bluuebunny/crossref_metadata_2025 huggingface dataset:
“We hear everyday, ‘this isn’t me.’” Navigating tensions and opportunities to translate interests toward entrepreneurial making
Authors: Dahn Maggie , Peppler Kylie A. , Ito Mizuko
Published: January 2023

Out-of-school time (OST) makerspaces are spaces for youth to engage in exploratory practices and deepen STEM interests in personally meaningful ways. Many youth—especially teens—additionally benefit from supportive relationships (e.g., caring adult mentors, peer mentors) in these spaces to help them uncover their interests and translate them into long-term trajectories of maker practice. Using a connected learning lens, this paper focuses on supportive adult relationships at a high school OST program (Sunrise of Philadelphia), and the ways in which practices around interest identification and development within its makerspace entrepreneurship program meaningfully impacted learning trajectories for youth by connecting them to new STEM opportunities, knowledge, and experiences. Through an illustrative case study, we present a portrait-of-practice that shows how OST educators facilitated brokering to connect youth to resources, mentoring, materials, and new communities that transcended their specific program. This manuscript contributes to known practices for translating youth interests in makerspaces, including incorporating youth voice and choice and making cultural connections to entrepreneurship opportunities. This case contributes to an understudied area of entrepreneurship education programs and activities that are needed in educational (K-12) makerspaces.
Effect of nocturnal hypoxemia on glycemic control among diabetic Saudi patients presenting with obstructive sleep apnea
Authors: Mahmoud Mahmoud I. , Alotaibi Raed K. , Almusally Rayyan , Shafiek Hanaa , Elamin Yasir , Alhaj Ziad , AlBaker Waleed , Elfaki Alaeldin , Qutub Hatem , Albahrani Suha J. , Alabdrabalnabi Fatima M. , Al Saeed Zahra A. , Al Argan Reem , Al.Rubaish Fatima , Alqurashi Yousef D. , Jatoi Noor-Ahmed , Alharmaly Abdullah H. , Almubarak Zainab Z. , Al Said Abir H. , Albahrani Nada
Published: January 2023

Background

Obstructive sleep apnea (OSA) is a prevalent disease that is associated with an increased incidence of type II diabetes mellitus (DM) if left untreated. We aimed to determine the association between glycosylated hemoglobin (HbA1c) levels and both nocturnal hypoxemia and apnea-hypopnea index (AHI) among a Saudi patients with OSA.

Methods

A cross-sectional study that enrolled 103 adult patients diagnosed with DM and confirmed to have OSA by full night attended polysomnography between 2018 and 2021. Those who presented with acute illness, chronic obstructive pulmonary disease (COPD)/restrictive lung diseases causing sleep-related hypoxemia, or no available HbA1c level within 6 months before polysomnography were excluded from the study. Univariate and multivariate linear regression analyses between HbA1c levels and parameters of interest were tested.

Results

Sixty-seven (65%) of the studied population had uncontrolled DM (HbA1c ≥7%). In univariate regression analysis, there was a significant positive association between HbA1c, and sleep time spent with an oxygen saturation below 90% (T90), female gender, and body mass index (BMI) (p<0.05) but not AHI, or associated comorbidities (p>0.05). In the multivariate analysis, HbA1c was positively associated with increasing T90 (p<0.05), and ODI (p<0.05), but not with AHI (p>0.05).

Conclusion

Nocturnal hypoxemia could be an important factor affecting glycemic control in patients with OSA suffering from DM irrespective of the severity of both diseases.
Circulating estradiol and its biologically active metabolites in endometriosis and in relation to pain symptoms
Authors: Emond Jean-Philippe , Caron Patrick , Pušić Maja , Turcotte Véronique , Simonyan David , Vogler Andrej , Osredkar Joško , Rižner Tea Lanišnik , Guillemette Chantal
Published: January 2023

Objectives

Endometriosis (EM) is an estrogen-dominant inflammatory disease linked to infertility that affects women of reproductive age. EM lesions respond to hormonal signals that regulate uterine tissue growth and trigger inflammation and pain. The objective of this study was to evaluate whether estradiol (E2) and its biologically active metabolites are differentially associated with EM given their estrogenic and non-estrogenic actions including proliferative and inflammatory properties.

Design

We performed a retrospective study of 209 EM cases and 115 women without EM.

Methods

Pain-related outcomes were assessed using surveys with validated scales. Preoperative serum levels of estradiol (E2) and estrone (E1), their 2-, 4- and 16- hydroxylated (OH) and methylated (MeO) derivatives (n=16) were measured by mass spectrometry. We evaluated the associations between estrogen levels and EM anatomic sites, surgical stage, risk of EM, and symptoms reported by women. Spearman correlations established the relationships between circulating steroids.

Results

Of the sixteen estrogens profiled, eleven were detected above quantification limits in most individuals. Steroids were positively correlated, except 2-hydroxy 3MeO-E1 (2OH-3MeO-E1). Higher 2OH-3MeO-E1 was linked to an increased risk of EM (Odd ratio (OR)=1.91 (95%CI 1.09-3.34); P=0.025). Ovarian EM cases displayed enhanced 2-hydroxylation with higher 2MeO-E1 and 2OH-E1 levels (P< 0.009). Abdominal, pelvic and back pain symptoms were also linked to higher 2OH-3MeO-E1 levels (OR=1.86; 95%CI 1.06-3.27; P=0.032).

