Τρίτη, 25 Ιουνίου 2019

Cellular and Molecular Life Sciences

Helicobacter pylori infection and gastrointestinal tract cancer biology: considering a double-edged sword reflection


Adult stem cells at work: regenerating skeletal muscle

Abstract

Skeletal muscle regeneration is a finely tuned process involving the activation of various cellular and molecular processes. Satellite cells, the stem cells of skeletal muscle, are indispensable for skeletal muscle regeneration. Their functionality is critically modulated by intrinsic signaling pathways as well as by interactions with the stem cell niche. Here, we discuss the properties of satellite cells, including heterogeneity regarding gene expression and/or their phenotypic traits and the contribution of satellite cells to skeletal muscle regeneration. We also summarize the process of regeneration with a specific emphasis on signaling pathways, cytoskeletal rearrangements, the importance of miRNAs, and the contribution of non-satellite cells such as immune cells, fibro-adipogenic progenitor cells, and PW1-positive/Pax7-negative interstitial cells.



Progress on chicken T cell immunity to viruses

Abstract

Avian virus infection remains one of the most important threats to the poultry industry. Pathogens such as avian influenza virus (AIV), avian infectious bronchitis virus (IBV), and infectious bursal disease virus (IBDV) are normally controlled by antibodies specific for surface proteins and cellular immune responses. However, standard vaccines aimed at inducing neutralizing antibodies must be administered annually and can be rendered ineffective because immune-selective pressure results in the continuous mutation of viral surface proteins of different strains circulating from year to year. Chicken T cells have been shown to play a crucial role in fighting virus infection, offering lasting and cross-strain protection, and offer the potential for developing universal vaccines. This review provides an overview of our current knowledge of chicken T cell immunity to viruses. More importantly, we point out the limitations and barriers of current research and a potential direction for future studies.



Characterization of functional subgroups among genetically identified cholinergic neurons in the pedunculopontine nucleus

Abstract

The pedunculopontine nucleus (PPN) is a part of the reticular activating system which is composed of cholinergic, glutamatergic and GABAergic neurons. Early electrophysiological studies characterized and grouped PPN neurons based on certain functional properties (i.e., the presence or absence of the A-current, spike latency, and low threshold spikes). Although other electrophysiological characteristics of these neurons were also described (as high threshold membrane potential oscillations, great differences in spontaneous firing rate and the presence or absence of the M-current), systematic assessment of these properties and correlation of them with morphological markers are still missing. In this work, we conducted electrophysiological experiments on brain slices of genetically identified cholinergic neurons in the PPN. Electrophysiological properties were compared with rostrocaudal location of the neuronal soma and selected morphometric features obtained with post hoc reconstruction. We found that functional subgroups had different proportions in the rostral and caudal subregions of the nucleus. Neurons with A-current can be divided to early-firing and late-firing neurons, where the latter type was found exclusively in the caudal subregion. Similar to this, different parameters of high threshold membrane potential oscillations also showed characteristic rostrocaudal distribution. Furthermore, based on our data, we propose that high threshold oscillations rather emerge from neuronal somata and not from the proximal dendrites. In summary, we demonstrated the existence and spatial distribution of functional subgroups of genetically identified PPN cholinergic neurons, which are in accordance with differences found in projection and in vivo functional findings of the subregions. Being aware of functional differences of PPN subregions will help the design and analysis of experiments using genetically encoded opto- and chemogenetic markers for in vivo experiments.



Helicobacter pylori infection and gastric cancer biology: tempering a double-edged sword

