bluuebunny/crossref_metadata_2025 huggingface dataset:
Tendency of dynamic vasoactive and inotropic medications data as a robust predictor of mortality in patients with septic shock: An analysis of the MIMIC-IV database
Authors: Ning Yi-Le , Sun Ce , Xu Xiang-Hui , Li Li , Ke Yan-Ji , Mai Ye , Lin Xin-Feng , Yang Zhong-Qi , Xian Shao-Xiang , Chen Wei-Tao
Published: March 2023

Background

Septic shock patients fundamentally require delicate vasoactive and inotropic agent administration, which could be quantitatively and objectively evaluated by the vasoactive–inotropic score (VIS); however, whether the dynamic trends of high-time-resolution VIS alter the clinical outcomes remains unclear. Thus, this study proposes the term VIS Reduction Rate (VRR) to generalise the tendency of dynamic VIS, to explore the association of VRR and mortality for patients with septic shock.

Methods

We applied dynamic and static VIS data to predict ICU mortality by two models: the long short-term memory (LSTM) deep learning model, and the extreme gradient boosting (XGBoost), respectively. The specific target cohort was extracted from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database by the sophisticated structured query language (SQL). Enrolled patients were divided into four groups by VRR value: ≥50%, 0 ~ 50%, −50% ~ 0, and < −50%. Statistical approaches included pairwise propensity score matching (PSM), Cox proportional hazards regression, and two doubly robust estimation models to ensure the robustness of the results. The primary and secondary outcomes were ICU mortality and in-hospital mortality, respectively.

Results

VRR simplifies the dosing trends of vasoactive and inotropic agents represented by dynamic VIS data while requiring fewer data. In total, 8,887 septic shock patients were included. Compared with the VRR ≥50% group, the 0 ~ 50%, −50% ~ 0, and < −50% groups had significantly higher ICU mortality [hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.17–1.50, p < 0.001; HR 1.79, 95% CI 1.44–2.22, p < 0.001; HR 2.07, 95% CI 1.61–2.66, p < 0.001, respectively] and in-hospital mortality [HR 1.43, 95% CI 1.28–1.60, p < 0.001; HR 1.75, 95% CI 1.45–2.11, p < 0.001; HR 2.00, 95% CI 1.61–2.49, p < 0.001, respectively]. Similar findings were observed in two doubly robust estimation models.

Conclusion

The trends of dynamic VIS in ICU might help intensivists to stratify the prognosis of adult patients with septic shock. A lower decline of VIS was remarkably associated with higher ICU and in-hospital mortality among septic shock patients receiving vasoactive–inotropic therapy for more than 24 h.
Post-operative atrial fibrillation after cardiac surgery: Challenges throughout the patient journey
Authors: McIntyre William F.
Published: March 2023

Atrial fibrillation (AF) is the most common complication of cardiac surgery, occurring in up to half of patients. Post-operative AF (POAF) refers to new-onset AF in a patient without a history of AF that occurs within the first 4 weeks after cardiac surgery. POAF is associated with short-term mortality and morbidity, but its long-term significance is unclear. This article reviews existing evidence and research challenges for the management of POAF in patients who have had cardiac surgery. Specific challenges are discussed in four phases of care. Pre-operatively, clinicians need to be able to identify high-risk patients, and initiate prophylaxis to prevent POAF. In hospital, when POAF is detected, clinicians need to manage symptoms, stabilize hemodynamics and prevent increases in length of stay. In the month after discharge, the focus is on minimizing symptoms and preventing readmission. Some patients require short term oral anticoagulation for stroke prevention. Over the long term (2–3  months after surgery and beyond), clinicians need to identify which patients with POAF have paroxysmal or persistent AF and can benefit from evidence-based therapies for AF, including long-term oral anticoagulation.
Causes of academic dropout in higher education in Andalusia and proposals for its prevention at university: A systematic review
Authors: de la Cruz-Campos Juan-Carlos , Victoria-Maldonado Juan-José , Martínez-Domingo José-Antonio , Campos-Soto María-Natalia
Published: March 2023

Introduction

One of the main problems facing the university system is the high student dropout rate due to a number of variables, accentuated by the COVID-19 pandemic. This is a problem not only in Spanish universities but is prevalent worldwide. It is therefore important to understand and analyze the underlying reasons for dropout so that it can be addressed and mechanisms implemented to limit dropout in higher education to the greatest extent possible.

Method

A systematic review was carried out summarizing the results of studies and reports on university dropout in Spain and specifically in the universities of the Autonomous Community of Andalusia. The review was conducted in accordance with the PRISMA statement by searching the scientific databases Scopus and Web of Science, limiting the search to articles published between 2010 and 2022.

Results

The main publications in both Spain and the Autonomous Community of Andalusia were identified. The review included the main causes of university dropout indicated in each of the selected studies and the proposals to reduce it, including educational policies, the rise of distance education, academic failure in basic educational stages, and social, personal, psychological, and economic variables.