Conclusions

The 2-hydroxylation pathway emerges as an unfavorable feature of EM, and is associated with ovarian EM and pain related outcomes.
Muscle-specific deletion of Arid5b causes metabolic changes in skeletal muscle that affect adipose tissue and liver
Authors: Murray Jennifer , Ehsani Ali , Najjar Liza , Zhang Guoxiang , Itakura Keiichi
Published: January 2023

Emerging evidence suggests that AT-Rich Interaction Domain 5b (Arid5b) may play a role in energy metabolism in various tissues. To study the metabolic function of Arid5b in skeletal muscle, we generated skeletal muscle-specific Arid5b knockout (Arid5b MKO) mice. We found that Arid5b MKO skeletal muscles preferentially utilized fatty acids for energy generation with a corresponding increase in FABP4 expression. Interestingly, in Arid5b MKO mice, the adipose tissue weight decreased significantly. One possible mechanism for the decrease in adipose tissue weight could be the increase in phospho-HSL and HSL expression in white adipose tissue. While glucose uptake increased in an insulin-independent manner in Arid5b MKO skeletal muscle, glucose oxidation was reduced in conjunction with downregulation of the mitochondrial pyruvate carrier (MPC). We found that glucose was diverted into the pentose phosphate pathway as well as converted into lactate through glycolysis for export to the bloodstream, fueling the Cori cycle. Our data show that muscle-specific deletion of Arid5b leads to changes in fuel utilization in skeletal muscle that influences metabolism in other tissues. These results suggest that Arid5b regulates systemic metabolism by modulating fuel selection.
Hormonal therapy is effective and safe for cryptorchidism caused by idiopathic hypogonadotropic hypogonadism in adult males
Authors: Sun Taotao , Xu Wenchao , Xu Hao , Chen Yinwei , Niu Yonghua , Wang Daoqi , Wang Tao , Yang Weimin , Liu Jihong
Published: January 2023

Background

Hormonal therapy is a reasonable treatment for cryptorchidism caused by idiopathic hypogonadotropic hypogonadism (IHH). However, the clinical evidence on whether it is effective and safe for the treatment of cryptorchidism caused by IHH is lacking.

Aim

To evaluate the effect of hormonal therapy in testicular descent, puberty development, and spermatogenesis in adult males with cryptorchidism caused by IHH.

Methods

This retrospective study included 51 patients with cryptorchidism caused by IHH from the Andrology Clinic of University affiliated teaching hospital. Patients were divided into two groups: group A patients received hormonal therapy; group B patients received surgical treatment for cryptorchidism followed by hormonal therapy.

Results

The rate of successful testicular descent following hormonal therapy (19/32 in group A) or surgical treatment (11/19 in group B) shows no statistically significant difference. There was also no statistically significant difference in penile length, Tanner stage of pubic hair, testicular volume, and success rate of spermatogenesis between the two groups. Testicular atrophy was seen in a single patient in group B.

Conclusions

Hormone therapy in adult males with cryptorchidism caused by IHH is effective and safe regarding testicular descent, puberty development, and spermatogenesis. This study provides new insight into the treatment of cryptorchidism caused by IHH and highlights that hormonal therapy could be an effective, safe, and economic treatment option for cryptorchidism in males caused by IHH.
Relationship between serum thyroid hormones and their associated metabolites, and gene expression bioindicators in the back skin of Rana [Lithobates] catesbeiana tadpoles and frogs during metamorphosis
Authors: Poulsen Rikke , Jackman Shireen H. , Hansen Martin , Helbing Caren C.
Published: January 2023

Anuran metamorphosis is characterized by profound morphological changes including remodeling of tissues and organs. This transition is initiated by thyroid hormones (THs). However, the current knowledge of changing levels of THs during metamorphosis relies on pooled samples using methods known for high variability with sparse reporting of measured variation. Moreover, establishing a clear linkage between key gene expression bioindicators and TH levels throughout the metamorphic process is needed. Using state-of-the-art ultra-high performance liquid chromatography isotope-dilution tandem mass spectrometry, we targeted 12 THs and metabolites in the serum of Rana [Lithobates] catesbeiana (n=5-10) across seven distinct postembryonic stages beginning with premetamorphic tadpoles (Gosner stage 31-33) and continuing through metamorphosis to a juvenile frog (Gosner stage 46). TH levels were related to TH-relevant gene transcripts (thra, thrb, and thibz) in back skin of the same individual animals. Significant increases from basal levels were observed for thyroxine (T4) and 3,3’,5-triiodothyronine (T3) at Gosner stage 41, reaching maximal levels at Gosner stage 44 (28 ± 10 and 2.3 ± 0.5 ng/mL, respectively), and decreasing to basal levels in juvenile frogs. In contrast, 3,5-diiodothyronine (T2) increased significantly at Gosner stage 40 and was maintained elevated until stage 44. While thra transcript levels remained constant and then decreased at the end of metamorphic climax, thrb and thibz were induced to maximal levels at Gosner stage 41, followed by a decrease to basal levels in the froglet. This exemplifies the exquisite timing of events during metamorphosis as classic early response genes are transcribed in anticipation of peak TH concentrations. The distinct T2 concentration profile suggests a biological role of this biomolecule in anuran postembryonic development and an additional aspect that may be a target of anthropogenic chemicals that can disrupt anuran metamorphosis and TH signalling. Hence, as a second aim of the study, we set out to find additional bioindicators of metamorphosis, which can aid future investigations of developmental disruption. Using a sensitive nanoLC-Orbitrap system an untargeted analysis workflow was applied. Among 6,062 endogenous metabolites, 421 showed metamorphosis-dependent concentration dynamics. These potential bioindicators included several carnitines, prostaglandins and some steroid hormones.
Effectiveness and safety of hydrogen inhalation as an adjunct treatment in Chinese type 2 diabetes patients: A retrospective, observational, double-arm, real-life clinical study
Authors: Zhao Ziyi , Ji Hongxiang , Zhao Yunsheng , Liu Zeyu , Sun Ruitao , Li Yuquan , Ni Tongshang
Published: January 2023

