bluuebunny/crossref_metadata_2025 huggingface dataset:
Lung Allograft Epithelium DNA Methylation Age Is Associated With Graft Chronologic Age and Primary Graft Dysfunction
Authors: Dugger Daniel T. , Calabrese Daniel R. , Gao Ying , Deiter Fred , Tsao Tasha , Maheshwari Julia , Hays Steven R. , Leard Lorriana , Kleinhenz Mary Ellen , Shah Rupal , Golden Jeff , Kukreja Jasleen , Gordon Erin D. , Singer Jonathan P. , Greenland John R.
Published: October 2021

Advanced donor age is a risk factor for poor survival following lung transplantation. However, recent work identifying epigenetic determinants of aging has shown that biologic age may not always reflect chronologic age and that stressors can accelerate biologic aging. We hypothesized that lung allografts that experienced primary graft dysfunction (PGD), characterized by poor oxygenation in the first three post-transplant days, would have increased biologic age. We cultured airway epithelial cells isolated by transbronchial brush at 1-year bronchoscopies from 13 subjects with severe PGD and 15 controls matched on age and transplant indication. We measured epigenetic age using the Horvath epigenetic clock. Linear models were used to determine the association of airway epigenetic age with chronologic ages and PGD status, adjusted for recipient PGD risk factors. Survival models assessed the association with chronic lung allograft dysfunction (CLAD) or death. Distributions of promoter methylation within pathways were compared between groups. DNA methyltransferase (DNMT) activity was quantified in airway epithelial cells under hypoxic or normoxic conditions. Airway epigenetic age appeared younger but was strongly associated with the age of the allograft (slope 0.38 per year, 95% CI 0.27–0.48). There was no correlation between epigenetic age and recipient age (P = 0.96). Epigenetic age was 6.5 years greater (95% CI 1.7–11.2) in subjects who had experienced PGD, and this effect remained significant after adjusting for donor and recipient characteristics (P = 0.03). Epigenetic age was not associated with CLAD-free survival risk (P = 0.11). Analysis of differential methylation of promoters of key biologic pathways revealed hypomethylation in regions related to hypoxia, inflammation, and metabolism-associated pathways. Accordingly, airway epithelial cells cultured in hypoxic conditions showed suppressed DNMT activity. While airway methylation age was primarily determined by donor chronologic age, early injury in the form of PGD was associated with increased allograft epigenetic age. These data show how PGD might suppress key promoter methylation resulting in long-term impacts on the allograft.
Distribution, Feeding Habits, and Growth of Chub Mackerel, Scomber japonicus, Larvae During a High-Stock Period in the Northern Satsunan Area, Southern Japan
Authors: Kume Gen , Shigemura Taichi , Okanishi Masahiro , Hirai Junya , Shiozaki Kazuhiro , Ichinomiya Mutsuo , Komorita Tomohiro , Habano Akimasa , Makino Fumihiro , Kobari Toru
Published: October 2021

To evaluate the importance of the northern Satsunan area in southern Japan as a spawning and nursery ground for chub mackerel (Scomber japonicus), we investigated the early life history characteristics (e.g., larval distribution, feeding habits, and growth) ofS. japonicusover five successive years. This area is considered the main habitat and spawning ground of the congeneric species,S. australasicus. Using polymerase chain reaction-restriction fragment length polymorphism analysis, we first confirmed thatS. japonicuslarvae were abundant in the northern Satsunan area, potentially representing a major spawning and nursery ground in the Japanese Pacific coastal area. The number of recorded larvae started to increase in 2016, corresponding to the population dynamics of the Pacific stock of the species, which has shown increasing trends in recent years. Morphological and DNA metabarcoding analyses of gut contents and stable isotope analysis showed that, in addition to copepods, the larvae fed substantially on appendicularians. The trophic pathway involving appendicularians might support the feeding habits ofS. japonicus, promoting its coexistence with other dominant species. Both the instantaneous growth rate and daily specific growth rate were comparable to those in the southern East China Sea, which is the main spawning and nursery ground of the species. Our data strongly suggest that the northern Satsunan area has favorable conditions for sustaining high larval population densities, even during phases with high population numbers. Our results provide insights for the fisheries management forS. japonicusin the Japanese Pacific coastal area, especially during high-stock periods.
Kelp in the Eastern Canadian Arctic: Current and Future Predictions of Habitat Suitability and Cover
Authors: Goldsmit Jesica , Schlegel Robert W. , Filbee-Dexter Karen , MacGregor Kathleen A. , Johnson Ladd E. , Mundy Christopher J. , Savoie Amanda M. , McKindsey Christopher W. , Howland Kimberly L. , Archambault Philippe
Published: October 2021

