bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic modifications of critical regulators provide new insights into regulation modes of raw-starch-digesting enzyme expression in Penicillium
Authors: Zhao Shengfang , Xiang Boyu , Yang Le , Chen Jie , Zhu Cui , Chen Yu , Cui Jun , Hu Shengbiao , Hu Yibo 
Published: May 2022

Abstract
Background
Starch is a very abundant and renewable carbohydrate and an important feedstock for industrial applications. However, most starch-based products are not cost-efficient due to the high energy input needed in traditional enzymatic starch conversion processes. Raw-starch-digesting enzymes (RSDEs) from filamentous fungi have great commercial value in starch processing. However, the regulatory mechanisms associated with their production in filamentous fungi remain unknown.

Results
In this study, we reported the novel finding that cellulolytic fungus Penicillium oxalicum 114-2 has broad RSDE activity. Four regulators, including the amylase transcription activator AmyR, the catabolite repression repressor CreA, the group III G protein α subunit PGA3, and the nonhistone chromosomal protein HepA, have been found to play a crucial regulatory role in RSDE expression. Enzymatic assays revealed that RSDE production significantly increased after the overexpression of AmyR and HepA, the deletion of CreA and the dominant activation of PGA3. RT-qPCR analysis demonstrated that there is a mutual regulation mode between the four regulators, and then formed a cascade regulation mechanism that is involved in RSDE expression. Comparative transcriptomic analysis between the wild-type strain and genetically engineered strains revealed differentially expressed genes that may mediate the RSDE expression.

Conclusions
The four different types of regulators were systematically investigated and found to form a regulatory network controlling RSDE gene expression. Our results provide a new insight into the regulatory mechanism of fungal amylolytic enzyme expression and offer a theoretical basis to rationally improve the RSDE yield in the future.
Alternative splicing diversifies the skeletal muscle transcriptome during prolonged spaceflight
Authors: Henrich Mason , Ha Pin , Wang Yuanyuan , Ting Kang , Stodieck Louis , Soo Chia , Adams John S. , Chun Rene 
Published: May 2022

AbstractBackgroundAs the interest in manned spaceflight increases, so does the requirement to understand the transcriptomic mechanisms that underlay the detrimental physiological adaptations of skeletal muscle to microgravity. While microgravity-induced differential gene expression (DGE) has been extensively investigated, the contribution of differential alternative splicing (DAS) to the plasticity and functional status of the skeletal muscle transcriptome has not been studied in an animal model. Therefore, by evaluating both DGE and DAS across spaceflight, we set out to provide the first comprehensive characterization of the transcriptomic landscape of skeletal muscle during exposure to microgravity.MethodsRNA-sequencing, immunohistochemistry, and morphological analyses were conducted utilizing total RNA and tissue sections isolated from the gastrocnemius and quadriceps muscles of 30-week-old female BALB/c mice exposed to microgravity or ground control conditions for 9 weeks.ResultsIn response to microgravity, the skeletal muscle transcriptome was remodeled via both DGE and DAS. Importantly, while DGE showed variable gene network enrichment, DAS was enriched in structural and functional gene networks of skeletal muscle, resulting in the expression of alternatively spliced transcript isoforms that have been associated with the physiological changes to skeletal muscle in microgravity, including muscle atrophy and altered fiber type function. Finally, RNA-binding proteins, which are required for regulation of pre-mRNA splicing, were themselves differentially spliced but not differentially expressed, an upstream event that is speculated to account for the downstream splicing changes identified in target skeletal muscle genes.ConclusionsOur work serves as the first investigation of coordinate changes in DGE and DAS in large limb muscles across spaceflight. It opens up a new opportunity to understand (i) the molecular mechanisms by which splice variants of skeletal muscle genes regulate the physiological adaptations of skeletal muscle to microgravity and (ii) how small molecule splicing regulator therapies might thwart muscle atrophy and alterations to fiber type function during prolonged spaceflight.
A minimal bile salt excretory pump promoter allows bile acid-driven physiological regulation of transgene expression from a gene therapy vector
Authors: Martínez-García Javier , Molina Manuela , Odriozola Leticia , Molina Angie , González-Aseguinolaza Gloria , Weber Nicholas D. , Smerdou Cristian 
Published: May 2022

Abstract
Background
Bile acid (BA) homeostasis is mainly regulated by bile salt excretory pump (BSEP), a hepatocyte transporter that transfers BAs to the bile. BSEP expression is regulated by BA levels through activation of farnesoid X receptor transcription factor, which binds to the inverted repeat (IR-1) element in the BSEP promoter. Gene therapy of cholestatic diseases could benefit from using vectors carrying endogenous promoters physiologically regulated by BAs, however their large size limits this approach, especially when using adeno-associated viral vector (AAV) vectors.