Aim

To analyze the effectiveness and safety of hydrogen inhalation (HI) therapy as an adjunct treatment in Chinese type 2 diabetes mellitus (T2DM) patients in a real-life clinical setting.

Methods

This observational, non-interventional, retrospective, double-arm, 6-month clinical study included T2DM patients receiving conventional anti-diabetes medication with or without HI initiation from 2018 to 2021. Patients were assigned to the HI group or non-HI group (control group) after 1:1 propensity score matching (PSM). The mean change in glycated hemoglobin (HbA1c) after 6 months in different groups was evaluated primarily. The secondary outcome was composed of the mean change of fasting plasma glucose (FPG), weight, lipid profile, and homeostasis model assessment. Logistics regression was performed to evaluate the likelihood of reaching different HbA1c levels after 6-month treatment between the groups. Adverse event (AE) was also evaluated in patients of both groups.

Results

In total, 1088 patients were selected into the analysis. Compared to the control group, subjects in HI group maintained greater improvement in the level of HbA1c (-0.94% vs -0.46%), FPG (-22.7 mg/dL vs -11.7 mg/dL), total cholesterol (-12.9 mg/dL vs -4.4 mg/dL), HOMA-IR (-0.76 vs -0.17) and HOMA-β (8.2% vs 1.98%) with all p< 0.001 post the treatment. Logistics regression revealed that the likelihood of reaching HbA1c< 7%, ≥ 7% to< 8% and > 1% reduction at the follow-up period was higher in the HI group, while patients in the control group were more likely to attain HbA1c ≥ 9%. Patients in HI group was observed a lower incidence of several AEs including hypoglycemia (2.0% vs 6.8%), vomiting (2.6% vs 7.4%), constipation (1.7% vs 4.4%) and giddiness (3.3% vs 6.3%) with significance in comparison to the control group.

Conclusion

HI as an adjunct therapy ameliorates glycemic control, lipid metabolism, insulin resistance and AE incidence of T2DM patients after 6-month treatment, presenting a noteworthy inspiration to existing clinical diabetic treatment.
Theabrownin ameliorates liver inflammation, oxidative stress, and fibrosis in MCD diet-fed C57BL/6J mice
Authors: Zhen Qingcai , Liang Qijian , Wang Hongchun , Zheng Yan , Lu Zhongting , Bian Chunyong , Zhao Xiulan , Guo Xin
Published: January 2023

Introduction

Nonalcoholic steatohepatitis (NASH), also known as metabolic steatohepatitis, is a clinical syndrome with pathological changes like alcoholic hepatitis but without a history of excessive alcohol consumption. NASH is closely related to metabolic disorders such as obesity, insulin resistance, type 2 diabetes mellitus, and hyperlipidemia. Its main characteristics are hepatocyte steatosis with hepatocyte injury and inflammation. In severe cases, it can develop into liver cirrhosis. At present, there is no special treatment for NASH. Theabrownin (TB) is the main pigment substance in fermented tea. Theabrownin has beneficial effects on lipid metabolism and intestinal flora. However, the effect of theabrownin on NASH has not been studied.

Methods

This study was aimed at exploring the effects of theabrownin from Fuzhuan brick tea on NASH. 8-week-old mice were randomly assigned to three groups and fed with chow diet (CD), methionine and choline sufficient (MCS) diet (MCS Ctrl), which is a Methionine/choline deficient (MCD) control diet, and MCD diet. After 5 weeks of feeding, the MCD group mice were randomly divided into two groups and were gavaged with double distilled water (MCD Ctrl) or theabrownin (MCD TB) (200mg/kg body weight, dissolved in double distilled water) every day for another 4 weeks respectively, while continuing MCD diet feeding.

Results

We found that theabrownin treatment could not improve liver mass loss and steatosis. However, theabrownin ameliorated liver injury and decreased liver inflammatory response. Theabrownin also alleviated liver oxidative stress and fibrosis. Furthermore, our results showed that theabrownin increased hepatic level of fibroblast growth factor 21 (FGF21) and reduced the phosphorylation of mitogen-activated protein kinase p38 in MCD diet-fed mice.
Evaluation on substitution of energy transition—An empirical analysis based on factor elasticity
Authors: Li Liang , Xiong Weiwei , Duan Weijing , Xiong Yiran
Published: January 2023