Climate change is transforming marine ecosystems through the expansion and contraction of species’ ranges. Sea ice loss and warming temperatures are expected to expand habitat availability for macroalgae along long stretches of Arctic coastlines. To better understand the current distribution of kelp forests in the Eastern Canadian Arctic, kelps were sampled along the coasts for species identifications and percent cover. The sampling effort was supplemented with occurrence records from global biodiversity databases, searches in the literature, and museum records. Environmental information and occurrence records were used to develop ensemble models for predicting habitat suitability and a Random Forest model to predict kelp cover for the dominant kelp species in the region – Agarum clathratum, Alaria esculenta, and Laminariaceae species (Laminaria solidungula and Saccharina latissima). Ice thickness, sea temperature and salinity explained the highest percentage of kelp distribution. Both modeling approaches showed that the current extent of arctic kelps is potentially much greater than the available records suggest. These modeling approaches were projected into the future using predicted environmental data for 2050 and 2100 based on the most extreme emission scenario (RCP 8.5). The models agreed that predicted distribution of kelp in the Eastern Canadian Arctic is likely to expand to more northern locations under future emissions scenarios, with the exception of the endemic arctic kelp L. solidungula, which is more likely to lose a significant proportion of suitable habitat. However, there were differences among species regarding predicted cover for both current and future projections. Notwithstanding model-specific variation, it is evident that kelps are widespread throughout the area and likely contribute significantly to the functioning of current Arctic ecosystems. Our results emphasize the importance of kelp in Arctic ecosystems and the underestimation of their potential distribution there.
Integrated Application of Transcriptomics and Metabolomics Reveals the Energy Allocation-Mediated Mechanisms of Growth-Defense Trade-Offs in Crassostrea gigas and Crassostrea angulata
Authors: Wang Chaogang , Li Ao , Wang Wei , Cong Rihao , Wang Luping , Zhang Guofan , Li Li
Published: October 2021

Understanding the genetic basis of trait variations and their coordination between relative species or populations distributing in different environmental conditions is important in evolutionary biology. In marine ectotherms, growth-defense trade-offs are a common ecological and evolutionary phenomenon. However, the biochemical and molecular mechanisms that govern these trade-offs in marine ectotherms in the evolutionary perspective remain poorly investigated. Oysters are among the most important species in global aquaculture. Crassostrea gigas (C. gigas) and Crassostrea angulata (C. angulata) are two allopatric congeneric dominant oyster species that inhabit the northern and southern intertidal areas of China. Wild C. gigas and C. angulata were spawned, and their F1 progeny were cultured in the same sites to reduce the environmental effects. Untargeted metabolomics and transcriptomics, together with phenotypic parameters including morphological traits (growth performance), nutritional content (glycogen, crude fat, and fatty acid content), physiology (normalized oxygen consumption rate and total antioxidant capacity) were applied to assess metabolic and transcript divergences between C. gigas and C. angulata. Integrated analyses of metabolites and transcriptomes showed that C. gigas allocated more energy to storage and defense by suppressing glycolysis, fatty acid oxidation and by upregulating fatty acid synthesis, antioxidant gene expression, and related metabolites. The metabolic and transcript results were further confirmed by the phenotypic data that C. gigas has higher glycogen and crude fat content and fatty acid unsaturation and stronger antioxidant capacity than C. angulata. In contrast, C. angulata exhibited better growth performance and a higher oxygen consumption rate. These findings suggest that C. angulata allocates more energy to growth, which is embodied in its stronger aerobic capacity and higher levels of protein synthesis genes, metabolites, and growth-related biomarkers. This study will help to enlighten the evolutionary patterns and genetic basis of growth-defense trade-offs in marine ectotherms and the biochemical and molecular mechanisms underlying energy allocation. Also, the key genes and metabolites of glycogen and fatty acids pathway identified in this study will be applied for meat quality improvement in the oyster industry.
The Abnormal Imaging of SARS-CoV-2: A Predictive Measure of Disease Severity
Authors: Pan Shangwen , Shu Huaqing , Wang Yaxin , Li Ruiting , Zhou Ting , Yu Yuan , Xu Jiqian , Xiong Wei , Yang Xiaobo , Zhang Jiancheng , Yuan Yin , Yuan Shiying , Shang You
Published: October 2021

To investigate the characteristics of SARS-CoV-2 pneumonia and evaluate whether CT scans, especially at a certain CT level, could be used to predict the severity of SARS-CoV-2 pneumonia. In total 118 confirmed patients had been enrolled. All data including epidemiological, clinical characteristics, laboratory results, and images were collected and analyzed when they were administrated for the first time. All patients were divided into two groups. There were 106 severe/critical patients and 12 common ones. A total of 38 of the patients were women. The mean age was 50.5 ± 11.5 years. Overall, 80 patients had a history of exposure. The median time from onset of symptoms to administration was 8.0 days. The main symptoms included fever, cough, anorexia, fatigue, myalgia, headaches, and chills. Lymphocytes and platelets decreased and lactate dehydrogenase increased with increased diseased severity (P < 0.05). Calcium and chloride ions were decreased more significantly in severe/critical patients than in common ones (P < 0.05). The main comorbidities were diabetes, chronic cardiovascular disease, and chronic pulmonary disease, which occurred in 47 patients. In all 69 patients had respiratory failure, which is the most common SARS-CoV-2 complication, and liver dysfunction presented in 37 patients. Nine patients received mechanical ventilation therapy. One patient received continuous blood purification and extracorporeal membrane oxygenation (EMCO) treatments. The average stay was 18.1 ± 10.8 days. Four patients died. The median of the radiographic score was four in common, and five in the severe/critical illness, which was a significant difference between the two groups. The radiographic score was in negative correlation with OI (ρ = −0.467, P < 0.01). The OI in severe/critically ill cases decreased significantly as the disease progressed, which was related to the lesion area in the left lung and right lungs (ρ = 0.688, R = 0.733). OI, the lesion area in the left lung and right lungs, lymphocytes, etc. were associated with different degrees of SARS-CoV-2 pneumonia (P < 0.05). The lesion area in both lungs were possible predictive factors for severe/critical cases. Patients with SARS-CoV-2 pneumonia showed obvious clinical manifestations and laboratory result changes. Combining clinical features and the quantity of the lesion area in the fourth level of CT could effectively predict severe/critical SARS-CoV-2 cases.
Alternative Approaches for the Management of Diabetic Foot Ulcers
Authors: Pouget Cassandra , Dunyach-Remy Catherine , Pantel Alix , Boutet-Dubois Adeline , Schuldiner Sophie , Sotto Albert , Lavigne Jean-Philippe , Loubet Paul
Published: October 2021