Abstract

Helicobacter pylori (H. pylori) infection affects an estimated 4.4 billion people globally. Moreover, H. pylori presents the most significant risk factor for gastric cancer and low-grade mucosa-associated lymphoid tissue (MALT) lymphoma, and it is the first example of bacterial infection linked to carcinogenesis. Here, we contend that H. pylori research, which focuses on a cancer-causing pathogen resident in a relatively accessible organ, the stomach, could constitute an exemplar for microbial-related carcinogenesis in less tractable organs, such as the pancreas and lung. In this context, molecular biological approaches that could reap rewards are reviewed, including: (1) gastric cancer dynamics, particularly the role of stem cells and the heterogeneity of neoplastic cells, which are currently being investigated at the single-cell sequencing level; (2) mechanobiology, and the role of three-dimensional organoids and matrix metalloproteases; and (3) the connection between H. pylori and host pathophysiology and the gut microbiome. In the context of H. pylori's contribution to gastric cancer, several important conundrums remain to be fully elucidated. From among them, this article discusses (1) why H. pylori infection, which causes both gastric and duodenal inflammation, is only linked to gastric cancer; (2) whether a "precision oncomicrobiology" approach could enable a fine-tuning of the expression of only cancer-implicated H. pylori genes while maintaining beneficial H. pylori-mediated factors in extra-gastric tissues; and (3) the feasibility of using antibiotics targeting the microbial DNA damage system, which shares commonalities with mechanisms for human cell replication, as chemopreventives. Additional therapeutic perspectives are also discussed.



A role for polycystin-1 and polycystin-2 in neural progenitor cell differentiation

Abstract

Polycystin-1 (PC1) and polycystin-2 (PC2) are transmembrane proteins encoded by the Pkd1 and Pkd2 genes, respectively. Mutations in these genes are causative for the development of autosomal-dominant polycystic kidney disease. A prominent feature of this disease is an unbalanced cell proliferation. PC1 and PC2 physically interact to form a complex, which localizes to the primary cilia of renal epithelial cells. Recently, PC1 and PC2 have also been described to be present in primary cilia of radial glial cells (RGCs) and to contribute to the planar cell polarity of late RGCs and E1 ependymal cells. As neural progenitor cells (NPCs), early RGCs have to balance proliferation for expansion, or for self-renewal and differentiation to generate neurons. It is not known whether the polycystins play a role in this process. Here, we show that PC1 and PC2 are expressed in RGCs of the developing mouse cerebral cortex during neurogenesis. Loss-of-function analysis and cell-based assays reveal that a reduction of PC1 or PC2 expression leads to increased NPC proliferation, while the differentiation to neurons becomes impaired. The increased NPC proliferation is preceded by enhanced Notch signaling and accompanied by a rise in the number of symmetric cell divisions. The transcription factor STAT3 seems to be mechanistically important for polycystin signaling in NPCs as either STAT3 knockdown or inhibition of STAT3 function abrogates the increased proliferation driven by reduced polycystin expression. Our findings indicate that PC1 and PC2 are critical for maintaining a balance between proliferation and differentiation of NPCs.



Advances in targeted degradation of endogenous proteins

Abstract

Protein silencing is often employed as a means to aid investigations in protein function and is increasingly desired as a therapeutic approach. Several types of protein silencing methodologies have been developed, including targeting the encoding genes, transcripts, the process of translation or the protein directly. Despite these advances, most silencing systems suffer from limitations. Silencing protein expression through genetic ablation, for example by CRISPR/Cas9 genome editing, is irreversible, time consuming and not always feasible. Similarly, RNA interference approaches warrant prolonged treatments, can lead to incomplete protein depletion and are often associated with off-target effects. Targeted proteolysis has the potential to overcome some of these limitations. The field of targeted proteolysis has witnessed the emergence of many methodologies aimed at targeting specific proteins for degradation in a spatio-temporal manner. In this review, we provide an appraisal of the different targeted proteolytic systems and discuss their applications in understanding protein function, as well as their potential in therapeutics.