The study explores into the dynamic change features and technological differences in substitution between factors and energy sources for various types of China’s technological progresses from 1990 to 2020. The measurement for such a study is conducted from the perspective of factor substitution by employing the transcendental logarithmic production function. The results reveal that the sources of contribution to China’s economic development are mainly attributed to non-energy factors such as capital and labor, as capital and labor can effectively substitute energy, and non-fossil energy sources possess certain comparative advantages over fossil energy sources in terms of technology within energy factors. With such an increase in substitution, the trend of clean energy substitution for fossil energy is irreversible. Accordingly, it is proposed that the path for energy conservation and consumption reduction via energy transformation be achieved by increasing input into capital and labor to improve the utilization efficiency of these two factors from the perspective of factor substitution. Meanwhile, preferences should be delivered for the development of non-fossil energy sources in terms of technology bias and input scale.
Pre-disaster transmission maintenance scheduling considering network topology optimization
Authors: Zhang Weixin , Shao Changzheng , Hu Bo , Xie Kaigui
Published: January 2023

Several devastating experiences with extreme natural disasters demonstrate that improving power system resilience is becoming increasingly important. This paper proposes a pre-disaster transmission maintenance scheduling considering network topology optimization to ensure the power system economics before disasters and power system resilience during disasters. The transmission line fragility is distinguished and considered in the proposed optimization model to determine the maintenance scheduling of defective lines that minimizes load shedding during disasters. The proposed model is established as a tri-level optimization problem that is further reformulated to a bi-level problem utilizing duality theory. The column-and-constraint generation (C&CG) algorithm is employed to solve the equivalent robust optimization problem. Finally, the proposed model and its solution algorithm are implemented on the modified IEEE RTS-79 system. The significant cost savings and increased resilience illustrate the effectiveness of the proposed model.
Quantifying human-animal contact rates in Malaysian Borneo: Influence of agricultural landscapes on contact with potential zoonotic disease reservoirs
Authors: Klim Hannah , William Timothy , Chua Tock H. , Rajahram Giri S. , Drakeley Chris J. , Carroll Miles W. , Fornace Kimberly M.
Published: January 2023

Changing landscapes across the globe, but particularly in Southeast Asia, are pushing humans and animals closer together and may increase the likelihood of zoonotic spillover events. Malaysian Borneo is hypothesized to be at high risk of spillover events due to proximity between reservoir species and humans caused by recent deforestation in the region. However, the relationship between landscape and human-animal contact rates has yet to be quantified. An environmentally stratified cross-sectional survey was conducted in Sabah, Malaysia in 2015, collecting geolocated questionnaire data on potential risk factors for contact with animals for 10,100 individuals. 51% of individuals reported contact with poultry, 46% with NHPs, 30% with bats, and 2% with swine. Generalised linear mixed models identified occupational and demographic factors associated with increased contact with these species, which varied when comparing wildlife to domesticated animals. Reported contact rates with each animal group were integrated with remote sensing-derived environmental data within a Bayesian framework to identify regions with high probabilities of contact with animal reservoirs. We have identified high spatial heterogeneity of contact with animals and clear associations between agricultural practices and high animal rates. This approach will help inform public health campaigns in at-risk populations and can improve pathogen surveillance efforts on Malaysian Borneo. This method can additionally serve as a framework for researchers looking to identify targets for future pathogen detection in a chosen region of study.
Construction and validation of an aging-related gene signature predicting the prognosis of pancreatic cancer
Authors: Wang Dengchuan , Zhang Yonggang , Wang Xiaokang , Zhang Limei , Xu Shi
Published: January 2023

Background: Pancreatic cancer is a malignancy with a high mortality rate and worse prognosis. Recently, public databases and bioinformatics tools make it easy to develop the prognostic risk model of pancreatic cancer, but the aging-related risk signature has not been reported. The present study aimed to identify an aging-related risk signature with potential prognostic value for pancreatic cancer patients.

Method: Gene expression profiling and human clinical information of pancreatic cancer were derived from The Cancer Genome Atlas database (TCGA). Aging-related gene sets were downloaded from The Molecular Signatures Database and aging-related genes were obtained from the Human Ageing Genomic Resources database. Firstly, Gene set enrichment analysis was carried out to investigate the role of aging process in pancreatic cancer. Secondly, differentially expressed genes and aging-related prognostic genes were screened on the basis of the overall survival information. Then, univariate COX and LASSO analysis were performed to establish an aging-related risk signature of pancreatic cancer patients. To facilitate clinical application, a nomogram was established to predict the survival rates of PCa patients. The correlations of risk score with clinical features and immune status were evaluated. Finally, potential therapeutic drugs were screened based on the connectivity map (Cmap) database and verified by molecular docking. For further validation, the protein levels of aging-related genes in normal and tumor tissues were detected in the Human Protein Atlas (HPA) database.

Result: The genes of pancreatic cancer were markedly enriched in several aging-associated signaling pathways. We identified 14 key aging-related genes related to prognosis from 9,020 differentially expressed genes and establish an aging-related risk signature. This risk model indicated a strong prognostic capability both in the training set of TCGA cohort and the validation set of PACA-CA cohort and GSE62452 cohort. A nomogram combining risk score and clinical variables was built, and calibration curve and Decision curve analysis (DCA) have proved that it has a good predictive value. Additionally, the risk score was tightly linked with tumor immune microenvironment, immune checkpoints and proinflammatory factors. Moreover, a candidate drug, BRD-A47144777, was screened and verified by molecular docking, indicating this drug has the potential to treat PCa. The protein expression levels of GSK3B, SERPINE1, TOP2A, FEN1 and HIC1 were consistent with our predicted results.