Diabetic foot ulcers (DFU) represent a growing public health problem. The emergence of multidrug-resistant (MDR) bacteria is a complication due to the difficulties in distinguishing between infection and colonization in DFU. Another problem lies in biofilm formation on the skin surface of DFU. Biofilm is an important pathophysiology step in DFU and may contribute to healing delays. Both MDR bacteria and biofilm producing microorganism create hostile conditions to antibiotic action that lead to chronicity of the wound, followed by infection and, in the worst scenario, lower limb amputation. In this context, alternative approaches to antibiotics for the management of DFU would be very welcome. In this review, we discuss current knowledge on biofilm in DFU and we focus on some new alternative solutions for the management of these wounds, such as antibiofilm approaches that could prevent the establishment of microbial biofilms and wound chronicity. These innovative therapeutic strategies could replace or complement the classical strategy for the management of DFU to improve the healing process.
Brain Structural and Functional Connectivity: A Review of Combined Works of Diffusion Magnetic Resonance Imaging and Electro-Encephalography
Authors: Babaeeghazvini Parinaz , Rueda-Delgado Laura M. , Gooijers Jolien , Swinnen Stephan P. , Daffertshofer Andreas
Published: October 2021

Implications of structural connections within and between brain regions for their functional counterpart are timely points of discussion. White matter microstructural organization and functional activity can be assessed in unison. At first glance, however, the corresponding findings appear variable, both in the healthy brain and in numerous neuro-pathologies. To identify consistent associations between structural and functional connectivity and possible impacts for the clinic, we reviewed the literature of combined recordings of electro-encephalography (EEG) and diffusion-based magnetic resonance imaging (MRI). It appears that the strength of event-related EEG activity increases with increased integrity of structural connectivity, while latency drops. This agrees with a simple mechanistic perspective: the nature of microstructural white matter influences the transfer of activity. The EEG, however, is often assessed for its spectral content. Spectral power shows associations with structural connectivity that can be negative or positive often dependent on the frequencies under study. Functional connectivity shows even more variations, which are difficult to rank. This might be caused by the diversity of paradigms being investigated, from sleep and resting state to cognitive and motor tasks, from healthy participants to patients. More challenging, though, is the potential dependency of findings on the kind of analysis applied. While this does not diminish the principal capacity of EEG and diffusion-based MRI co-registration, it highlights the urgency to standardize especially EEG analysis.
A Review of miRNAs as Biomarkers and Effect of Dietary Modulation in Obesity Associated Cognitive Decline and Neurodegenerative Disorders
Authors: Perdoncin Maddie , Konrad Alec , Wyner Joshua R. , Lohana Samir , Pillai Sneha S. , Pereira Duane G. , Lakhani Hari Vishal , Sodhi Komal
Published: October 2021

There has been a progressive increase in the prevalence of obesity and its comorbidities such as type 2 diabetes and cardiovascular diseases worldwide. Recent studies have suggested that the crosstalk between adipose tissue and central nervous system (CNS), through cellular mediators and signaling pathways, may causally link obesity with cognitive decline and give rise to neurodegenerative disorders. Several mechanisms have been proposed in obesity, including inflammation, oxidative stress, insulin resistance, altered lipid and cholesterol homeostasis, which may result in neuroinflammation, altered brain insulin signaling, amyloid-beta (Aβ) deposition and neuronal cell death. Since obesity is associated with functional and morphological alterations in the adipose tissues, the resulting peripheral immune response augments the development and progression of cognitive decline and increases susceptibility of neurodegenerative disorders, such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD). Studies have also elucidated an important role of high fat diet in the exacerbation of these clinical conditions. However, the underlying factors that propel and sustain this obesity associated cognitive decline and neurodegeneration, remains highly elusive. Moreover, the mechanisms linking these phenomena are not well-understood. The cumulative line of evidence have demonstrated an important role of microRNAs (miRNAs), a class of small non-coding RNAs that regulate gene expression and transcriptional changes, as biomarkers of pathophysiological conditions. Despite the lack of utility in current clinical practices, miRNAs have been shown to be highly specific and sensitive to the clinical condition being studied. Based on these observations, this review aims to assess the role of several miRNAs and aim to elucidate underlying mechanisms that link obesity with cognitive decline and neurodegenerative disorders. Furthermore, this review will also provide evidence for the effect of dietary modulation which can potentially ameliorate cognitive decline and neurodegenerative diseases associated with obesity.
Somatostatin Neurons in the Mouse Pontine Nucleus Activate GABAA Receptor Mediated Synaptic Currents in Locus Coeruleus Neurons
Authors: Garcia DuBar Selena , Cosio Daniela , Korthas Holly , Van Batavia Jason P. , Zderic Stephen A. , Sahibzada Niaz , Valentino Rita J. , Vicini Stefano
Published: October 2021