Results
We evaluated the functionality and BA-mediated regulation of minimal versions of human and mouse BSEP promoters containing IR-1 using AAV vectors expressing luciferase. Unexpectedly, a minimal mouse BSEP promoter (imPr) showed higher BA-mediated expression and inducibility than a minimal human promoter (ihPr) or than full-length BSEP promoters in human hepatic cells. In addition, in mice receiving an AAV8 vector carrying imPr promoter-driven luciferase expression was efficiently regulated by administration of a BA-enriched diet. Interestingly, this vector also expressed significantly higher luciferase levels in Abcb4−/− mice, which have high levels of BAs, compared to wild type mice, or to mice receiving a vector containing the luciferase gene downstream of the constitutive alpha-1 antitrypsin promoter. In contrast, the AAV vector containing ihPr showed very low luciferase expression with no inducibility. Finally, we optimized imPr by adding three IR-1 repeats at its 5′ end. This new promoter provided higher levels of luciferase than imPr both in vitro and in vivo.

Conclusions
The imPr could represent a useful tool for gene therapy approaches in which physiological BA regulation is desired.
The multifaceted role of the SASP in atherosclerosis: from mechanisms to therapeutic opportunities
Authors: Sun Yu , Wang Xia , Liu Tianwei , Zhu Xiaoyan , Pan Xudong 
Published: May 2022

Abstract
Background
The global population of older individuals is growing, and ageing is a key risk factor for atherosclerotic cardiovascular diseases. Abnormal accumulation of senescent cells can cause potentially deleterious effects on the organism with age. As a vital marker of cellular senescence, the senescence-associated secretory phenotype (SASP) is a novel mechanism to link cellular senescence with atherosclerosis.

Main body
In this review, we concretely describe the characteristics of the SASP and its regulation mechanisms. Importantly, we provide novel perspectives on how the SASP can promote atherosclerosis. The SASP from different types of senescent cells have vital roles in atherosclerosis progression. As a significant mediator of the harmful effects of senescent cells, it can play a pro-atherogenic role by producing inflammation and immune dysfunction. Furthermore, the SASP can deliver senescence signals to the surrounding vascular cells, gradually contributing to the development of atherosclerosis. Finally, we focus on a variety of novel therapeutic strategies aimed to reduce the burden of atherosclerosis in elderly individuals by targeting senescent cells and inhibiting the regulatory mechanisms of the SASP.

Conclusion
This review systematically summarizes the multiple roles of the SASP in atherosclerosis and can contribute to the exploration of new therapeutic opportunities.
Bone morphogenetic protein signaling regulation of AMPK and PI3K in lung cancer cells and C. elegans
Authors: Vora Mehul , Mondal Arindam , Jia Dongxuan , Gaddipati Pranya , Akel Moumen , Gilleran John , Roberge Jacques , Rongo Christopher , Langenfeld John 
Published: May 2022

Abstract
Background
Bone morphogenetic protein (BMP) is a phylogenetically conserved signaling pathway required for development that is aberrantly expressed in several age-related diseases including cancer, Alzheimer’s disease, obesity, and cardiovascular disease. Aberrant BMP signaling in mice leads to obesity, suggesting it may alter normal metabolism. The role of BMP signaling regulating cancer metabolism is not known.

Methods
To examine BMP regulation of metabolism, C. elegans harboring BMP gain-of-function (gof) and loss-of-function (lof) mutations were examined for changes in activity of catabolic and anabolic metabolism utilizing Western blot analysis and fluorescent reporters. AMP activated kinase (AMPK) gof and lof mutants were used to examine AMPK regulation of BMP signaling. H1299 (LKB1 wild-type), A549 (LKB1 lof), and A549-LKB1 (LKB1 restored) lung cancer cell lines were used to study BMP regulation of catabolic and anabolic metabolism. Studies were done using recombinant BMP ligands to activate BMP signaling, and BMP receptor specific inhibitors and siRNA to inhibit signaling.