Conclusion: In conclusion, we identified an aging-related signature and nomogram with high prediction performance of survival and immune cell infiltration for pancreatic cancer. This signature might potentially help in providing personalized immunotherapy for patients with pancreatic cancer.
Promoting patient engagement in cancer genomics research programs: An environmental scan
Authors: Schuster Anne L. R. , Crossnohere Norah L. , Paskett Jonathan , Thomas Neena , Hampel Heather , Ma Qin , Tiner Jessica C. , Paskett Electra D. , Bridges John F. P.
Published: January 2023

Background:A national priority in the United States is to promote patient engagement in cancer genomics research, especially among diverse and understudied populations. Several cancer genomics research programs have emerged to accomplish this priority, yet questions remain about the meaning and methods of patient engagement. This study explored how cancer genomics research programs define engagement and what strategies they use to engage patients across stages in the conduct of research.

Methods:An environmental scan was conducted of cancer genomics research programs focused on patient engagement. Research programs were identified and characterized using materials identified from publicly available sources (e.g., websites), a targeted literature review, and interviews with key informants. Descriptive information about the programs and their definitions of engagement, were synthesized using thematic analysis. The engagement strategies were synthesized and mapped to different stages in the conduct of research, including recruitment, consent, data collection, sharing results, and retention.

Results:Ten research programs were identified, examples of which include the Cancer Moonshot Biobank, the MyPART Network, NCI-CONNECT, and the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. All programs aimed to include understudied or underrepresented populations. Based on publicly available information, four programs explicitly defined engagement. These definitions similarly characterized engagement as being interpersonal, reciprocal, and continuous. Five general strategies of engagement were identified across the programs: 1) digital (such as websites) and 2) non-digital communications (such as radio broadcasts, or printed brochures); 3) partnering with community organizations; 4) providing incentives; and 5) affiliating with non-academic medical centers. Digital communications were the only strategy used across all stages of the conduct of research. Programs tailored these strategies to their study goals, including overcoming barriers to research participation among diverse populations.

Conclusion:Programs studying cancer genomics are deeply committed to increasing research participation among diverse populations through patient engagement. Yet, the field needs to reach a consensus on the meaning of patient engagement, develop a taxonomy of patient engagement measures in cancer genomics research, and identify optimal strategies to engage patients in cancer genomics. Addressing these needs could enable patient engagement to fulfill its potential and accelerate the pace of cancer genomic discoveries.
Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine
Authors: Heidbreder Karin , Sommer Katrin , Wiendl Maximilian , Müller Tanja M. , Atreya Imke , Hildner Kai , Neurath Markus F. , Zundler Sebastian
Published: January 2023

Introduction

Macrophages play an important role in intestinal wound healing. However, the trajectories from circulating monocytes to gut macrophages are incompletely understood.

Methods

Taking advantage of mice depleted for non-classical monocytes due to deficiency for the transcription factor Nr4a1, we addressed the relevance of non-classical monocytes for large intestinal wound healing using flow cytometry, in vivo wound healing assays and immunofluorescence.

Results

We show that wound healing in Nr4a1-deficient mice is substantially delayed and associated with reduced peri-lesional presence of macrophages with a wound healing phenotype.

Discussion

Our data suggest that non-classical monocytes are biased towards wound healing macrophages. These insights might help to understand, how targeting monocyte recruitment to the intestine can be used to modulate intestinal macrophage functions.
Specificity of the innate immune responses to different classes of non-tuberculous mycobacteria
Authors: Hu Wanbin , Koch Bjørn E. V. , Lamers Gerda E. M. , Forn-Cuní Gabriel , Spaink Herman P.
Published: January 2023

Mycobacterium avium is the most common nontuberculous mycobacterium (NTM) species causing infectious disease. Here, we characterized a M. avium infection model in zebrafish larvae, and compared it to M. marinum infection, a model of tuberculosis. M. avium bacteria are efficiently phagocytosed and frequently induce granuloma-like structures in zebrafish larvae. Although macrophages can respond to both mycobacterial infections, their migration speed is faster in infections caused by M. marinum. Tlr2 is conservatively involved in most aspects of the defense against both mycobacterial infections. However, Tlr2 has a function in the migration speed of macrophages and neutrophils to infection sites with M. marinum that is not observed with M. avium. Using RNAseq analysis, we found a distinct transcriptome response in cytokine-cytokine receptor interaction for M. avium and M. marinum infection. In addition, we found differences in gene expression in metabolic pathways, phagosome formation, matrix remodeling, and apoptosis in response to these mycobacterial infections. In conclusion, we characterized a new M. avium infection model in zebrafish that can be further used in studying pathological mechanisms for NTM-caused diseases.
Dual targeting of mTOR/IL-17A and autophagy by fisetin alleviates psoriasis-like skin inflammation
Authors: Roy Tithi , Banang-Mbeumi Sergette , Boateng Samuel T. , Ruiz Emmanuelle M. , Chamcheu Roxane-Cherille N. , Kang Lin , King Judy A. , Walker Anthony L. , Nagalo Bolni Marius , Kousoulas Konstantin G. , Esnault Stephane , Huang Shile , Chamcheu Jean Christopher
Published: January 2023