The pontine nuclei comprising the locus coeruleus (LC) and Barrington’s nucleus (BRN) amongst others form the neural circuitry(s) that coordinates arousal and voiding behaviors. However, little is known about the synaptic connectivity of neurons within or across these nuclei. These include corticotropin-releasing factor (CRF+) expressing neurons in the BRN that control bladder contraction and somatostatin expressing (SST+) neurons whose role in this region has not been discerned. To determine the synaptic connectivity of these neurons, we employed optogenetic stimulation with recordings from BRN and LC neurons in brain stem slices of channelrhodopsin-2 expressing SST or CRF neurons. Optogenetic stimulation of CRF+ BRN neurons of CrfCre;chr2-yfp mice had little effect on either CRF+ BRN neurons, CRF– BRN neurons, or LC neurons. In contrast, in SstCre;chr2-yfp mice light-activated inhibitory postsynaptic currents (IPSCs) were reliably observed in a majority of LC but not BRN neurons. The GABAA receptor antagonist, bicuculline, completely abolished the light-induced IPSCs. To ascertain if these neurons were part of the neural circuitry that controls the bladder, the trans-synaptic tracer, pseudorabies virus (PRV) was injected into the bladder wall of CrfCre;tdTomato or SstCre;tdTomato mice. At 68–72 h post-viral infection, PRV labeled neurons were present only in the BRN, being preponderant in CRF+ neurons with few SST+ BRN neurons labeled from the bladder. At 76 and 96 h post-virus injection, increased labeling was observed in both BRN and LC neurons. Our results suggest SST+ neurons rather than CRF+ neurons in BRN can regulate the activity of LC neurons.
Both Acidic pH Value and Binding Interactions of Tartaric Acid With α-Glucosidase Cause the Enzyme Inhibition: The Mechanism in α-Glucosidase Inhibition of Four Caffeic and Tartaric Acid Derivates
Authors: Li Wenyue , Song Yi , Sun Wanshu , Yang Xi , Liu Xuebo , Sun Lijun
Published: October 2021

The inhibition mechanism of four caffeic and tartaric acid derivates, including caffeic acid (CA), tartaric acid (TA), caftaric acid (CFA) and chicoric acid (CHA) against α-glucosidase was characterized by substrate depletion, fluorescence quenching, isothermal titration calorimetry (ITC) and molecular docking. TA and CA were found with the highest and no inhibition effect respectively, and caffeoyl substitution at 2 and/or 3-OH of TA significantly decreased its inhibition. The enzyme inhibition effects of organic acids were not in an inhibitor concentration-dependent mode, and there was a rush increase in inhibition at a respective acidic pH value, especially for CFA and CHA, suggesting the important role of acidic pH in the enzyme inhibition for both compounds. Besides, CA, CFA and CHA were shown with strong quenching effects on α-glucosidase fluorescence because of π-conjugations between aromatic ring of caffeoyl moiety and that of enzyme fluorescent residues. However, no fluorescence quenching effect was observed for TA due to lack of aromatic ring. Additionally, a direct binding interaction behavior was observed for TA with α-glucosidase according to the fitted independent binding model in ITC, but not for CFA and CHA. Therefore, both acidic pH and binding interactions of TA with α-glucosidase resulted in the enzyme inhibition.
The Therapeutic Challenge of Disseminated Bone Marrow Metastasis From HR-Positive HER2-Negative Breast Cancer: Case Report and Review of the Literature
Authors: Garufi Giovanna , Carbognin Luisa , Orlandi Armando , Palazzo Antonella , Tortora Giampaolo , Bria Emilio
Published: October 2021

The efficacy and safety of the combination of endocrine therapy (ET) and CDK4/6 inhibitors for patients with hormone receptor (HR)-positive HER2-negative metastatic breast cancer (BC) presenting with visceral crisis or life-threatening conditions represent a challenge for daily clinical practice. Indeed, the peculiarity of this clinical presentation (signs and symptoms of rapidly progressive disease) does not allow to include such patients in a trial aiming for drug approval. On the basis of the scientific evidence available so far, chemotherapy represents the standard of care according to guidelines, on the basis of the more rapid activity in comparison with ET alone. Besides, the combination of ET and CDK4/6 inhibitors have demonstrated in clinical trials to have clinically impactful activity in a short time, thus suggesting a potential role in advanced tumors that require rapid response. Herein, we report the clinical history of a young woman with HR-positive HER2-negative metastatic BC and a pancytopenia due to carcinomatosis of the bone marrow receiving letrozole and leuprorelin plus the CDK4/6 inhibitor palbociclib, who significantly derived clinical benefit from treatment. Considering that these peculiar cases are excluded from clinical trials, the estimation of the magnitude of the benefit of the newer ET combination may potentially represent a practical question for large case series and real-world studies.
Immunomodulatory Effects of Perioperative Dexmedetomidine in Ovarian Cancer: An In Vitro and Xenograft Mouse Model Study
Authors: Shin Seokyung , Kim Ki Jun , Hwang Hye Jeong , Noh Sewon , Oh Ju Eun , Yoo Young-Chul
Published: October 2021

Background

The surgical stress response (SSR) causes immunosuppression which may cause residual tumor growth and micrometastasis after cancer surgery. We investigated whether dexmedetomidine affects cancer cell behavior and immune function in an ovarian cancer xenograft mouse model.

Methods

The effect of dexmedetomidine on cell viability and cell cycle was assessed using SK-OV-3 cells at drug concentrations of 0.5, 0.1, 5, and 10 µg mL-1. BALB/c nude mice were used for the ovarian cancer model with the Dexmedetomidine group (n=6) undergoing surgery with dexmedetomidine infusion and the Control group (n=6) with saline infusion for 4 weeks. Natural killer (NK) cell activity, serum proinflammatory cytokines, and cortisol were measured at predetermined time points and tumor burden was assessed 4 weeks after surgery.