Conclusion

There is a lack of research on university dropout, with only 25% of Spanish universities having carried out research on this subject in the last 12 years. The studies analyzed conclude that the most frequent causes of university dropout are associated with low academic performance, poor social support in the new academic environment, low socio-economic status, pessimism, and lack of motivation, together with other less significant factors such as poor relationships with teachers, lack of vocation, work incompatibility, and previous academic performance. Further research on the causes of university dropout and its prevention is needed both before university entrance, by providing meaningful information to secondary school students, and during the university stay, through institutional and teaching policies that improve family support and social roots, produce positive academic experiences, favor associationism, and encourage activities that improve planning and time management, together with cognitive learning strategies, motivational strategies and the use of advanced learning materials [such as Information and Communication Technology (ICT) tools].
Different cell compositions and a novel somatic KCNJ5 variant found in a patient with bilateral adrenocortical adenomas secreting aldosterone and cortisol
Authors: Zhao Liling , Wan Jinjing , Wang Yujun , Yang Wenjun , Liang Qi , Wang Jinrong , Jin Ping
Published: March 2023

Introduction

This study aimed to explore the possible pathogenesis of a rare case of co-existing Cushing’s syndrome (CS) and primary aldosteronism (PA) caused by bilateral adrenocortical adenomas secreting aldosterone and cortisol, respectively.

Methods

A 41-year-old Chinese woman with severe hypertension and hypokalemia for 5 and 2 years, respectively, was referred to our hospital. She had a Cushingoid appearance. Preoperative endocrinological examinations revealed autonomous cortisol and aldosterone secretion. Computed tomography revealed bilateral adrenal adenomas. Subsequently, adrenal vein sampling and sequential left and right partial adrenalectomy indicated the presence of a left aldosterone-producing tumor and a right cortisol-producing tumor. Pathological examination included immunohistochemical analysis of the resected specimens. Secretions of aldosterone and cortisol were observed both in vivo and in vitro. Further, whole-exome sequencing was performed for DNA that was extracted from peripheral blood leukocytes and bilateral adrenal adenomas in order to determine whether the patient had relevant variants associated with PA and CS.

Results

Immunohistochemical staining revealed that the left adenoma primarily comprised clear cells expressing CYP11B2, whereas the right adenoma comprised both eosinophilic compact and clear cells expressing CYP11B1. The mRNA levels of steroidogenic enzymes (including CYP11B1 and CYP17A1) were high in the right adenoma, whereas CYP11B2 was highly expressed in the left adenoma. A novel somatic heterozygous missense variant—KCNJ5 c.503T > G (p.L168R)—was detected in the left adrenal adenoma, but no other causative variants associated with PA and CS were detected in the peripheral blood or right adrenocortical adenoma. In the primary cell culture of the resected hyperplastic adrenal adenomas, verapamil and nifedipine, which are two calcium channel blockers, markedly inhibited the secretion of both aldosterone and cortisol.

Conclusion

We present an extremely rare case of bilateral adrenocortical adenomas with distinct secretion of aldosterone and cortisol. The heterogeneity of the tumor cell compositions of aldosterone- and cortisol-producing adenoma (A/CPA) and somatic mutation of KCNJ5 may have led to different hormone secretions in the bilateral adrenal adenomas.
Single-cell RNA sequencing reveals the role of cell heterogeneity in the sex difference in primary hyperparathyroidism
Authors: Lu Shuai , Chen Xi , Gong Maoqi , Chen Shuo , Zhang Jianyu , Zhang Xigong , Wu Chengai , Cui Aimin , Jiang Xieyuan
Published: March 2023

Objective

To explore the difference in parathyroid tissue-derived cells between male and female PHPT patients.

Methods

Resected parathyroid tissues were collected from PHPT patients of both sexes. Single cells were isolated and sequenced for RNA expression profiles. The cell sequencing data were annotated by cell type, followed by population analysis, functional analysis, pathway analysis, cell communication analysis, differential gene expression analysis, and pseudotime trajectory analysis. The subcluster analyses were also performed in the parathyroid cells.

Results

No substantial difference in the cell population, function, or communication is found between the two sexes. The interferon-a response, oxidative phosphorylation, and reactive oxygen species pathways are up-regulated in females than in male patients, mainly contributed by fibroblast cells, endothelial cells, parathyroid cells, and myeloid cells, which also have significantly more up-regulated pathways and cellular interactions than the other three cell types. The subcluster analysis of parathyroid cells identified five subpopulations: SPARCL1-OC and ISG15-OC are predominant in females, while more S100A13-PCC and PTHLH-OC are found in males. The cellular functions are also elevated in females compared with males. Cells from female patients show a higher expression level of parathyroid hormone (PTH) but a lower expression level of parathyroid hormone-like hormone (PTHLH). The cell pseudotime trajectory and pathway analyses show that the oxyphil cells may be more mature and functionally active than the chief cells in both sexes.

Conclusion

These findings suggest that the sex difference in PHPT may be caused by the differentially expressed genes and activated pathways in different cell types in the parathyroid tissue. The heterogeneity of parathyroid cell subpopulations, especially in oxyphil cells, may be associated with the sex differences in PHPT pathogenesis.
Influence of forest infrastructure on the responses of ecosystem services to climate extremes in the Midwest and Northeast United States from 1980 to 2019
Authors: Kicklighter David W. , Lin Tzu-Shun , Zhang Jiaqi , Chen Mengye , Vörösmarty Charles J. , Jain Atul K. , Melillo Jerry M.
Published: March 2023