Psoriasis is a chronic autoimmune inflammatory skin disorder characterized by epidermal hyperplasia and aberrant immune response. In addition to aberrant cytokine production, psoriasis is associated with activation of the Akt/mTOR pathway. mTOR/S6K1 regulates T-lymphocyte activation and migration, keratinocytes proliferation and is upregulated in psoriatic lesions. Several drugs that target Th1/Th17 cytokines or their receptors have been approved for treating psoriasis in humans with variable results necessitating improved therapies. Fisetin, a natural dietary polyphenol with anti-oxidant and anti-proliferative properties, covalently binds mTOR/S6K1. The effects of fisetin on psoriasis and its underlying mechanisms have not been clearly defined. Here, we evaluated the immunomodulatory effects of fisetin on Th1/Th17-cytokine-activated adult human epidermal keratinocytes (HEKa) and anti-CD3/CD28-stimulated inflammatory CD4+ T cells and compared these activities with those of rapamycin (an mTOR inhibitor). Transcriptomic analysis of HEKa revealed 12,713 differentially expressed genes (DEGs) in the fisetin-treated group compared to 7,374 DEGs in the rapamycin-treated group, both individually compared to a cytokine treated group. Gene ontology analysis revealed enriched functional groups related to PI3K/Akt/mTOR signaling pathways, psoriasis, and epidermal development. Using in silico molecular modeling, we observed a high binding affinity of fisetin to IL-17A. In vitro, fisetin significantly inhibited mTOR activity, increased the expression of autophagy markers LC3A/B and Atg5 in HEKa cells and suppressed the secretion of IL-17A by activated CD4+ T lymphocytes or T lymphocytes co-cultured with HEKa. Topical administration of fisetin in an imiquimod (IMQ)-induced mouse psoriasis model exhibited a better effect than rapamycin in reducing psoriasis-like inflammation and Akt/mTOR phosphorylation and promoting keratinocyte differentiation and autophagy in mice skin lesions. Fisetin also significantly inhibited T-lymphocytes and F4/80+ macrophage infiltration into skin. We conclude that fisetin potently inhibits IL-17A and the Akt/mTOR pathway and promotes keratinocyte differentiation and autophagy to alleviate IMQ-induced psoriasis-like disease in mice. Altogether, our findings suggest fisetin as a potential treatment for psoriasis and possibly other inflammatory skin diseases.
Hepatocytes: A key role in liver inflammation
Authors: Gong Jin , Tu Wei , Liu Jingmei , Tian Dean
Published: January 2023

Hepatocytes, the major parenchymal cells in the liver, are responsible for a variety of cellular functions including carbohydrate, lipid and protein metabolism, detoxification and immune cell activation to maintain liver homeotasis. Recent studies show hepatocytes play a pivotal role in liver inflammation. After receiving liver insults and inflammatory signals, hepatocytes may undergo organelle damage, and further respond by releasing mediators and expressing molecules that can act in the microenvironment as well as initiate a robust inflammatory response. In this review, we summarize how the hepatic organelle damage link to liver inflammation and introduce numerous hepatocyte-derived pro-inflammatory factors in response to chronic liver injury.
Engineered soluble ACE2 receptor: Responding to change with change
Authors: Li Guangyao , Qian Kewen , Zhang Shuyi , Fu Wenyan , Zhao Jian , Lei Changhai , Hu Shi
Published: January 2023

SARS coronavirus 2 (SARS-CoV-2) invades the human body by binding to major receptors such as ACE2 via its S-spike protein, so the interaction of receptor-binding sites has been a hot topic in the development of coronavirus drugs. At present, the clinical progress in monoclonal antibody therapy that occurred early in the pandemic is gradually showing signs of slowing. While recombinant soluble ACE2, as an alternative therapy, has been modified by many engineering methods, both the safety and functional aspects are approaching maturity, and this therapy shows great potential for broadly neutralizing coronaviruses, but its progress in clinical development remains stalled. Therefore, there are still several key problems to be considered and solved for recombinant soluble ACE2 to be approved as a clinical treatment as soon as possible.
Single-cell atlas reveals different immune environments between stable and vulnerable atherosclerotic plaques
Authors: Ge Peicong , Li Hao , Ya Xiaolong , Xu Yiqiao , Ma Long , He Qiheng , Wang Rong , Liu Zechen , Zhang Qian , Zhang Yan , Wang Wenjing , Zhang Dong , Zhao Jizong
Published: January 2023

Introduction

Regardless of the degree of stenosis, vulnerable plaque is an important cause of ischemic stroke and thrombotic complications. The changes of the immune microenvironment within plaques seem to be an important factor affecting the characteristics of the plaque. However, the differences of immune microenvironment between stable and vulnerable plaques were remained unknown.

Methods

In this study, RNA-sequencing was performed on superficial temporal arteries from 5 traumatic patients and plaques from 3 atherosclerotic patients to preliminary identify the key immune response processes in plaques. Mass cytometry (CyTOF) technology was used to explore differences in immune composition between 9 vulnerable plaques and 12 stable plaques. Finally, immunofluorescence technique was used to validate our findings in the previous analysis.

Results

Our results showed that more CD86+CD68+ M1 pro-inflammatory macrophages were found in vulnerable plaques, while CD4+T memory cells were mainly found in stable plaques. In addition, a CD11c+ subset of CD4+T cells with higher IFN-r secretion was found within the vulnerable plaque. In two subsets of B cells, CD19+CD20-B cells in vulnerable plaques secreted more TNF-a and IL-6, while CD19-CD20+B cells expressed more PD-1 molecules.