Results
BMP signaling in both C. elegans and cancer cells is responsive to nutrient conditions. In both C. elegans and lung cancer cell lines BMP suppressed AMPK, the master regulator of catabolism, while activating PI3K, a regulator of anabolism. In lung cancer cells, inhibition of BMP signaling by siRNA or small molecules increased AMPK activity, and this increase was mediated by activation of LKB1. BMP2 ligand suppressed AMPK activation during starvation. BMP2 ligand decreased expression of TCA cycle intermediates and non-essential amino acids in H1299 cells. Furthermore, we show that BMP activation of PI3K is mediated through BMP type II receptor. We also observed feedback signaling, as AMPK suppressed BMP signaling, whereas PI3K increased BMP signaling.

Conclusion
These studies show that BMP signaling suppresses catabolic metabolism and stimulates anabolic metabolism. We identified feedback mechanisms where catabolic induced signaling mediated by AMPK negatively regulates BMP signaling, whereas anabolic signaling produces a positive feedback regulation of BMP signing through Akt. These mechanisms were conserved in both lung cancer cells and C. elegans. These studies suggest that aberrant BMP signaling causes dysregulation of metabolism that is a potential mechanism by which BMP promotes survival of cancer cells.
Gut microbiome mediates the protective effects of exercise after myocardial infarction
Authors: Zhou Qiulian , Deng Jiali , Pan Xue , Meng Danni , Zhu Yujiao , Bai Yuzheng , Shi Chao , Duan Yi , Wang Tianhui , Li Xinli , Sluijter Joost PG , Xiao Junjie 
Published: May 2022

Abstract
Background
Gut microbiota plays important roles in health maintenance and diseases. Physical exercise has been demonstrated to be able to modulate gut microbiota. However, the potential role of gut microbiome in exercise protection to myocardial infarction (MI) remains unclear.

Results
Here, we discovered exercise training ameliorated cardiac dysfunction and changed gut microbial richness and community structure post-MI. Moreover, gut microbiota pre-depletion abolished the protective effects of exercise training in MI mice. Furthermore, mice receiving microbiota transplants from exercised MI mice had better cardiac function compared to mice receiving microbiota transplants from non-exercised MI mice. Mechanistically, we analyzed metabolomics in fecal samples from exercised mice post-MI and identified 3-Hydroxyphenylacetic acid (3-HPA) and 4-Hydroxybenzoic acid (4-HBA), which could be applied individually to protect cardiac dysfunction post-MI and apoptosis through NRF2.

Conclusions
Together, our study provides new insights into the role of gut microbiome in exercise protection to MI, offers opportunities to modulate cardiovascular diseases by exercise, microbiome and gut microbiota-derived 3-HPA and 4-HBA.
Extracellular miR-6723-5p could serve as a biomarker of limbal epithelial stem/progenitor cell population
Authors: Ruiz M. , González S. , Bonnet C. , Deng S. X. 
Published: May 2022

Abstract
Background
Dysfunction or loss of limbal stem cells can result in limbal stem cell deficiency (LSCD), a disease that cause corneal opacity, pain, and loss of vision. Cultivated limbal epithelial transplantation (CLET) can be used to restore stem cell niche homeostasis and replenish the progenitor pool. Transplantation has been reported with high success rate, but there is an unmet need of prognostic markers that correlate with clinical outcomes. To date, the progenitor content in the graft is the only parameter that has been retrospectively linked to success.

Methods
In this study, we investigate extracellular micro RNAs (miRNAs) associated with stem/progenitor cells in cultivated limbal epithelial cells (cLECs). Using micro RNA sequencing and linear regression modelling, we identify a miRNA signature in cultures containing high proportion of stem/progenitor cells. We then develop a robust RNA extraction workflow from culture media to confirm a positive miRNA correlation with stem/progenitor cell proportion.

Results
miR-6723-5p is associated with cultures containing high proportion of stem/progenitor cells, and is detected in the basal layer of corneal epithelium.