Forests provide several critical ecosystem services that help to support human society. Alteration of forest infrastructure by changes in land use, atmospheric chemistry, and climate change influence the ability of forests to provide these ecosystem services and their sensitivity to existing and future extreme climate events. Here, we explore how the evolving forest infrastructure of the Midwest and Northeast United States influences carbon sequestration, biomass increment (i.e., change in vegetation carbon), biomass burning associated with fuelwood and slash removal, the creation of wood products, and runoff between 1980 and 2019 within the context of changing environmental conditions and extreme climate events using a coupled modeling and assessment framework. For the 40-year study period, the region’s forests functioned as a net atmospheric carbon sink of 687 Tg C with similar amounts of carbon sequestered in the Midwest and the Northeast. Most of the carbon has been sequestered in vegetation (+771 Tg C) with more carbon stored in Midwestern trees than in Northeastern trees to provide a larger resource for potential wood products in the future. Runoff from forests has also provided 4,651 billion m3of water for potential use by humans during the study period with the Northeastern forests providing about 2.4 times more water than the Midwestern forests. Our analyses indicate that climate variability, as particularly influenced by heat waves, has the dominant effect on the ability of forest ecosystems to sequester atmospheric CO2to mitigate climate change, create new wood biomass for future fuel and wood products, and provide runoff for potential human use. Forest carbon sequestration and biomass increment appear to be more sensitive to heat waves in the Midwest than the Northeast while forest runoff appears to be more sensitive in the Northeast than the Midwest. Land-use change, driven by expanding suburban areas and cropland abandonment, has enhanced the detrimental heat-wave effects in Midwestern forests over time, but moderated these effects in Northeastern forests. When developing climate stabilization, energy production and water security policies, it will be important to consider how evolving forest infrastructure modifies ecosystem services and their responses to extreme climate events over time.
Research on environmental regulation, environmental protection tax, and earnings management
Authors: Fu Shiwen , Yuan Jianguo , Xiao Deyun , Chen Zhiqiang , Yang Gaorong
Published: March 2023

After the Chinese government put forward carbon peaking and carbon neutrality goals, the intensity of environmental regulation has reached an unprecedented height. Using a sample of heavily polluted A-share listed companies in Shanghai and Shenzhen from 2012 to 2018, we discuss the influence mechanism of environmental regulation and environmental tax on corporate earnings management in this study. We use multiple regression models to empirically verify the impact of environmental regulation, environmental tax, and their combined effect on corporate earnings management. We find that environmental regulations promote enterprises’ upward real earnings management and inhibit enterprises’ upward accrual earnings management. However, environmental taxes discourage firms from upward accrual earnings management. Moreover, environmental regulations and environmental tax jointly promote enterprises’ upward accrual earnings management and real earnings management. And there is heterogeneity among different enterprise natures, different enterprise sizes, enterprises in regions with different degrees of marketization, different intensities of government investment in environmental protection, and whether enterprises disclose their environmental protection concepts. The contribution of this paper is to put environmental regulation, environmental protection tax, and earnings management in the same analytical framework. We aim to combine the government’s macro policy with the enterprise’s micro behavior and to deeply analyze the impact and mechanism of environmental regulation, environmental protection tax, and their combined effect on enterprise earnings management. By analyzing the heterogeneity of these impacts from multiple dimensions, this study tries to expand the research horizon, fill the research gap, and provide theoretical support for the government to formulate comprehensive environmental regulation policies.
Urban-driven decrease in arthropod richness and diversity associated with group-specific changes in arthropod abundance
Authors: Chatelain Marion , Rüdisser Johannes , Traugott Michael
Published: March 2023

Habitat loss and fragmentation caused by land-use changes in urbanised landscapes are main drivers of biodiversity loss and changes in species assemblages. While the effects of urbanisation on arthropods has received increasing attention in the last decade, most of the studies were taxon-specific, limited in time and/or covering only part of the habitats along the rural-urban gradient. To comprehensively assess the effects of urbanisation on arthropod communities, here, we sampled arthropods at 180 sites within an urban mosaic in the city of Innsbruck (Austria) using a systematic grid. At each site, arthropods were collected in three micro-habitats: the canopy, the bush layer and tree bark. They were identified to the family, infra-order or order level, depending on the taxonomic group. Urbanisation level was estimated by five different proxies extracted from land use/land cover data (e.g., impervious surface cover), all of them calculated in a 100, 500, and 1,000 m radius around the sampling points, and three indexes based on distance to settlements. We tested for the effects of different levels of urbanisation on (i) overall arthropod abundance, richness and diversity and (ii) community composition using redundancy analyses. In the canopy and the bush layer, arthropod richness and diversity decreased with increasing urbanisation level, suggesting that urbanisation acts as a filter on taxonomic groups. Our data on arthropod abundance further support this hypothesis and suggest that urbanisation disfavours wingless groups, particularly so on trees. Indeed, urbanisation was correlated to lower abundances of spiders and springtails, but higher abundances of aphids, barklice and flies. Arthropod community composition was better explained by a set of urbanisation proxies, especially impervious surface cover measured in a 100, 500, and 1,000 m radius. Arthropods are key elements of food webs and their availability in urban environments is expected to have bottom-up effects, thus shaping foraging behaviour, distribution, and/or success of species at higher trophic levels. Studying ecological networks in urban ecosystems is the next step that will allow to understand how urbanisation alters biodiversity.
The shared genetic architecture of suicidal behaviour and psychiatric disorders: A genomic structural equation modelling study
Authors: Kootbodien Tahira , London Leslie , Martin Lorna J. , Defo Joel , Ramesar Raj
Published: March 2023

Background: Suicidal behaviour (SB) refers to behaviours, ranging from non-fatal suicidal behaviour, such as suicidal ideation and attempt, to completed suicide. Despite recent advancements in genomic technology and statistical methods, it is unclear to what extent the spectrum of suicidal behaviour is explained by shared genetic aetiology.