Results

Dexmedetomidine had no effect on cell viability or cell cycle. Following a sharp decrease on postoperative day (POD) 1, NK cell activity recovered faster in the Dexmedetomidine group with significant difference vs. the Control group on POD 3 (P=0.028). In the Dexmedetomidine group, cortisol levels were lower on POD 3 (P=0.004) and TNF-α levels were lower at 4 weeks after surgery (P<0.001) compared to the Control group. The Dexmedetomidine group showed lower tumor burden at 4 weeks vs. the Control group as observed by both tumor weight (P<0.001) and thein vivoimaging system (P=0.03).

Conclusions

Dexmedetomidine infusion may improve ovarian cancer surgery outcome by suppressing the SSR and stress mediator release. Further studies are needed to elucidate the mechanisms by which dexmedetomidine acts on cancer and immune cells.
Prophylaxis Against Thromboembolic Events During Chemotherapy for Germ Cell Cancer
Authors: Meng Xiaosong , Ahmed Murtaza , Courtney Kevin D. , Arafat Waddah , Ibrahim Ibrahim , Margulis Vitaly , Nichols Craig , Bagrodia Aditya
Published: October 2021

Introduction

Patients with advanced germ cell tumors (GCT) receiving cisplatin-based chemotherapy have high rates of thromboembolic events (TEE) which can negatively affect their overall survival. While primary TEE prophylaxis during chemotherapy may prevent these events, it is unclear which patients will benefit in this setting.

Materials and Methods

A review of PubMed/Medline was conducted in December 2020 and all pertinent articles were evaluated for relevancy and quality of data for inclusion in the review.

Results

Studies on patients receiving initial cisplatin-based chemotherapy for advanced GCT have reported up to a 19% rate of TEE. This high rate may be associated with multiple factors including retroperitoneal lymphadenopathy, advanced clinical stage, high risk Khorana scores and presence of a central line. Large phase III clinical trials have demonstrated the benefit of low-molecular-weight-heparin and direct oral anticoagulants for primary prophylaxis and against recurrent TEE. However, primary prophylaxis is currently underutilized with GCT patients starting chemotherapy.

Conclusion

Precise models to predict TEE risk and consideration of anticoagulation are difficult to develop owing to the relatively uncommon nature of GCT and lack of representation in primary TEE prophylaxis clinical trials. Despite these limitations, we believe that the benefits of prophylactic anticoagulation outweigh the risk of major bleeding in select GCT patients with higher risk of TEE. We have developed a simple algorithm to help guide TEE prophylaxis selection based on patient factors and route of chemotherapy administration. Given the high rate of TEE in GCT patients, we believe better utilization of primary prophylaxis in patient starting cisplatin-based chemotherapy will have clinical benefit.
Mitochondrial Effects on Seeds of Cancer Survival in Leukemia
Authors: El-Shaqanqery Hend E. , Mohamed Rania Hassan , Sayed Ahmed A.
Published: October 2021

The cancer metabolic alteration is considered a hallmark and fast becoming a road for therapeutic intervention. Mitochondria have been regarded as essential cell elements that fuel the metabolic needs of most cancer cell types. Leukemia stem cells (LSCs) are a heterogeneous, highly self-renewing, and pluripotent cell population within leukemic cells. The most important source of ATP and metabolites to fulfill the bioenergetics and biosynthetic needs of most cancer stem cells is the mitochondria. In addition, mitochondria have a core role in autophagy and cell death and are the main source of reactive oxygen species (ROS) generation. Overall, growing evidence now shows that mitochondrial activities and pathways have changed to adapt with different types of leukemia, thus mitochondrial metabolism could be targeted for blood malignancy therapy. This review focuses on the function of mitochondria in LSC of the different leukemia types.
Role of N6-Methyladenosine (m6A) Methylation Regulators in Hepatocellular Carcinoma
Authors: Qu Nanfang , Bo Xiaotong , Li Bin , Ma Lei , Wang Feng , Zheng Qinghua , Xiao Xuhua , Huang Fengmei , Shi Yuanyuan , Zhang Xuemei
Published: October 2021

Liver cancer is the fifth most common malignant tumor in terms of incidence and the third leading cause of cancer-related mortality globally. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Although great progress has been made in surgical techniques, hepatic artery chemoembolization, molecular targeting and immunotherapy, the prognosis of liver cancer patients remains very poor. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells and regulates various stages of the RNA life cycle. Many studies have reported that the abnormal expression of m6A-related regulators in HCC represent diagnostic and prognostic markers and potential therapeutic targets. In this review, firstly, we introduce the latest research on m6A-related regulators in detail. Next, we summarize the mechanism of each regulator in the pathogenesis and progression of HCC. Finally, we summarize the potential diagnostic, prognostic and therapeutic value of the regulators currently reported in HCC.
The Emerging Roles of Long Noncoding RNAs as Hallmarks of Lung Cancer
Authors: Jiang Jun , Lu Yuan , Zhang Fang , Huang Jie , Ren Xin-ling , Zhang Rui
Published: October 2021

Noncoding ribonucleic acids (ncRNAs) are closely associated with tumor initiation, growth, and progress in lung cancer. Long ncRNAs (lncRNAs), as one of the three subclasses of ncRNAs, play important roles in chromatin modification, transcription, and post-transcriptional processing. Various lncRNAs have recently been reported to be dysfunctional or dysregulated in cancers and have pro- or anti-tumor potential. Importantly, as a new class of cancer biomarkers, studies have demonstrated the plausibility of using certain subsets of lncRNAs as promising diagnostic, therapeutic, or prognostic strategies to manage cancers. This review focuses on lncRNAs associated with hallmarks of lung cancer, especially those discovered in the last five years. The expression levels of these lncRNAs in tumor samples are discussed, alongside their mechanisms of action, drug resistance, and potential as diagnostic and prognostic markers for lung cancer.
Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?
Authors: Henson Sian M. , Aksentijevic Dunja
Published: October 2021