Conclusions
These results indicate that miR-6723-5p could potentially serve as a stem/progenitor cell marker in cLECs.
Convergent evolution and multi-wave clonal invasion in H3 K27-altered diffuse midline gliomas treated with a PDGFR inhibitor
Authors: Arunachalam Sasi , Szlachta Karol , Brady Samuel W. , Ma Xiaotu , Ju Bensheng , Shaner Bridget , Mulder Heather L. , Easton John , Raphael Benjamin J. , Myers Matthew , Tinkle Christopher , Allen Sariah J. , Orr Brent A. , Wetmore Cynthia J. , Baker Suzanne J. , Zhang Jinghui 
Published: May 2022

AbstractThe majority of diffuse midline gliomas, H3 K27-altered (DMG-H3 K27-a), are infiltrating pediatric brain tumors that arise in the pons with no effective treatment. To understand how clonal evolution contributes to the tumor’s invasive spread, we performed exome sequencing and SNP array profiling on 49 multi-region autopsy samples from 11 patients with pontine DMG-H3 K27-a enrolled in a phase I clinical trial of PDGFR inhibitor crenolanib. For each patient, a phylogenetic tree was constructed by testing multiple possible clonal evolution models to select the one consistent with somatic mutations and copy number variations across all tumor regions. The tree was then used to deconvolute subclonal composition and prevalence at each tumor region to study convergent evolution and invasion patterns. Somatic variants in the PI3K pathway, a late event, are enriched in our cohort, affecting 70% of patients. Convergent evolution of PI3K at distinct phylogenetic branches was detected in 40% of the patients. 24 (~ 50%) of tumor regions were occupied by subclones of mixed lineages with varying molecular ages, indicating multiple waves of invasion across the pons and extrapontine. Subclones harboring a PDGFRA amplicon, including one that amplified a PDGRFAY849C mutant allele, were detected in four patients; their presence in extrapontine tumor and normal brain samples imply their involvement in extrapontine invasion. Our study expands the current knowledge on tumor invasion patterns in DMG-H3 K27-a, which may inform the design of future clinical trials.
The response of the hydrological cycle to temperature changes in recent and distant climatic history
Authors: Pratap Shailendra , Markonis Yannis 
Published: May 2022

AbstractThe relationship between the hydrological cycle and the temperature is rather complex and of great importance to human socioeconomic activities. The prevailing theory suggests that as temperature increases the hydrological cycle is intensified. Practically, this means more and heavier precipitation. However, the exact magnitude of hydrological cycle response and its spatio-temporal characteristics is still under investigation. Looking back in Earth’s hydroclimatic history, it is easy to find some periods where global temperature was substantially different than present. Here, we examine some of these periods to present the current knowledge about past hydrological cycle variability (specifically precipitation), and its relationship to temperature. The periods under investigation are the Mid-Miocene Climate Optimum, the Eemian Interglacial Stage, the Last Glacial Maximum, the Heinrich and Dansgaard–Oeschger Events, the Bølling–Allerød, the Younger Dryas, the 8.2 ka event, the Medieval Climate Anomaly, and the Little Ice Age. We report that the hypothesis that a warmer climate is a wetter climate could be an oversimplification, because the response of water cycle appears to be spatio-temporally heterogeneous.
Stress response and virulence factors in bacterial pathogens relevant for Chilean aquaculture: current status and outlook of our knowledge
Authors: Fuentes Derie E. , Acuña Lillian G. , Calderón Iván L. 
Published: May 2022

AbstractThe study of the stress responses in bacteria has given us a wealth of information regarding the mechanisms employed by these bacteria in aggressive or even non-optimal living conditions. This information has been applied by several researchers to identify molecular targets related to pathogeny, virulence, and survival, among others, and to design new prophylactic or therapeutic strategies against them. In this study, our knowledge of these mechanisms has been summarized with emphasis on some aquatic pathogenic bacteria of relevance to the health and productive aspects of Chilean salmon farming (Piscirickettsia salmonis, Tenacibaculum spp., Renibacterium salmoninarum, and Yersinia ruckeri). This study will aid further investigations aimed at shedding more light on possible lines of action for these pathogens in the coming years.
Myelin oligodendrocyte glycoprotein antibody-associated optic neuritis and myelitis in COVID-19: a case report and a review of the literature
Authors: Colantonio Mark A. , Nwafor Divine C. , Jaiswal Shruti , Shrestha Ashish K. , Elkhooly Mahmoud , Rollins Steven , Wen Sijin , Sriwastava Shitiz 
Published: May 2022

Abstract
Background
Our case explored the spectrum of autoimmune and infectious neurological complications of Coronavirus Disease 2019. In addition, we also reviewed and discussed clinical features, neuroimaging, CSF findings, and outcomes in patients with COVID-19-associated Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD) CNS inflammatory disorder.