Methods: We identified nine genome-wide association statistics of suicidal behaviour (sample sizes, n, ranging from 62,648 to 125,844), ten psychiatric traits [n up to 386,533] and collectively, nine summary datasets of anthropometric, behavioural and socioeconomic-related traits [n ranging from 58,610 to 941,280]. We calculated the genetic correlation among these traits and modelled this using genomic structural equation modelling, identified shared biological processes and pathways between suicidal behaviour and psychiatric disorders and evaluated potential causal associations using Mendelian randomisation.

Results: Among populations of European ancestry, we observed strong positive genetic correlations between suicide ideation, attempt and self-harm (rg range, 0.71–1.09) and moderate to strong genetic correlations between suicidal behaviour traits and a range of psychiatric disorders, most notably, major depression disorder (rg = 0.86, p = 1.62 × 10−36). Multivariate analysis revealed a common factor structure for suicidal behaviour traits, major depression, attention deficit hyperactivity disorder (ADHD) and alcohol use disorder. The derived common factor explained 38.7% of the shared variance across the traits. We identified 2,951 genes and 98 sub-network hub genes associated with the common factor, including pathways associated with developmental biology, signal transduction and RNA degradation. We found suggestive evidence for the protective effects of higher household income level on suicide attempt [OR = 0.55 (0.44–0.70), p = 1.29 × 10−5] and while further investigation is needed, a nominal significant effect of smoking on suicide attempt [OR = 1.24 (1.04–1.44), p = 0.026].

Conclusion: Our findings provide evidence of shared aetiology between suicidal behaviour and psychiatric disorders and indicate potential common molecular mechanisms contributing to the overlapping pathophysiology. These findings provide a better understanding of the complex genetic architecture of suicidal behaviour and have implications for the prevention and treatment of suicidal behaviour.
Tumor-associated macrophages respond to chemotherapy by detrimental transcriptional reprogramming and suppressing stabilin-1 mediated clearance of EGF
Authors: Larionova Irina , Kiselev Artem , Kazakova Elena , Liu Tengfei , Patysheva Marina , Iamshchikov Pavel , Liu Quan , Mossel Dieuwertje M. , Riabov Vladimir , Rakina Militsa , Sergushichev Alexey , Bezgodova Natalia , Vtorushin Sergei , Litviakov Nikolai , Denisov Evgeny , Koshkin Philipp , Pyankov Denis , Tsyganov Matvei , Ibragimova Marina , Cherdyntseva Nadezhda , Kzhyshkowska Julia
Published: March 2023

Introduction

Tumor resistance to chemotherapy and metastatic relapse account for more than 90% of cancer specific mortality. Tumor-associated macrophages (TAMs) can process chemotherapeutic agents and impair their action. Little is known about the direct effects of chemotherapy on TAMs.

Methods

The effect of chemotherapeutic platinum agent cisplatin was assessed in the model system of human ex vivo TAMs. Whole-transcriptome sequencing for paired TAMs stimulated and not stimulated by cisplatin was analysed by NGS. Endocytic uptake of EGF was quantified by flow cytometry. Confocal microscopy was used to visualize stabilin-1-mediated internalization and endocytic trafficking of EGF in CHO cells expressing ectopically recombinant stabilin-1 and in stabilin-1+ TAMs. In cohort of patients with breast cancer, the effect of platinum therapy on the transcriptome of TAMs was validated, and differential expression of regulators of endocytosis was identified.

Results

Here we show that chemotherapeutic agent cisplatin can initiate detrimental transcriptional and functional programs in TAMs, without significant impairment of their viability. We focused on the clearance function of TAMs that controls composition of tumor microenvironment. For the first time we demonstrated that TAMs’ scavenger receptor stabilin-1 is responsible for the clearance of epidermal growth factor (EGF), a potent stimulator of tumor growth. Cisplatin suppressed both overall and EGF-specific endocytosis in TAMs by bidirectional mode: suppression of positive regulators and stimulation of negative regulators of endocytosis, with strongest effect on synaptotagmin-11 (SYT11), confirmed in patients with breast cancer.

Conclusion

Our data demonstrate that synergistic action of cytostatic agents and innovative immunomodulators is required to overcome cancer therapy resistance.
The combination of oxaliplatin and anti-PD-1 inhibitor promotes immune cells infiltration and enhances anti-tumor effect of PD-1 blockade in bladder cancer
Authors: Zhao Zihan , Liu Siyang , Sun Rui , Zhu Wenjie , Zhang Yulin , Liu Tianyao , Li Tianhang , Jiang Ning , Guo Hongqian , Yang Rong
Published: March 2023

Introduction

Bladder cancer (BLCA) is a highly malignant tumor of the urinary system, but the prognosis and survival rates have little improvement based on current therapeutic strategy. Immune checkpoint inhibitors (ICIs) therapy revolutionized the treatment of BLCA, but the clinical application of ICIs is limited by low response rate. Oxaliplatin (OXP), a second line chemotherapy drug for BLCA, may reshape the tumor immune microenvironment (TIME) via recruiting immune cells. Here, we conducted the study of oxaliplatin combined with anti-PD-1 inhibitor in BLCA mice models.