The role of ASXL1 in hematopoiesis and myeloid malignancies

Abstract

Recent high-throughput genome-wide sequencing studies have identified recurrent somatic mutations in myeloid neoplasms. An epigenetic regulator, Additional sex combs-like 1 (ASXL1), is one of the most frequently mutated genes in all subtypes of myeloid malignancies. ASXL1 mutations are also frequently detected in clonal hematopoiesis, which is associated with an increased risk of mortality. Therefore, it is important to understand how ASXL1 mutations contribute to clonal expansion and myeloid transformation in hematopoietic cells. Studies using ASXL1-depleted human hematopoietic cells and Asxl1 knockout mice have shown that deletion of wild-type ASXL1 protein leads to impaired hematopoiesis and accelerates myeloid malignancies via loss of interaction with polycomb repressive complex 2 proteins. On the other hand, ASXL1 mutations in myeloid neoplasms typically occur near the last exon and result in the expression of C-terminally truncated mutant ASXL1 protein. Biological studies and biochemical analyses of this variant have shed light on its dominant-negative and gain-of-function features in myeloid transformation via a variety of epigenetic changes. Based on these results, it would be possible to establish novel promising therapeutic strategies for myeloid malignancies harboring ASXL1mutations by blocking interactions between ASXL1 and associating epigenetic regulators. Here, we summarize the clinical implications of ASXL1 mutations, the role of wild-type ASXL1 in normal hematopoiesis, and oncogenic functions of mutant ASXL1 in myeloid neoplasms.



E2F1 mediates the downregulation of POLD1 in replicative senescence

Abstract

POLD1, the catalytic subunit of DNA Pol δ, plays an important role in DNA synthesis and DNA damage repair, and POLD1 is downregulated in replicative senescence and mediates cell aging. However, the mechanisms of age-related downregulation of POLD1 expression have not been elucidated. In this study, four potential CpG islands in the POLD1 promoter were found, and the methylation levels of the POLD1 promoter were increased in aging 2BS cells, WI-38 cells and peripheral blood lymphocytes, especially at a single site, CpG 36, in CpG island 3. Then, the transcription factor E2F1 was observed to bind to these sites. The binding affinity of E2F1 for the POLD1 promoter was found to show age-related attenuation and was confirmed to be positively regulated by the E2F1 level and negatively regulated by POLD1 promoter methylation. Moreover, cell senescence characteristics were observed in the cells transfected with shRNA-E2F1 and could contribute to the downregulation of POLD1 induced by the E2F1 decline. Collectively, these results indicated that the attenuation of the binding affinity of E2F1 for the POLD1 promoter, mediated by an age-related decline in E2F1 and increased methylation of CpG island 3, downregulates POLD1 expression in aging.



Multiple roles of CTDK-I throughout the cell

Abstract

The heterotrimeric carboxy-terminal domain kinase I (CTDK-I) in yeast is a cyclin-dependent kinase complex that is evolutionally conserved throughout eukaryotes and phosphorylates the C-terminal domain of the largest subunit of RNA polymerase II (RNApII) on the second-position serine (Ser2) residue of YSPTSPS heptapeptide repeats. CTDK-I plays indispensable roles in transcription elongation and transcription-coupled processing, such as the 3′-end processing of nascent mRNA transcripts. However, recent studies have revealed additional roles of CTDK-I beyond its primary effect on transcription by RNApII. Here, we describe recent advances in the regulation of genomic stability and rDNA integrity by CTDK-I and highlight the previously underappreciated cellular roles of CTDK-I in rRNA synthesis by RNA polymerase I and translational initiation and elongation. These multiple roles of CTDK-I throughout the cell expand our understanding of how this complex functions to coordinate diverse cellular processes through gene expression and how the human orthologue exerts its roles in diseased states such as tumorigenesis.