Case presentation
Here we presented a case of post-Coronavirus Disease 2019 infection Myelin Oligodendrocyte Glycoprotein Antibody Disorder in a 41-year-old male who presented with gait instability, urinary retention, and confusion. Workup done in hospital showed transverse myelitis in cervical spine region and left optic neuritis. Laboratory findings showed Myelin Oligodendrocyte Glycoprotein-IgG antibodies were positive in serum (1:100), suggestive of post-COVID Myelin Oligodendrocyte Glycoprotein Antibody Disorder.

Conclusion
To our knowledge, this is the first comprehensive case report and the literature review that includes the clinical features, neuroimaging, CSF findings, and outcomes in COVID-19-associated Myelin Oligodendrocyte Glycoprotein Antibody Disorder.
Reasons behind high rate of non-compliance to scheduled office visits in hypertensive patients: results from the Egyptian registry of specialized hypertension clinics
Authors: Youssef Ghada , Mohamed Marwa , Abdel Hamid Magdy , El Remisy Dalia 
Published: May 2022

Abstract
Background
Hypertensive patients’ compliance to the clinic’s follow-up visits is associated with a better blood pressure control. The aim of this study was to detect the reasons of non-compliance to office visits in Egyptian hypertensive patients.

Results
This is an observational, prospective, cross-sectional research study where patients were enrolled from the registry of the specialized hypertension clinics of 9 university hospitals. Those who attended less than 3 office visits, throughout the registry period, were considered non-compliant and were contacted through the phone. A simple questionnaire was prepared, which included questions about the reasons of non-compliance to follow up. There were 3014 patients eligible for inclusion in this study but only 649 patients (21.5%) completed the questionnaire. Patients claimed that the reasons of non-compliance to the follow up visits in the specialized hypertension clinics were as follows: 444 patients (68.4%) preferred to follow up elsewhere mostly in pharmacies, 53 patients (8.2%) claimed that the healthcare service was unsatisfactory, 94 patients (14.5%) were asymptomatic, and 110 patients (16.9%) said that the clinic was far from their homes. Despite non-compliance to office visits, 366 patients (59.2%) were compliant to their antihypertensive medications and 312 (48.1%) patients were compliant to salt restriction. About 34% of patients used herbs, mainly hibiscus, as adjuvant to their antihypertensive medications.

Conclusions
Reasons for non-compliance to office visits in hypertensive patients were either patient-related, or healthcare-related. To improve patients’ compliance, physicians need to educate their patients about hypertension, patients need to follow their doctors’ instructions as regard medications, salt restriction and scheduled office visits, and governments need to provide better and cheaper healthcare services.
A case of Rosai-Dorfman’s disease as isolated mediastinal lymphadenopathy: a diagnostic challenge
Authors: Modi Mahavir , Devi Kaumudi 
Published: May 2022

Abstract
Background
Mediastinal lymphadenopathy is seen in a variety of diseases, like tuberculosis, sarcoidosis, and metastasis. The diagnosis can be confirmed by tissue sampling with endobronchial ultrasound and transbronchial needle aspirate. A middle-aged male presented to us with a history similar to tuberculosis, and was on empirical anti-tuberculosis treatment was evaluated again by EBUS-TBNA and proved to be Rosai-Dorfman’s disease. This case report emphasizes on confirming the cases of mediastinal lymphadenopathy with tissue sampling.

Conclusion
All mediastinal lymphadenopathy should be evaluated in detail as the symptoms of the possible diseases, like tuberculosis, sarcoidosis, Kikuchi’s disease, Rosai-Dorfman’s disease, and malignancy can be similar. Hence, tissue sampling will confirm the diagnosis and help in appropriate management.