Methods

The 6-8 weeks old female C57BL/6J mice were used to establish subcutaneous model of bladder tumor. After tumors developed, mice were given tail vein injections of PBS or oxaliplatin (2.5 mg/kg) and/or anti-PD-1 antibody (10 mg/kg). Tumor tissue samples and peripheral blood mononuclear cell (PBMC) were collected to systemically evaluate the efficiency and safety of combination OXP and anti-PD-1 inhibitor. The change of immune cells populations and the corresponding phenotypic diversity in TIME and PBMC were analysed by flow cytometry.

Results

Tumor growth experiments clarified that the combination therapy was more efficient than medication alone. Flow cytometry analysis of tumor samples showed significant differences between untreated and treated mice. Oxaliplatin influences the TIME by increasing immune cells infiltration, including CD3+ T cells, CD4+ T cells, CD8+ T cells, dendritic cells (DC cells) and natural killer cells (NK cells). As for infiltrating cells, oxaliplatin upregulated the expression of CD134 and downregulated TIM-3 of CD4+ T cells, downregulated the PD-L1 expression of DC cells, which contributed to improve the anti-tumor effect and the treatment response of ICIs. Additionally, the evaluation of PBMC found that there were no significant changes in immune cell subsets and phenotypes, which validated the safety of the combination therapy. These results show the therapeutic potential for the combination of OXP and anti-PD-1 inhibitor in BLCA.

Conclusion

OXP could increase the infiltration of immune cells in TIME to promote the anti-tumor activity of anti-PD-1 inhibitor. The present research provided an appropriate rationale of combination chemotherapy and immunotherapy therapy for BLCA.
Human papillomavirus in the setting of immunodeficiency: Pathogenesis and the emergence of next-generation therapies to reduce the high associated cancer risk
Authors: Hewavisenti Rehana V. , Arena Joshua , Ahlenstiel Chantelle L. , Sasson Sarah C.
Published: March 2023

Human papillomavirus (HPV), a common sexually transmitted virus infecting mucosal or cutaneous stratified epithelia, is implicated in the rising of associated cancers worldwide. While HPV infection can be cleared by an adequate immune response, immunocompromised individuals can develop persistent, treatment-refractory, and progressive disease. Primary immunodeficiencies (PIDs) associated with HPV-related disease include inborn errors of GATA, EVER1/2, and CXCR4 mutations, resulting in defective cellular function. People living with secondary immunodeficiency (e.g. solid-organ transplants recipients of immunosuppression) and acquired immunodeficiency (e.g. concurrent human immunodeficiency virus (HIV) infection) are also at significant risk of HPV-related disease. Immunocompromised people are highly susceptible to the development of cutaneous and mucosal warts, and cervical, anogenital and oropharyngeal carcinomas. The specific mechanisms underlying high-risk HPV-driven cancer development in immunocompromised hosts are not well understood. Current treatments for HPV-related cancers include surgery with adjuvant chemotherapy and/or radiotherapy, with clinical trials underway to investigate the use of anti-PD-1 therapy. In the setting of HIV co-infection, persistent high-grade anal intraepithelial neoplasia can occur despite suppressive antiretroviral therapy, resulting in an ongoing risk for transformation to overt malignancy. Although therapeutic vaccines against HPV are under development, the efficacy of these in the setting of PID, secondary- or acquired- immunodeficiencies remains unclear. RNA-based therapeutic targeting of the HPV genome or mRNA transcript has become a promising next-generation therapeutic avenue. In this review, we summarise the current understanding of HPV pathogenesis, immune evasion, and malignant transformation, with a focus on key PIDs, secondary immunodeficiencies, and HIV infection. Current management and vaccine regimes are outlined in relation to HPV-driven cancer, and specifically, the need for more effective therapeutic strategies for immunocompromised hosts. The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.
Identification of cuproptosis hub genes contributing to the immune microenvironment in ulcerative colitis using bioinformatic analysis and experimental verification
Authors: Yang Cejun , Wang Wendi , Li Sang , Qiao Zhengkang , Ma Xiaoqian , Yang Min , Zhang Juan , Cao Lu , Yao Shanhu , Yang Zhe , Wang Wei
Published: March 2023

Instruction

Ulcerative colitis (UC) can cause a variety of immune-mediated intestinal dysfunctions and is a significant model of inflammatory bowel disease (IBD). Colorectal cancer (CRC) mostly occurs in patients with ulcerative colitis. Cuproptosis is a type of procedural death that is associated with different types of diseases to various degrees.

Methods

We used a combination of bioinformatic prediction and experimental verification to study the correlation between copper poisoning and UC. We used the Gene Expression Omnibus database to obtain disease gene expression data and then identified relevant genes involved in various expression levels in normal and UC samples. The Kyoto Encyclopedia of Genes and Genomes pathway analysis was performed to cluster the genes that are highly responsible and find the central interaction in gene crosstalk. Notably, DLD, DLAT, and PDHA1 were present in high-scoring PPI networks. In addition, hub gene expression information in UC tissues was integrated to estimate the relationship between UC copper poisoning and the immune environment.