Conclusion

In conclusion, our study suggested that M1-like macrophages are the major cell subset affecting plaque stability, while functional B cells may also contribute to plaque stability.
Neuroinflammation of traumatic brain injury: Roles of extracellular vesicles
Authors: Liu Xilei , Zhang Lan , Cao Yiyao , Jia Haoran , Li Xiaotian , Li Fanjian , Zhang Shu , Zhang Jianning
Published: January 2023

Traumatic brain injury (TBI) is a major cause of neurological disorder or death, with a heavy burden on individuals and families. While sustained primary insult leads to damage, subsequent secondary events are considered key pathophysiological characteristics post-TBI, and the inflammatory response is a prominent contributor to the secondary cascade. Neuroinflammation is a multifaceted physiological response and exerts both positive and negative effects on TBI. Extracellular vesicles (EVs), as messengers for intercellular communication, are involved in biological and pathological processes in central nervous system (CNS) diseases and injuries. The number and characteristics of EVs and their cargo in the CNS and peripheral circulation undergo tremendous changes in response to TBI, and these EVs regulate neuroinflammatory reactions by activating prominent receptors on receptor cells or delivering pro- or anti-inflammatory cargo to receptor cells. The purpose of this review is to discuss the possible neuroinflammatory mechanisms of EVs and loading in the context of TBI. Furthermore, we summarize the potential role of diverse types of cell-derived EVs in inflammation following TBI.
Exosomes: A potential tool for immunotherapy of ovarian cancer
Authors: Gong Xiangjin , Chi Hao , Strohmer Dorothee Franziska , Teichmann Alexander Tobias , Xia Zhijia , Wang Qin
Published: January 2023

Ovarian cancer is a malignant tumor of the female reproductive system, with a very poor prognosis and high mortality rates. Chemotherapy and radiotherapy are the most common treatments for ovarian cancer, with unsatisfactory results. Exosomes are a subpopulation of extracellular vesicles, which have a diameter of approximately 30–100 nm and are secreted by many different types of cells in various body fluids. Exosomes are highly stable and are effective carriers of immunotherapeutic drugs. Recent studies have shown that exosomes are involved in various cellular responses in the tumor microenvironment, influencing the development and therapeutic efficacy of ovarian cancer, and exhibiting dual roles in inhibiting and promoting tumor development. Exosomes also contain a variety of genes related to ovarian cancer immunotherapy that could be potential biomarkers for ovarian cancer diagnosis and prognosis. Undoubtedly, exosomes have great therapeutic potential in the field of ovarian cancer immunotherapy. However, translation of this idea to the clinic has not occurred. Therefore, it is important to understand how exosomes could be used in ovarian cancer immunotherapy to regulate tumor progression. In this review, we summarize the biomarkers of exosomes in different body fluids related to immunotherapy in ovarian cancer and the potential mechanisms by which exosomes influence immunotherapeutic response. We also discuss the prospects for clinical application of exosome-based immunotherapy in ovarian cancer.
Protective effects of blocking PD-1 pathway on retinal ganglion cells in a mouse model of chronic ocular hypertension
Authors: Sheng Siqi , Ma Yixian , Zou Yue , Hu Fangyuan , Chen Ling
Published: January 2023

Purpose

In this study, we aimed to investigate whether Programmed cell death 1 ligand 1/programmed cell death 1 ligand 2 (PD-L1/PD-L2) double knockout (dKO) has a protective effect on RGCs in a mouse model of chronic ocular hypertension (COHT).

Methods

We used superparamagnetic iron oxide to induce COHT in mice. Apoptosis of retinal ganglion cells (RGCs) and activation of microglia were evaluated using western blotting (WB) and immunofluorescence staining of the mouse retina. In addition, we also conducted transcriptome sequencing and further gene expression analyses using the gene ontology (GO) and Kyoto Encyclopedia of Genes (KEGG) database.

Results

In the mouse model of COHT, PD-L1/PD-L2 prevented the apoptosis of RGCs to some extent. Blocking the programmed cell death 1 (PD-1) pathway also increased the number of anti-inflammatory M2-activated microglia and enhanced the phosphorylation of its related pathway signal transducer and activator of transcription (STAT)6. Sequencing results showed that this protective effect may have been achieved by regulating the NF−B, tumour necrosis factor (TNF), PI3K/Akt and toll-like receptor signaling pathway etc.

Conclusion

Blocking the PD-1 pathway has a protective effect on RGCs in the mouse model of COHT induced by superparamagnetic iron oxide.
Gut bacterial species in late trimester of pregnant sows influence the occurrence of stillborn piglet through pro-inflammation response
Authors: Chen Zhe , Yang Hui , Fu Hao , Wu Lin , Liu Min , Jiang Hui , Liu Qin , Wang Yaxiang , Xiong Shuqi , Zhou Mengqing , Sun Xiao , Chen Congying , Huang Lusheng
Published: January 2023