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
High-Resolution Measurements of Leakage Flow Inside the Hinge of a Large-scale Bileaflet Mechanical Heart Valve Hinge Model
Abstract Purpose It is believed that non-physiological leakage flow through hinge gaps during diastole contributes to thrombus formation in Bileaflet Mechanical Heart Valves (BMHVs). Because of the small scale and difficulty of experimental access, fluid dynamics inside the hinge cavity has not yet been characterised in detail. The objective is to investigate small-scale structure inside the hinge experimentally, and gain insight into...
Latest Results for Cardiovascular Engineering and Technology
15m
Automatic Segmentation, Detection, and Diagnosis of Abdominal Aortic Aneurysm (AAA) Using Convolutional Neural Networks and Hough Circles Algorithm
Abstract Purpose An abdominal aortic aneurysm (AAA) is known as a cardiovascular disease involving localized deformation (swelling or enlargement) of aorta occurring between the renal and iliac arteries. AAA would jeopardize patients' lives due to its rupturing risk, so prompt recognition and diagnosis of this disorder is vital. Although computed tomography angiography (CTA) is the preferred imaging modality used by radiologist for diagnosing...
Latest Results for Cardiovascular Engineering and Technology
15m
Optimization of a Transcatheter Heart Valve Frame Using Patient-Specific Computer Simulation
Abstract Purpose This study proposes a new framework to optimize the design of a transcatheter aortic valve through patient-specific finite element and fluid dynamics simulation. Methods Two geometrical parameters of the frame, the diameter at ventricular inflow and the height of the first row of cells, were examined using the central composite design. The...
Latest Results for Cardiovascular Engineering and Technology
15m
Preload Sensitivity with TORVAD Counterpulse Support Prevents Suction and Overpumping
Abstract Purpose This study compares preload sensitivity of continuous flow (CF) VAD support to counterpulsation using the Windmill toroidal VAD (TORVAD). The TORVAD is a two-piston rotary pump that ejects 30 mL in early diastole, which increases cardiac output while preserving aortic valve flow. Methods Preload sensitivity was compared for CF vs. TORVAD...
Latest Results for Cardiovascular Engineering and Technology
15m
Asymmetric Dynamics of the Native Aortic Annulus Evaluated by Force Transducer and Sonomicrometry in a Porcine Model
Abstract Purpose With new repair techniques of the aortic root and valve emerging, a detailed understanding of the dynamics of the aortic annulus and valve is required for optimal results. The objective of this study was to characterize geometrical changes and force distribution of the native porcine aortic annulus throughout the cardiac cycle. Methods Measurements...
Latest Results for Cardiovascular Engineering and Technology
15m
The Length Versus Diameter Relationship and Radial Force Properties of the Amplatzer™ Vascular Plug Type IV: Observations for Oversizing
Abstract Background In palliated single ventricle patients aortopulmonary collateralization is a cause for significant loss of cardiovascular efficiency. In larger vessels, device occlusion becomes an alternative to embolization with multiple coils. The physical characteristics of the Amplatzer ™ Vascular Plug Type IV (AVPIV) are potentially conducive to oversizing the device allowing coverage of a longer portion of vessel. Despite...
Latest Results for Cardiovascular Engineering and Technology
15m
A Tunable Resonance Cantilever for Cardiac Energy Harvesting
Abstract Purpose Energy harvesting from cardiac motion is an attractive means to avoid the use of batteries in implantable sensors and pacemakers. A single implantable device would ideally integrate both sensing and self-powering functionality. Methods This work describes a novel electromagnetic system that achieves high sensitivity detection...
Latest Results for Cardiovascular Engineering and Technology
15m
MRI and Blood Flow in Human Arteries: Are There Any Adverse Effects?
Abstract Purpose To explore if there are any adverse effects on blood flow in human beings when they are exposed to high or ultra high intensity magnetic fields in MRI, by investigating both qualitatively and quantitatively the effects of such fields on the velocity of blood and medically significant hemodynamic wall parameters such as wall shear stress (WSS), oscillatory shear index (OSI) and relative residence time (RRT) in four...
Latest Results for Cardiovascular Engineering and Technology
15m