Inflammation is well understood to be a physiological process of ageing however it also underlies many chronic diseases, including conditions without an obvious pathogenic inflammatory element. Recent findings have unequivocally identified type 2 diabetes (T2D) as a chronic inflammatory disease characterized by inflammation and immune senescence. Immunosenescence is a hallmark of the prolonged low-grade systemic inflammation, in particular associated with metabolic syndrome and can be a cause as well as a consequence of T2D. Diabetes is a risk factor for cardiovascular mortality and remodelling and with particular changes to myocardial structure, function, metabolism and energetics collectively resulting in diabetic cardiomyopathy. Both cardiomyocytes and immune cells undergo metabolic remodelling in T2D and as a result become trapped in a vicious cycle of lost metabolic flexibility, thus losing their key adaptive mechanisms to dynamic changes in O2 and nutrient availability. Immunosenescence driven by metabolic stress may be both the cause and key contributing factor to cardiac dysfunction in diabetic cardiomyopathy by inducing metabolic perturbations that can lead to impaired energetics, a strong predictor of cardiac mortality. Here we review our current understanding of the cross-talk between inflammaging and cardiomyocytes in T2D cardiomyopathy. We discuss potential mechanisms of metabolic convergence between cell types which, we hypothesize, might tip the balance between resolution of the inflammation versus adverse cardiac metabolic remodelling in T2D cardiomyopathy. A better understanding of the multiple biological paradigms leading to T2D cardiomyopathy including the immunosenescence associated with inflammaging will provide a powerful target for successful therapeutic interventions.
Effects of Cytochrome P450 and Transporter Polymorphisms on the Bioavailability and Safety of Dutasteride and Tamsulosin
Authors: Villapalos-García Gonzalo , Zubiaur Pablo , Navares-Gómez Marcos , Saiz-Rodríguez Miriam , Mejía-Abril Gina , Martín-Vílchez Samuel , Román Manuel , Ochoa Dolores , Abad-Santos Francisco
Published: October 2021

Dutasteride and tamsulosin are one of the first-line combination therapies for the management of benign prostatic hyperplasia (BPH). Despite being more effective than monotherapies, they produce frequent adverse drug reactions (ADRs). Institutions such as Food and Drug Administration and European Medicines Agency recommend precaution with CYP2D6 poor metabolizers (PMs) that receive CYP3A4 inhibitors and tamsulosin. However, no specific pharmacogenetic guideline exists for tamsulosin. Furthermore, to date, no pharmacogenetic information is available for dutasteride. Henceforth, we studied the pharmacokinetics and safety of dutasteride/tamsulosin 0.5 mg/0.4 mg capsules according to 76 polymorphisms in 17 candidate pharmacogenes. The study population comprised 79 healthy male volunteers enrolled in three bioequivalence, phase-I, crossover, open, randomized clinical trials with different study designs: the first was single dose in fed state, the second was a single dose in fasting state, and the third was a multiple dose. As key findings, CYP2D6 PMs (i.e., *4/*4 and *4/*5 subjects) and intermediate metabolizers (IMs) (i.e., *1/*4, *1/*5, *4/*15 individuals) presented higher AUC (p = 0.004), higher t1/2 (p = 0.008), and lower Cl/F (p = 0.006) when compared with NMs (*1/*1 individuals) and UMs (1/*1 × 2 individuals) after multiple testing correction. Moreover, fed volunteers showed significantly higher tmax than fasting individuals. Nominally significant associations were observed between dutasteride exposure and CYP3A4 and CYP3A5 genotype and between tamsulosin and ABCG2, CYP3A5, and SLC22A1 genotypes. No association between the occurrence of adverse drug reactions and genotype was observed. Nonetheless, higher incidence of adverse events was found in a multiple-dose clinical trial. Based on our results, we suggest that dose adjustments for PMs and UMs could be considered to ensure drug safety and effectiveness, respectively. Further studies are warranted to confirm other pharmacogenetic associations.
Suppression of PTRF Alleviates Post-Infectious Irritable Bowel Syndrome via Downregulation of the TLR4 Pathway in Rats
Authors: Zhou Hui-hui , Zhang Ye-ming , Zhang Sheng-peng , Xu Qi-xiang , Tian Ya-qing , Li Ping , Cao Di , Zheng Yong-qiu
Published: October 2021

Background: Accumulating evidence suggests that the polymerase I and transcript release factor (PTRF), a key component of the caveolae structure on the plasma membrane, plays a pivotal role in suppressing the progression of colorectal cancers. However, the role of PTRF in the development of functional gastrointestinal (GI) disorders remains unclear. Post-infectious irritable bowel syndrome (PI-IBS) is a common functional GI disorder that occurs after an acute GI infection. Here, we focused on the role of PTRF in the occurrence of PI-IBS and investigated the underlying mechanisms.

Methods: Lipopolysaccharide (LPS) (5 μg/ml) was used to induce inflammatory injury in human primary colonic epithelial cells (HCoEpiCs). Furthermore, a rat model of PI-IBS was used to study the role of PTRF. Intestinal sensitivity was assessed based on the fecal water content. A two-bottle sucrose intake test was used to evaluate behavioral changes. Furthermore, shRNA-mediated knockdown of PTRF was performed both in vitro and in vivo. We detected the expression of PTRF in colonic mucosal tissues through immunohistochemistry (IHC), western blotting (WB), and immunofluorescence (IF) analysis. Luciferase activity was quantified using a luciferase assay. Co-localization of PTRF and Toll-like receptor 4 (TLR4) was detected using IF analysis. The activation of the signaling pathways downstream of TLR4, including the iNOs, p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) pathways, was detected via WB. The levels of NO, IL-1β, IL-6, and TNF-α were measured using enzyme-linked immunosorbent assays.

