui , Xu Guanglan , Hong Xiaohua
Published: August 2022

Background: 7-Methylguanosine (m7G) is an important posttranscriptional modification that regulates gene expression and is involved in tumorigenesis and development. Tumor microenvironment has been proven to be highly involved in tumor progression and prognosis. However, how m7G-associated genes affect the tumor microenvironment of patients with lung adenocarcinoma (LUAD) remains to be further clarified.

Methods: The genetic alterations of m7G-associated genes and their associations with the prognosis and tumor microenvironment in LUAD patients were systemically analyzed. An m7G-Riskscore was established and analyzed for its performance in disease prognosis and association with patient response to immunotherapy. Expression of the model genes at the protein level was investigated through ex vivo experiments. A nomogram was finally obtained based on the m7G-Riskscore and several significant clinical pathological features.

Results: m7G-Associated genes were obtained from five LUAD datasets from The Cancer Genome Atlas and Gene Expression Omnibus databases, and their expression pattern was determined. Based on the m7G-associated genes, three LUAD clusters were defined. The differentially expressed genes from the three clusters were screened and used to further divide the LUAD patients into two gene clusters. It was demonstrated that the alterations of m7G-associated genes were associated with the clinical pathological features, prognosis, and tumor immune infiltration in LUAD patients. An m7G-Riskscore including CAND1, RRM2, and SLC2A1 was obtained with robust and accurate prognostic performance. WB and cell immunofluorescence also showed significant dysregulation of CAND1, RRM2, and SLC2A1 in LUAD. In addition, a nomogram was established to improve the clinical feasibility of the m7G-Riskscore. Correlation analysis revealed that patients with a lower m7G-Riskscore had higher immune and stromal scores, responded well to chemotherapeutics and multiple targeted drugs, and survived longer. Patients with a higher m7G-Riskscore tended to suffer from a higher tumor mutation burden. Furthermore, the m7G-Riskscore exhibited significant associations with immune cell infiltration and cancer stemness.

Conclusion: This study systemically analyzed m7G-associated genes and identified their potential role in tumor microenvironment and prognosis in patients with LUAD. The findings of the present study may help better understand LUAD from the m7G perspective and also provide a new thought toward the prognosis and treatment of LUAD.
Nucleotide polymorphisms of the maize ZmFWL7 gene and their association with ear-related traits
Authors: Tao Tianyun , Huang Qianfeng , Zuo Zhihao , Lu Yue , Su Xiaomin , Xu Yang , Li Pengcheng , Xu Chenwu , Yang Zefeng
Published: August 2022

Plant fw2.2-like (FWL) genes, encoding proteins harboring a placenta-specific eight domain, have been suggested to control fruit and grain size through regulating cell division, differentiation, and expansion. Here, we re-sequenced the nucleotide sequences of the maize ZmFWL7 gene, a member of the FWL family, in 256 elite maize inbred lines, and the associations of nucleotide polymorphisms in this locus with 11 ear-related traits were further detected. A total of 175 variants, including 159 SNPs and 16 InDels, were identified in the ZmFWL7 locus. Although the promoter and downstream regions showed higher nucleotide polymorphism, the coding region also possessed 61 SNPs and 6 InDels. Eleven polymorphic sites in the ZmFWL7 locus were found to be significantly associated with eight ear-related traits. Among them, two nonsynonymous SNPs (SNP2370 and SNP2898) showed significant association with hundred kernel weight (HKW), and contributed to 7.11% and 8.62% of the phenotypic variations, respectively. In addition, the SNP2898 was associated with kernel width (KW), and contributed to 7.57% of the phenotypic variations. Notably, the elite allele T of SNP2370 was absent in teosintes and landraces, while its frequency in inbred lines was increased to 12.89%. By contrast, the frequency of the elite allele A of SNP2898 was 3.12% in teosintes, and it was raised to 12.68% and 19.92% in landraces and inbred lines, respectively. Neutral tests show that this locus wasn’t artificially chosen during the process of domestication and genetic improvement. Our results revealed that the elite allelic variants in ZmFWL7 might possess potential for the genetic improvement of maize ear-related traits.
Dynamic change of IDO1 activity predicts survival in patients with unresectable stage III NSCLC and chemoradiotherapy
Authors: Wu Linfang , Wang Daquan , Chen Yanhua , Qian Mingmin , Xu Xin , Zhang Tao , Bi Nan , Wang Luhua
Published: August 2022

Objective

High activity of Indoleamine 2,3-dioxygenase1 (IDO1) in lung cancer patients converts tryptophan (Trp), which is the essential amino acid for T-cell metabolism, to kynurenine (Kyn) and consequently suppresses anti-tumor immune responses. We aimed to track the dynamics of IDO1 activity in stage III non-small cell lung cancer (NSCLC) patients who received first-line radiotherapy (RT) and explore its association with survival outcomes.