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174,00302841026182,alsfakia@gmail.com
At the Junction of Immunity and Barrier Function: The Immunomodulatory Protein TL1A May Also Regulate Intestinal Permeability
Latest Results for Digestive Diseases and Sciences
15m
Third Time's a Charm: Immunization Strategies for Hepatitis B in Immunosuppressed Patients with Inflammatory Bowel Disease
Latest Results for Digestive Diseases and Sciences
15m
Exocrine Pancreatic Insufficiency Following Acute Pancreatitis: True Association or EPIphenomenon?
Latest Results for Digestive Diseases and Sciences
15m
Breaking Down Barriers: How Understanding Celiac Disease Pathogenesis Informed the Development of Novel Treatments
Abstract For decades, the pathogenesis of a variety of human diseases has been attributed to increased intestinal paracellular permeability even though scientific evidence supporting this hypothesis has been tenuous. Nevertheless, during the past decade, there have been a growing number of publications focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect...
Latest Results for Digestive Diseases and Sciences
15m
Efficacy of Infliximab in Crohn's Disease Patients with Prior Primary-Nonresponse to Tumor Necrosis Factor Antagonists
Abstract Background Tumor necrosis factor antagonists (TNFs) are effective for moderate–severe Crohn's disease (CD). Approximately one-third of patients have primary-nonresponse to TNFs, which is reported to predict worse response to subsequent TNF therapy. However, this is based on treatment with subcutaneously (SC) administered, fixed-dose TNFs after failure of intravenously (IV) administered, weight-based TNFs. No study has specifically...
Latest Results for Digestive Diseases and Sciences
15m
CT in Crohn's Disease Is Beneficial for Patient Care and Should Not Be Feared
Latest Results for Digestive Diseases and Sciences
15m
Exocrine Pancreatic Insufficiency Following Acute Pancreatitis: Systematic Review and Meta-Analysis
Abstract Background/Objectives The epidemiology of exocrine pancreatic insufficiency (EPI) after acute pancreatitis (AP) is uncertain. We sought to determine the prevalence, progression, etiology and pancreatic enzyme replacement therapy (PERT) requirements for EPI during follow-up of AP by systematic review and meta-analysis. Methods Scopus,...
Latest Results for Digestive Diseases and Sciences
15m
Letter to the Editor: "Gastric Per Oral Endoscopic Myotomy (G-POEM) for the Treatment of Refractory Gastroparesis: Early Experience"
Latest Results for Digestive Diseases and Sciences


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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174,00302841026182,alsfakia@gmail.com
Cytologically Borderline Thyroid Nodules as a Key Target to Reduce Overdiagnosis and Overtreatment of Thyroid Cancer.
Related ArticlesCytologically Borderline Thyroid Nodules as a Key Target to Reduce Overdiagnosis and Overtreatment of Thyroid Cancer. Arch Pathol Lab Med. 2019 Jul;143(7):784-785 Authors: Kakudo K, Bychkov A PMID: 31225997 [PubMed - in process]
Archives of pathology and laboratory medicine
15m
In Reply.
Related ArticlesIn Reply. Arch Pathol Lab Med. 2019 Jul;143(7):783-784 Authors: Schnadig VJ PMID: 31225996 [PubMed - in process]
Archives of pathology and laboratory medicine
15m
Cancer Overdiagnosis: Pathologists in the Dock.
Related ArticlesCancer Overdiagnosis: Pathologists in the Dock. Arch Pathol Lab Med. 2019 Jul;143(7):781 Authors: Shah V, Scott-Coombes D, Varma M PMID: 31225994 [PubMed - in process]
Archives of pathology and laboratory medicine
15m
In Response to "Overdiagnosis of Thyroid Cancer: Is This Not an Ethical Issue for Pathologists As Well As Radiologists and Clinicians?"
Related ArticlesIn Response to "Overdiagnosis of Thyroid Cancer: Is This Not an Ethical Issue for Pathologists As Well As Radiologists and Clinicians?" Arch Pathol Lab Med. 2019 Jul;143(7):782-783 Authors: Renshaw AA, Gould EW PMID: 31225993 [PubMed - in process]
Archives of pathology and laboratory medicine
15m
In Response to "Cost Effectiveness of Intraoperative Gross Examination in Colorectal Resections".
Related ArticlesIn Response to "Cost Effectiveness of Intraoperative Gross Examination in Colorectal Resections". Arch Pathol Lab Med. 2019 Jul;143(7):785 Authors: Frankel KA PMID: 31225991 [PubMed - in process]
Archives of pathology and laboratory medicine
15m
Pearls and Updates in Dermatopathology for the General Surgical Pathologist: Experts Weigh In on What You Need to Know.
Related ArticlesPearls and Updates in Dermatopathology for the General Surgical Pathologist: Experts Weigh In on What You Need to Know. Arch Pathol Lab Med. 2019 Jul;143(7):786-788 Authors: Shalin SC, Gardner JM, Kaley JR PMID: 31225990 [PubMed - in process]
Archives of pathology and laboratory medicine
15m

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174,00302841026182,alsfakia@gmail.com

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