Results: LPS significantly induced PTRF expression and signaling downstream of TLR4, including p38, ERK, and JNK pathways, in HCoEpiCs. Moreover, shRNA-mediated knockdown of PTRF in HCoEpiCs significantly decreased the phosphorylation of JNK, ERK, and p38 and iNOS expression. In PI-IBS rats, the lack of PTRF not only reduced fecal water content and suppressed depressive behavior but also increased the body weight. Furthermore, we found a strong co-localization pattern for PTRF and TLR4. Consistently, the lack of PTRF impaired TLR4 signaling, as shown by the decreased levels of p-JNK, p-ERK, and p-p38, which are upstream factors involved in iNOS expression.

Conclusion: PTRF promoted PI-IBS and stimulated TLR4 signaling both in vitro and in vivo. The results of this study not only enlighten the pathogenesis of PI-IBS but also help us understand the biological activity of PTRF and provide an important basis for the clinical treatment of PI-IBS by targeting PTRF.
Evaluation of Host Defense Peptide (CaD23)-Antibiotic Interaction and Mechanism of Action: Insights From Experimental and Molecular Dynamics Simulations Studies
Authors: Ting Darren Shu Jeng , Li Jianguo , Verma Chandra S. , Goh Eunice T. L. , Nubile Mario , Mastropasqua Leonardo , Said Dalia G. , Beuerman Roger W. , Lakshminarayanan Rajamani , Mohammed Imran , Dua Harminder S.
Published: October 2021

Background/Aim: Host defense peptides (HDPs) have the potential to provide a novel solution to antimicrobial resistance (AMR) in view of their unique and broad-spectrum antimicrobial activities. We had recently developed a novel hybrid HDP based on LL-37 and human beta-defensin-2, named CaD23, which was shown to exhibit good in vivo antimicrobial efficacy against Staphylococcus aureus in a bacterial keratitis murine model. This study aimed to examine the potential CaD23-antibiotic synergism and the secondary structure and underlying mechanism of action of CaD23.

Methods: Peptide-antibiotic interaction was evaluated against S. aureus, methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa using established checkerboard and time-kill assays. Fractional inhibitory concentration index (FICI) was calculated and interpreted as synergistic (FIC<0.5), additive (FIC between 0.5–1.0), indifferent (FIC between >1.0 and ≤4), or antagonistic (FIC>4). SYTOX green uptake assay was performed to determine the membrane-permeabilising action of CaD23. Molecular dynamics (MD) simulations were performed to evaluate the interaction of CaD23 with bacterial and mammalian mimetic membranes. Circular dichroism (CD) spectroscopy was also performed to examine the secondary structures of CaD23.

Results: CaD23-amikacin and CaD23-levofloxacin combination treatment exhibited a strong additive effect against S. aureus SH1000 (FICI = 0.60–0.69) and MRSA43300 (FICI = 0.56–0.60) but an indifferent effect against P. aeruginosa (FIC = 1.03–1.15). CaD23 (at 25 μg/ml; 2xMIC) completely killed S. aureus within 30 min. When used at sub-MIC concentration (3.1 μg/ml; 0.25xMIC), it was able to expedite the antimicrobial action of amikacin against S. aureus by 50%. The rapid antimicrobial action of CaD23 was attributed to the underlying membrane-permeabilising mechanism of action, evidenced by the SYTOX green uptake assay and MD simulations studies. MD simulations revealed that cationicity, alpha-helicity, amphiphilicity and hydrophobicity (related to the Trp residue at C-terminal) play important roles in the antimicrobial action of CaD23. The secondary structures of CaD23 observed in MD simulations were validated by CD spectroscopy.

Conclusion: CaD23 is a novel alpha-helical, membrane-active synthetic HDP that can enhance and expedite the antimicrobial action of antibiotics against Gram-positive bacteria when used in combination. MD simulations serves as a powerful tool in revealing the peptide secondary structure, dissecting the mechanism of action, and guiding the design and optimisation of HDPs.
The Lipocalin Apolipoprotein D Functional Portrait: A Systematic Review
Authors: Sanchez Diego , Ganfornina Maria D.
Published: October 2021

Apolipoprotein D is a chordate gene early originated in the Lipocalin protein family. Among other features, regulation of its expression in a wide variety of disease conditions in humans, as apparently unrelated as neurodegeneration or breast cancer, have called for attention on this gene. Also, its presence in different tissues, from blood to brain, and different subcellular locations, from HDL lipoparticles to the interior of lysosomes or the surface of extracellular vesicles, poses an interesting challenge in deciphering its physiological function: Is ApoD a moonlighting protein, serving different roles in different cellular compartments, tissues, or organisms? Or does it have a unique biochemical mechanism of action that accounts for such apparently diverse roles in different physiological situations? To answer these questions, we have performed a systematic review of all primary publications where ApoD properties have been investigated in chordates. We conclude that ApoD ligand binding in the Lipocalin pocket, combined with an antioxidant activity performed at the rim of the pocket are properties sufficient to explain ApoD association with different lipid-based structures, where its physiological function is better described as lipid-management than by long-range lipid-transport. Controlling the redox state of these lipid structures in particular subcellular locations or extracellular structures, ApoD is able to modulate an enormous array of apparently diverse processes in the organism, both in health and disease. The new picture emerging from these data should help to put the physiological role of ApoD in new contexts and to inspire well-focused future research.
Molecular Fingerprinting and Hybridity Authentication in Cowpea Using Single Nucleotide Polymorphism Based Kompetitive Allele-Specific PCR Assay
Authors: Ongom Patrick Obia , Fatokun Christian , Togola Abou , Salvo Stella , Oyebode Oluwaseye Gideon , Ahmad Mansur Sani , Jockson Ishaya Daniel , Bala Garba , Boukar Ousmane
Published: October 2021