Materials and methods

Systemic IDO1 activity was calculated by Kyn : Trp ratio. Plasma levels of Kyn and Trp in 113 thoracic RT-received stage III NSCLC patients were measured by high-performance liquid chromatography before the initiation of RT. The dynamic change of IDO1 activity was followed in 24 patients by measuring the Kyn : Trp ratio before, during, and after RT administration.

Results

In 24 patients with dynamic tracking of plasma IDO1 activity, there were no significant alterations observed among the three time points (Friedman test, p = 0.13). The changing pattern of the Kyn : Trp ratio was divided into four groups: decreased consistently during RT, first increased, then decreased, increased consistently, first decreased then increased. Patients whose Kyn : Trp ratio kept decreasing or first increased then decreased were defined as the good-change group. The good-change status was identified as an independent positive factor for overall survival (OS) and progression-free survival (PFS) (p = 0.04; p = 0.01) in multivariate analysis among evaluated parameters. Patients with good change showed significantly superior local control than the bad-change group (p = 0.01, HR = 0.22). In 113 stage III NSCLC patients with pre-radiation Kyn : Trp ratio, a trend that high baseline IDO1 activity was associated with short OS was observed (p = 0.079).

Conclusion

Favorable change in IDO1 activity during RT was associated with superior OS, PFS, and local control. IDO1 activity is a promising biomarker for prognosis in stage III NSCLC patients.
Insulin B-chain hybrid peptides are agonists for T cells reactive to insulin B:9-23 in autoimmune diabetes
Authors: Wenzlau Janet M. , DiLisio James E. , Barbour Gene , Dang Mylinh , Hohenstein Anita C. , Nakayama Maki , Delong Thomas , Baker Rocky L. , Haskins Kathryn
Published: August 2022

Insulin is considered to be a key antigenic target of T cells in Type 1 Diabetes (T1D) and autoimmune diabetes in the NOD mouse with particular focus on the B-chain amino acid sequence B:9-23 as the primary epitope. Our lab previously discovered that hybrid insulin peptides (HIPs), comprised of insulin C-peptide fragments fused to other β-cell granule peptides, are ligands for several pathogenic CD4 T cell clones derived from NOD mice and for autoreactive CD4 T cells from T1D patients. A subset of CD4 T cell clones from our panel react to insulin and B:9-23 but only at high concentrations of antigen. We hypothesized that HIPs might also be formed from insulin B-chain sequences covalently bound to other endogenously cleaved ß-cell proteins. We report here on the identification of a B-chain HIP, termed the 6.3HIP, containing a fragment of B:9-23 joined to an endogenously processed peptide of ProSAAS, as a strong neo-epitope for the insulin-reactive CD4 T cell clone BDC-6.3. Using an I-Ag7 tetramer loaded with the 6.3HIP, we demonstrate that T cells reactive to this B-chain HIP can be readily detected in NOD mouse islet infiltrates. This work suggests that some portion of autoreactive T cells stimulated by insulin B:9-23 may be responding to B-chain HIPs as peptide ligands.
Penta-o-galloyl-beta-d-Glucose (PGG) inhibits inflammation in human rheumatoid arthritis synovial fibroblasts and rat adjuvant-induced arthritis model
Authors: Umar Sadiq , Singh Anil K. , Chourasia Mukesh , Rasmussen Stephanie M. , Ruth Jeffrey H. , Ahmed Salahuddin
Published: August 2022

O-GlcNAcylation is a reversible post-translational modification that regulates numerous cellular processes, including embryonic development as well as immune responses. However, its role in inflammation remains ambiguous. This study was designed to examine the role of O-GlcNAcylation in rheumatoid arthritis (RA) and its regulation using human RA patient-derived synovial fibroblasts (RASFs). The efficacy of penta-O-galloyl-beta-D-glucose (PGG), a potent anti-inflammatory molecule, in regulating inflammatory processes in human RASFs was also evaluated. Human synovial tissues and RASFs exhibited higher expression of O-GlcNAcylation compared to their non-diseased counterparts. Pretreatment of RASFs with Thiamet G, an inhibitor of O-GlcNAcase, markedly increased the O-GlcNAc-modified proteins and concomitantly inhibited the IL-1β-induced IL-6 and IL-8 production in human RASFs in vitro. Pretreatment of human RASFs with PGG (0.5-10 µM) abrogated IL-1β-induced IL-6 and IL-8 production in a dose-dependent manner. Immunoprecipitation analysis showed that PGG inhibited O-GlcNAcylation of TAB1 to reduce its association with TGF β-activated kinase 1 (TAK1) and its autophosphorylation, an essential signaling step in IL-1β-induced signaling pathways. Molecular docking in silico studies shows that PGG occupies the C174 position, an ATP-binding site in the kinase domain to inhibit TAK1 kinase activity. Oral administration of PGG (25 mg/kg/day) for 10 days from disease onset significantly ameliorated rat adjuvant-induced (AIA) in rats. PGG treatment reduced the phosphorylation of TAK1 in the treated joints compared to AIA joints, which correlated with the reduced disease severity and suppressed levels of serum IL-1β, GM-CSF, TNF-α, and RANKL. These findings suggest O-GlcNAcylation as a potential therapeutic target and provide the rationale for testing PGG or structurally similar molecule for their therapeutic efficacy.
Cannabidivarin alleviates neuroinflammation by targeting TLR4 co-receptor MD2 and improves morphine-mediated analgesia
Authors: Wang Xue , Lin Cong , Wu Siru , Zhang Tianshu , Wang Yibo , Jiang Yanfang , Wang Xiaohui
Published: August 2022

Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that regulates the activation of immune cells, which is a target for treating inflammation. In this study, Cannabidivarin (CBDV), an active component of Cannabis, was identified as an antagonist of TLR4. In vitro, intrinsic protein fluorescence titrations revealed that CBDV directly bound to TLR4 co-receptor myeloid differentiation protein 2 (MD2). Cellular thermal shift assay (CETSA) showed that CBDV binding decreased MD2 stability, which is consistent with in silico simulations that CBDV binding increased the flexibility of the internal loop of MD2. Moreover, CBDV was found to restrain LPS-induced activation of TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Hot plate test showed that CBDV potentiated morphine-induced antinociception. Furthermore, CBDV attenuated morphine analgesic tolerance as measured by the formalin test by specifically inhibiting chronic morphine-induced glial activation and pro-inflammatory factors expression in the nucleus accumbent. This study confirms that MD2 is a direct binding target of CBDV for the anti-neuroinflammatory effect and implies that CBDV has great translational potential in pain management.
Regulatory CAR-T cells in autoimmune diseases: Progress and current challenges
Authors: Riet Tobias , Chmielewski Markus
Published: August 2022

CAR (Chimeric Antigen Receptor) T-cell therapy has revolutionized the field of oncology in recent years. This innovative shift in cancer treatment also provides the opportunity to improve therapies for many patients suffering from various autoimmune diseases. Recent studies have confirmed the therapeutic suppressive potential of regulatory T cells (Tregs) to modulate immune response in autoimmune diseases. However, the polyclonal character of regulatory T cells and their unknown TCR specificity impaired their therapeutic potency in clinical implementation. Genetical engineering of these immune modulating cells to express antigen-specific receptors and using them therapeutically is a logical step on the way to overcome present limitations of the Treg strategy for the treatment of autoimmune diseases. Encouraging preclinical studies successfully demonstrated immune modulating properties of CAR Tregs in various mouse models. Still, there are many concerns about targeted Treg therapies relating to CAR target selectivity, suppressive functions, phenotype stability and safety aspects. Here, we summarize recent developments in CAR design, Treg biology and future strategies and perspectives in CAR Treg immunotherapy aiming at clinical translation.
Prenatal antibiotics exposure does not influence experimental allergic asthma in mice
Authors: Lingel Imke , Wilburn Adrienne N. , Hargis Julie , McAlees Jaclyn W. , Laumonnier Yves , Chougnet Claire A. , Deshmukh Hitesh , König Peter , Lewkowich Ian P. , Schmudde Inken
Published: August 2022

Changes in microbiome (dysbiosis) contribute to severity of allergic asthma. Preexisting epidemiological studies in humans correlate perinatal dysbiosis with increased long-term asthma severity. However, these studies cannot discriminate between prenatal and postnatal effects of dysbiosis and suffer from a high variability of dysbiotic causes ranging from antibiotic treatment, delivery by caesarian section to early-life breastfeeding practices. Given that maternal antibiotic exposure in mice increases the risk of newborn bacterial pneumonia in offspring, we hypothesized that prenatal maternal antibiotic-induced dysbiosis induces long-term immunological effects in the offspring that also increase long-term asthma severity. Therefore, dams were exposed to antibiotics (gentamycin, ampicillin, vancomycin) from embryonic day 15 until birth. Six weeks later, asthma was induced in the offspring by repeated applications of house dust mite extract. Airway function, cytokine production, pulmonary cell composition and distribution were assessed. Our study revealed that prenatally induced dysbiosis in mice led to an increase in pulmonary Th17+ non-conventional T cells with limited functional effect on airway resistance, pro-asthmatic Th2/Th17 cytokine production, pulmonary localization and cell-cell contacts. These data indicate that dysbiosis-related immune-modulation with long-term effects on asthma development occurs to a lesser extent prenatally and will allow to focus future studies on more decisive postnatal timeframes.