Results

In our study, the expression of DLD, DLAT, and PDHA1 in UC tissues was lower than that in normal tissues. The key genes associated with cuproptosis have therapeutic effects on immune infiltration. We verified the expression of DLD, DLAT, and PDHA1 using real-time quantitative polymerase chain reaction in mouse models of UC induced by DSS.

Discussion

Notably, this study clearly indicates that bioinformatic analysis performed to verify the experimental methods provides evidence that cuproptosis is associated with UC. This finding suggests that immune cell infiltration in UC patients is associated with cuproptosis. The key genes associated with cuproptosis can be helpful for discovering the molecular mechanism of UC, thus facilitating the improvement of UC treatment and preventing the associated CRC.
cGAS-dependent proinflammatory and immune homeostatic effects of the microtubule-targeting agent paclitaxel
Authors: Serpico Angela Flavia , Pisauro Caterina , Grieco Domenico
Published: March 2023

Taxanes are Microtubule-Targeting Agents (MTAs) that exert potent anticancer activity by directly killing cancer cells. However, recent evidence suggests that they may also stimulate inflammation and anticancer adaptive immunity and that these actions strongly contribute to their therapeutic efficacy. Details on how Taxanes may modulate inflammation and anticancer immunity are, nevertheless, still missing. We show here that at very low doses the Taxane Paclitaxel (Pxl) indeed induces a potent proinflammatory response in various cancer cell types in a cyclic GMP-AMP (cGAMP) synthase (cGAS)- and Stimulator of Interferon Genes (STING)-dependent manner, leading to interferon (IFN) signaling. However, we find that Pxl treatment also strongly upregulates the expression of the immune checkpoint protein Programmed Death-Ligand 1 (PD-L1) in cancer cells, therefore, inducing an inhibitory response to adaptive immunity potentially attenuating anticancer immunity and therapeutic success. These observations provide a mechanistic explanation of why clinical benefit may derive from the combination of Pxl with Immune Checkpoint Inhibitors (ICIs) and suggest that more accurately tailoring dosage and schedule of this combination therapy may provide benefit in the management of a larger number of cancer types and stages.
Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients
Authors: Ruschil Christoph , Gabernet Gisela , Kemmerer Constanze Louisa , Jarboui Mohamed Ali , Klose Franziska , Poli Sven , Ziemann Ulf , Nahnsen Sven , Kowarik Markus Christian
Published: March 2023

Introduction

B cells are acknowledged as crucial players in the pathogenesis of multiple sclerosis (MS). Several disease modifying drugs including cladribine have been shown to exert differential effects on peripheral blood B cell subsets. However, little is known regarding functional changes within the peripheral B cell populations. In this study, we obtained a detailed picture of B cell repertoire changes under cladribine treatment on a combined immunoglobulin (Ig) transcriptome and proteome level.

Methods

We performed next-generation sequencing of Ig heavy chain (IGH) transcripts and Ig mass spectrometry in cladribine-treated patients with relapsing-remitting multiple sclerosis (n = 8) at baseline and after 6 and 12 months of treatment in order to generate Ig transcriptome and Ig peptide libraries. Ig peptides were overlapped with the corresponding IGH transcriptome in order to analyze B cell clones on a combined transcriptome and proteome level.

Results

The analysis of peripheral blood B cell percentages pointed towards a significant decrease of memory B cells and an increase of naive B cells following cladribine therapy. While basic IGH repertoire parameters (e.g. variable heavy chain family usage and Ig subclasses) were only slightly affected by cladribine treatment, a significantly decreased number of clones and significantly lower diversity in the memory subset was noticeable at 6 months following treatment which was sustained at 12 months. When looking at B-cell clones comprising sequences from the different time-points, clones spanning between all three time-points were significantly more frequent than clones including sequences from two time-points. Furthermore, Ig proteome analyses showed that Ig transcriptome specific peptides could mostly be equally aligned to all three time-points pointing towards a proportion of B-cell clones that are maintained during treatment.

Discussion

Our findings suggest that peripheral B cell related treatment effects of cladribine tablets might be exerted through a reduction of possibly disease relevant clones in the memory B cell subset without disrupting the overall clonal composition of B cells. Our results -at least partially- might explain the relatively mild side effects regarding infections and the sustained immune response after vaccinations during treatment. However, exact disease driving B cell subsets and their effects remain unknown and should be addressed in future studies.
Pharmacological potential of Withania somnifera (L.) Dunal and Tinospora cordifolia (Willd.) Miers on the experimental models of COVID-19, T cell differentiation, and neutrophil functions
Authors: Rizvi Zaigham Abbas , Babele Prabhakar , Madan Upasna , Sadhu Srikanth , Tripathy Manas Ranjan , Goswami Sandeep , Mani Shailendra , Dikshit Madhu , Awasthi Amit
Published: March 2023