Optimization of a breeding program for increased genetic gain requires quality assurance (QA) and quality control (QC) at key phases of the breeding process. One vital phase in a breeding program that requires QC and QA is the choice of parents and successful hybridizations to combine parental attributes and create variations. The objective of this study was to determine parental diversity and confirm hybridity of cowpea F1 progenies using KASP (Kompetitive Allele-Specific PCR)-based single nucleotide polymorphism (SNP) markers. A total of 1,436 F1 plants were derived from crossing 220 cowpea breeding lines and landraces to 2 elite sister lines IT99K-573-1-1 and IT99K-573-2-1 as male parents, constituting 225 cross combinations. The progenies and the parents were genotyped with 17 QC SNP markers via high-throughput KASP genotyping assay. The QC markers differentiated the parents with mean efficiency of 37.90% and a range of 3.4–82.8%, revealing unique fingerprints of the parents. Neighbor-Joining cladogram divided the 222 parents into 3 clusters. Genetic distances between parents ranged from 0 to 3.74 with a mean of 2.41. Principal component analysis (PCA) depicted a considerable overlap between parents and F1 progenies with more scatters among parents than the F1s. The differentiation among parents and F1s was best contributed to by 82% of the markers. As expected, parents and F1s showed a significant contrast in proportion of heterozygous individuals, with mean values of 0.02 and 0.32, respectively. KASP markers detected true hybridity with 100% success rate in 72% of the populations. Overall, 79% of the putative F1 plants were true hybrids, 14% were selfed plants, and 7% were undetermined due to missing data and lack of marker polymorphism between parents. The study demonstrated an effective application of KASP-based SNP assay in fingerprinting, confirmation of hybridity, and early detection of false F1 plants. The results further uncovered the need to deploy markers as a QC step in a breeding program.
A Valsa mali Effector Protein 1 Targets Apple (Malus domestica) Pathogenesis-Related 10 Protein to Promote Virulence
Authors: Wang Weidong , Nie Jiajun , Lv Luqiong , Gong Wan , Wang Shuaile , Yang Mingming , Xu Liangsheng , Li Mingjun , Du Hongxia , Huang Lili
Published: October 2021

To successfully colonize the plants, the pathogenic microbes secrete a mass of effector proteins which manipulate host immunity. Apple valsa canker is a destructive disease caused by the weakly parasitic fungus Valsa mali. A previous study indicated that the V. mali effector protein 1 (VmEP1) is an essential virulence factor. However, the pathogenic mechanism of VmEP1 in V. mali remains poorly understood. In this study, we found that the apple (Malus domestica) pathogenesis-related 10 proteins (MdPR10) are the virulence target of VmEP1 using a yeast two-hybrid screening. By bimolecular fluorescence (BiFC) and coimmunoprecipitation (Co-IP), we confirmed that the VmEP1 interacts with MdPR10 in vivo. Silencing of MdPR10 notably enhanced the V. mali infection, and overexpression of MdPR10 markedly reduced its infection, which corroborates its positive role in plant immunity against V. mali. Furthermore, we showed that the co-expression of VmEP1 with MdPR10 compromised the MdPR10-mediated resistance to V. mali. Taken together, our results revealed a mechanism by which a V. mali effector protein suppresses the host immune responses by interfering with the MdPR10-mediated resistance to V. mali during the infection.
Emotional Processing and Its Association to Somatic Symptom Change in Emotional Awareness and Expression Therapy for Somatic Symptom Disorder: A Preliminary Mediation Investigation
Authors: Maroti Daniel , Ljótsson Brjánn , Lumley Mark A. , Schubiner Howard , Hallberg Henrik , Olsson Per-Åke , Johansson Robert
Published: October 2021

Objective: The aim of this study was to investigate emotional processing as a potential mediator in therapist-guided, internet-based Emotional Awareness and Expression Therapy (I-EAET) for somatic symptom disorder, using data from a previously published pilot study.

Methods: Participants (N = 52) engaged in a 9-week I-EAET treatment. Before treatment and each week during treatment (i.e., 10 weekly measurements), emotional processing was assessed with the Emotional Processing Scale-25 (EPS-25), which contains five subscales, and somatic symptoms were assessed with the Patient Health Questionnaire-15 (PHQ-15).

Results: Mediation analyses using linear mixed models showed that two EPS-25 subscales—Signs of Unprocessed Emotions and Impoverished Emotional Experience—were uniquely associated with somatic symptom reduction. The proportion of the mediated effect was 0.49, indicating that about half of the total association of the PHQ-15 with symptoms was accounted for by the two EPS-25 subscales.

Conclusion: This preliminary mediation analysis suggests that improved emotional processing is associated with change in somatic symptoms in I-EAET. However, randomized controlled and comparison trials are needed to establish that I-EAET creates the change in emotional processing and that such changes are specific to I-EAET.