Maternal gut microbiota is an important regulator for the metabolism and immunity of the fetus during pregnancy. Recent studies have indicated that maternal intestinal microbiota is closely linked to the development of fetus and infant health. Some bacterial metabolites are considered to be directly involved in immunoregulation of fetus during pregnancy. However, the detailed mechanisms are largely unknown. In this study, we exploited the potential correlation between the gut microbiota of pregnant sows and the occurrence of stillborn piglets by combining the 16S rRNA gene and metagenomic sequencing data, and fecal metabolome in different cohorts. The results showed that several bacterial species from Bacteroides, potential pathogens, and LPS-producing bacteria exhibited significantly higher abundances in the gut of sows giving birth to stillborn piglets. Especially, Bacteroides fragilis stood out as the key driver in both tested cohorts and showed the most significant association with the occurrence of stillborn piglets in the DN1 cohort. However, several species producing short-chain fatty acids (SCFAs), such as Prevotella copri, Clostridium butyricum and Faecalibacterium prausnitzii were enriched in the gut of normal sows. Functional capacity analysis of gut microbiome revealed that the pathways associated with infectious diseases and immune diseases were enriched in sows giving birth to stillborn piglets. However, energy metabolism had higher abundance in normal sows. Fecal metabolome profiling analysis found that Lysophosphatidylethanolamine and phosphatidylethanolamine which are the main components of cell membrane of Gram-negative bacteria showed significantly higher concentration in stillbirth sows, while SCFAs had higher concentration in normal sows. These metabolites were significantly associated with the stillborn-associated bacterial species including Bacteroides fragilis. Lipopolysaccharide (LPS), IL-1β, IL-6, FABP2, and zonulin had higher concentration in the serum of stillbirth sows, indicating increased intestinal permeability and pro-inflammatory response. The results from this study suggested that certain sow gut bacterial species in late trimester of pregnancy, e.g., an excess abundance of Bacteroides fragilis, produced high concentration of LPS which induced sow pro-inflammatory response and might cause the death of the relatively weak piglets in a farrow. This study provided novel evidences about the effect of maternal gut microbiota on the fetus development and health.
CD8+ T-cell immunity orchestrated by iNKT cells
Authors: Qin Yingyu , Bao Xueyang , Zheng Mingzhu
Published: January 2023

CD8+ T cells belonging to the adaptive immune system play key roles in defending against viral infections and cancers. The current CD8+ T cell-based immunotherapy has emerged as a superior therapeutic avenue for the eradication of tumor cells and long-term prevention of their recurrence in hematologic malignancies. It is believed that an effective adaptive immune response critically relies on the help of the innate compartment. Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that have been considered some of the first cells to respond to infections and can secrete a large amount of diverse cytokines and chemokines to widely modulate the innate and adaptive immune responders. Like CD8+ T cells, iNKT cells also play an important role in defense against intracellular pathogenic infections and cancers. In this review, we will discuss the CD8+ T-cell immunity contributed by iNKT cells, including iNKT cell-mediated cross-priming and memory formation, and discuss recent advances in our understanding of the mechanisms underlying memory CD8+ T-cell differentiation, as well as aging-induced impairment of T-cell immunity.
Knowledge landscape of tumor-associated macrophage research: A bibliometric and visual analysis
Authors: Zhou Feng , Liu Yang , Liu Cong , Wang Fangfei , Peng Jianxiang , Xie Yong , Zhou Xiaojiang
Published: January 2023

Background and aims

Tumor-associated macrophage (TAM) is a highly abundant immune population in tumor microenvironment, which plays an important role in tumor growth and progression. The aim of our study was to explore the development trends and research hotspots of TAM by bibliometric method.

Methods

The publications related to TAM were obtained from the Web of Science Core Collection database. Bibliometric analysis and visualization were conducted using VOSviewer, CiteSpace and R software.

Results

A total of 6,405 articles published between 2001 and 2021 were included. The United States and China received the most citations, whereas the University of Milan, the university of California San Francisco and Sun Yat-sen University were the main research institutions. Mantovani, Alberto from Humanitas University was the most productive authors with the most citations. Cancer Research published the most articles and received the most co-citations. Activation, angiogenesis, breast cancer, NF-κB and endothelial growth factor were important keywords in TAM research. Among them, PD-1/L1, nanoparticle, PI3Kγ, resistance and immune microenvironment have become the focus of attention in more recent research.

Conclusions

The research on TAM is rapidly evolving with active cooperation worldwide. Anticancer therapy targeting TAM is emerging and promising area of future research, especially in translational application. This may provide guidance and new insights for further research in the field of TAM.
Cancer-associated pyroptosis: A new license to kill tumor
Authors: Kong Qing , Zhang Zhibin
Published: January 2023

Pyroptosis is a programmed necrotic cell death mediated by pore-forming Gasdermin (GSDM) proteins. After being unleashed from the C-terminal auto-inhibitory domains by proteolytic cleavage, the N-terminal domains of GSDMs oligomerize and perforate on the plasma membrane to induce cytolytic pyroptosis, releasing immune mediators and alarming the immune system. Upon infection or danger signal perception, GSDMD that functions downstream of the inflammasome, a supramolecular complex for inflammatory caspase activation, is cleaved and activated by inflammasome-activated caspase-1/4/5/11 in immune cells and epithelial cells to trigger pyroptosis and exert anti-infection protection. Unlike this inflammasome-activated pyroptosis (IAP), recent studies also suggest an emerging role of cancer-associated pyroptosis (CAP), mediated by other GSDMs in cancer cells, in provoking anti-tumor immunity. IAP and CAP share common features like cell membrane rupture but also differ in occurrence sites, activating mechanisms, secreting cytokines and biological outcomes. Here we review the most recent knowledge of cancer-associated pyroptosis and present a promising avenue for developing therapeutic interventions to enhance anti-tumor immunity for cancer treatment.