Cytokine release syndrome (CRS) due to severe acute respiratory coronavirus-2 (SARS-CoV-2) infection leads to life-threatening pneumonia which has been associated with coronavirus disease (COVID-19) pathologies. Centuries-old Asian traditional medicines such as Withania somnifera (L.) Dunal (WS) and Tinospora cordifolia (Willd.) Miers (TC) possess potent immunomodulatory effects and were used by the AYUSH ministry, in India during the COVID-19 pandemic. In the present study, we investigated WS and TC’s anti-viral and immunomodulatory efficacy at the human equivalent doses using suitable in vitro and in vivo models. While both WS and TC showed immuno-modulatory potential, WS showed robust protection against loss in body weight, viral load, and pulmonary pathology in the hamster model of SARS-CoV2. In vitro pretreatment of mice and human neutrophils with WS and TC had no adverse effect on PMA, calcium ionophore, and TRLM-induced ROS generation, phagocytosis, bactericidal activity, and NETs formation. Interestingly, WS significantly suppressed the pro-inflammatory cytokines-induced Th1, Th2, and Th17 differentiation. We also used hACE2 transgenic mice to further investigate the efficacy of WS against acute SARS-CoV2 infection. Prophylactic treatment of WS in the hACE2 mice model showed significant protection against body weight loss, inflammation, and the lung viral load. The results obtained indicate that WS promoted the immunosuppressive environment in the hamster and hACE2 transgenic mice models and limited the worsening of the disease by reducing inflammation, suggesting that WS might be useful against other acute viral infections. The present study thus provides pre-clinical efficacy data to demonstrate a robust protective effect of WS against COVID-19 through its broader immunomodulatory activity
Inhibiting efferocytosis reverses macrophage-mediated immunosuppression in the leukemia microenvironment
Authors: Cruz Cruz Joselyn , Allison Kristen C. , Page Lauren S. , Jenkins Alexis J. , Wang Xiaodong , Earp H. Shelton , Frye Stephen V. , Graham Douglas K. , Verneris Michael R. , Lee-Sherick Alisa B.
Published: March 2023

Background

Previous studies show that the spleen and bone marrow can serve as leukemia microenvironments in which macrophages play a significant role in immune evasion and chemoresistance. We hypothesized that the macrophage driven tolerogenic process of efferocytosis is a major contributor to the immunosuppressive leukemia microenvironment and that this was driven by aberrant phosphatidylserine expression from cell turnover and cell membrane dysregulation.

Methods

Since MerTK is the prototypic efferocytosis receptor, we assessed whether the MerTK inhibitor MRX2843, which is currently in clinical trials, would reverse immune evasion and enhance immune-mediated clearance of leukemia cells.

Results

We found that inhibition of MerTK decreased leukemia-associated macrophage expression of M2 markers PD-L1, PD-L2, Tim-3, CD163 and Arginase-1 compared to vehicle-treated controls. Additionally, MerTK inhibition led to M1 macrophage repolarization including elevated CD86 and HLA-DR expression, and increased production of T cell activating cytokines, including IFN-β, IL-18, and IL-1β through activation of NF-κB. Collectively, this macrophage repolarization had downstream effects on T cells within the leukemia microenvironment, including decreased PD-1+Tim-3+ and LAG3+ checkpoint expression, and increased CD69+CD107a+ expression.

Discussion

These results demonstrate that MerTK inhibition using MRX2843 altered the leukemia microenvironment from tumor-permissive toward immune responsiveness to leukemia and culminated in improved immune-mediated clearance of AML.
Biophysical contexture of coastal biofilm-sediments varies heterogeneously and seasonally at the centimeter scale across the bed-water interface
Authors: Chen Xindi , Kang Yanyan , Zhang Qian , Jin Chuang , Zhao Kun
Published: March 2023

Coastal sediments filter and accumulate organic and inorganic materials from the terrestrial and marine environment, and thus provide a high diversity of microbial niches. However, sediment-based analyses typically examine bulk samples and seldom consider variation at a scale relevant to changes in environmental conditions, due to the lack of mid-long term field data which can cover both the seasonal and sediment depth variations. In this study, microbial production and bacterial community structure were determined together with grain parameters over 10 months of intertidal silty sands on Jiangsu Coast, China. We demonstrated that the microbiological effects did not merely present on the surface, but greatly varied and stratified in both physical and biological contexture within the top 4 cm layer. Bacterial community structure showed a clear vertical variation with higher operational taxonomic unit (OTU) numbers at 1~2 cm depth than in the top 2 mm, probably because of the decreasing disturbance by hydrodynamic forces. However, the microbial production rates and metabolic activities, represented by the production of extracellular polymeric substances (EPS), were always higher in the top. Seasonal changes were strongly reflected in the vertical patterns of EPS but could not explain the variation across sites. The overall EPS secretion in spring and summer was generally at high level than that in autumn and winter, with the maximum value of 5~6 times higher. Interestingly, the stratification of biological and physical properties followed a fixed relationship, where with the decrease of the grain size D50, the EPS content increased exponentially, and this relationship was independent of temporal or spatial variation. Despite the significant seasonal variation of microbial activity and sedimentary grain size individually, the basic function between EPS content and D50 however did not alter. Filling these knowledge gaps will not only help to decipher the fate of grain-biofilm aggregates and organic matter burial under global changes, but also provide field evidence for the development of sediment transport models as well as blue carbon models incorporating microbial processes.
Genome-wide identification, structural and evolutionary characteristics, and expression analysis of aquaporin gene family members in Mercenaria mercenaria
Authors: Zhou Cong , Lin Zhi-shu , Shi Ying , Feng Jie , Hu Zhi , Yang Mei-jie , Shi Pu , Li Yong-ren , Guo Yong-jun , Zhang Tao , Song Hao
Published: March 2023

Aquaporins (AQPs) are highly-selective transmembrane water transporters that are involved in the adaptation to environmental challenges. However, the structure, function, and evolution of AQPs in bivalves remain largely unknown. In this study, AQP gene family members were identified in nine bivalve species, and their abundance rangs from 7 to 15. Nine AQPs (MmAQPs) were identified in the genome of hard clam (Mercenaria mercenaria), which is a euryhaline bivalve that has evolved sophisticated osmoregulatory mechanisms and salinity adaptation. Structurally, all MmAQPs contain 6 or 12 transmembrane α-helices, a major intrinsic protein (MIP) domain, and 2 asparagine-proline-alanine (NPA) motifs. MmAQPs were classified into three subfamilies based on phylogenetic analysis: AQP1-like, AQP3-like, and AQP8-like. No AQP11-like subfamily member was identified in the genome of hard clam. Tandem duplication resulted in a lineage-specific expansion in AQP8-like subfamily in hard clams. MmAQP8 genes showed different expression sensitivity to different environmental stressors. The gene expression patterns of three MmAQP8 were similar under heat, hypoxia, and air exposure stress, but differed greatly under salinity stress, indicating that tandem duplication events may accelerate the functional divergence of AQP8 genes in hard clams. AQP3-like members may have undergone gene loss during evolution, resulting in weakened glycerol and urea penetration in hard clams. Three orthologs of MmAQPs were detected in the genomes of Cyclina sinensis and Archivesica marissinica through synteny analyses. Tissue expression profiles showed that MmAQP genes were highly expressed in the foot and hepatopancreas. Under environmental stress, the expression levels of most of the MmAQP genes changed significantly to maintain metabolic homeostasis. Several MmAQP genes were downregulated to reduce water permeability under salinity and air exposure stress. Several MmAQP genes were significantly upregulated to promote the transmembrane transport of ammonia and reactive oxygen species and activate anti-apoptotic responses to resist stress. This study provides a comprehensive understanding of the AQP gene family in hard clams, and lays a foundation for further studies to explore the functions of AQPs in bivalves.
CBD resistant Salmonella strains are susceptible to epsilon 34 phage tailspike protein
Authors: Ibrahim Iddrisu , Ayariga Joseph Atia , Xu Junhuan , Adebanjo Ayomide , Robertson Boakai K. , Samuel-Foo Michelle , Ajayi Olufemi S.
Published: March 2023

The rise of antimicrobial resistance is a global public health crisis that threatens the effective control and prevention of infections. Due to the emergence of pandrug-resistant bacteria, most antibiotics have lost their efficacy. Bacteriophages or their components are known to target bacterial cell walls, cell membranes, and lipopolysaccharides (LPS) and hydrolyze them. Bacteriophages being the natural predators of pathogenic bacteria, are inevitably categorized as “human friends”, thus fulfilling the adage that “the enemy of my enemy is my friend”. Leveraging on their lethal capabilities against pathogenic bacteria, researchers are searching for more ways to overcome the current antibiotic resistance challenge. In this study, we expressed and purified epsilon 34 phage tailspike protein (E34 TSP) from the E34 TSP gene, then assessed the ability of this bacteriophage protein in the killing of two CBD-resistant strains of Salmonella spp. We also assessed the ability of the tailspike protein to cause bacteria membrane disruption, and dehydrogenase depletion. We observed that the combined treatment of CBD-resistant strains of Salmonella with CBD and E34 TSP showed poor killing ability whereas the monotreatment with E34 TSP showed considerably higher killing efficiency. This study demonstrates that the inhibition of the bacteria by E34 TSP was due in part to membrane disruption, and dehydrogenase inactivation by the protein. The results of this work provides an interesting background to highlight the crucial role phage protein such as E34 TSP could play in pathogenic bacterial control.
SigE: A master regulator of Mycobacterium tuberculosis
Authors: Manganelli Riccardo , Cioetto-Mazzabò Laura , Segafreddo Greta , Boldrin Francesca , Sorze Davide , Conflitti Marta , Serafini Agnese , Provvedi Roberta
Published: March 2023

The Extracellular function (ECF) sigma factor SigE is one of the best characterized out of the 13 sigma factors encoded in theMycobacterium tuberculosischromosome. SigE is required for blocking phagosome maturation and full virulence in both mice and guinea pigs. Moreover, it is involved in the response to several environmental stresses as surface stress, oxidative stress, acidic pH, and phosphate starvation. Underscoring its importance inM. tuberculosisphysiology, SigE is subjected to a very complex regulatory system: depending on the environmental conditions, its expression is regulated by three different sigma factors (SigA, SigE, and SigH) and a two-component system (MprAB). SigE is also regulated at the post-translational level by an anti-sigma factor (RseA) which is regulated by the intracellular redox potential and by proteolysis following phosphorylation from PknB upon surface stress. The set of genes under its direct control includes other regulators, as SigB, ClgR, and MprAB, and genes involved in surface remodeling and stabilization. Recently SigE has been shown to interact with PhoP to activate a subset of genes in conditions of acidic pH. The complex structure of its regulatory network has been suggested to result in a bistable switch leading to the development of heterogeneous bacterial populations. This hypothesis has been recently reinforced by the finding of its involvement in the development of persister cells able to survive to the killing activity of several drugs.