Molecular and cellular mechanisms that regulate human erythropoiesis

Blood ◽  
2021 ◽  
Author(s):  
Alexis Leon Caulier ◽  
Vijay G. Sankaran
Keyword(s):  
Cytokine Signaling ◽  
Human Genetic Variation ◽  
Important Process ◽  
Cellular Mechanisms ◽  
Genetic Studies ◽  
Hemoglobin Switching ◽  
Signaling Mechanisms ◽  
Multiple Levels ◽  
Post Transcriptional Regulation ◽  
The Impact

To enable effective oxygen transport, approximately 200 billion red blood cells (RBCs) need to be produced every day in the bone marrow through the fine-tuned process of erythropoiesis. Erythropoiesis is regulated at multiple levels to ensure that defective RBC maturation or overproduction can be avoided. Here, we provide an overview of different layers of this control, ranging from cytokine signaling mechanisms that enable extrinsic regulation of RBC production to intrinsic transcriptional pathways necessary for effective erythropoiesis. Recent studies have also elucidated the importance of post-transcriptional regulation and highlighted additional gatekeeping mechanisms necessary for effective erythropoiesis. We additionally discuss the insights gained by studying human genetic variation impacting erythropoiesis and highlight the discovery of BCL11A as a regulator of hemoglobin switching through genetic studies. Finally, we provide an outlook of how our ability to measure multiple facets of this process at single-cell resolution, while accounting for the impact of human variation, will continue to refine our knowledge of erythropoiesis and how this process is perturbed in disease. As we learn more about this intricate and important process, additional opportunities to modulate erythropoiesis for therapeutic purposes will undoubtedly emerge.

scholarly journals Genetic variations influence brain changes in patients with attention-deficit hyperactivity disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Santosh K. Yadav ◽  
Ajaz A. Bhat ◽  
Sheema Hashem ◽  
Sabah Nisar ◽  
Madeeha Kamal ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Brain Imaging ◽  
Attention Deficit ◽  
Genetic Variations ◽  
Imaging Genetics ◽  
Treatment Modalities ◽  
Genetic Studies ◽  
Hyperactivity Disorder ◽  
Clinical Biomarkers ◽  
The Impact

AbstractAttention-deficit hyperactivity disorder (ADHD) is a neurological and neurodevelopmental childhood-onset disorder characterized by a persistent pattern of inattentiveness, impulsiveness, restlessness, and hyperactivity. These symptoms may continue in 55–66% of cases from childhood into adulthood. Even though the precise etiology of ADHD is not fully understood, it is considered as a multifactorial and heterogeneous disorder with several contributing factors such as heritability, auxiliary to neurodevelopmental issues, severe brain injuries, neuroinflammation, consanguineous marriages, premature birth, and exposure to environmental toxins. Neuroimaging and neurodevelopmental assessments may help to explore the possible role of genetic variations on ADHD neuropsychobiology. Multiple genetic studies have observed a strong genetic association with various aspects of neuropsychobiological functions, including neural abnormalities and delayed neurodevelopment in ADHD. The advancement in neuroimaging and molecular genomics offers the opportunity to analyze the impact of genetic variations alongside its dysregulated pathways on structural and functional derived brain imaging phenotypes in various neurological and psychiatric disorders, including ADHD. Recently, neuroimaging genomic studies observed a significant association of brain imaging phenotypes with genetic susceptibility in ADHD. Integrating the neuroimaging-derived phenotypes with genomics deciphers various neurobiological pathways that can be leveraged for the development of novel clinical biomarkers, new treatment modalities as well as therapeutic interventions for ADHD patients. In this review, we discuss the neurobiology of ADHD with particular emphasis on structural and functional changes in the ADHD brain and their interactions with complex genomic variations utilizing imaging genetics methodologies. We also highlight the genetic variants supposedly allied with the development of ADHD and how these, in turn, may affect the brain circuit function and related behaviors. In addition to reviewing imaging genetic studies, we also examine the need for complementary approaches at various levels of biological complexity and emphasize the importance of combining and integrating results to explore biological pathways involved in ADHD disorder. These approaches include animal models, computational biology, bioinformatics analyses, and multimodal imaging genetics studies.

scholarly journals Life during the pandemic: an international photo-elicitation study with medical students

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
M. Dworkin ◽  
T. Akintayo ◽  
D. Calem ◽  
C. Doran ◽  
A. Guth ◽  
...  
Keyword(s):  
Medical Students ◽  
Interpersonal Relationships ◽  
Photo Elicitation ◽  
Societal Implications ◽  
Global Health Research ◽  
Learning Program ◽  
Elicitation Study ◽  
The World ◽  
Multiple Levels ◽  
The Impact

Abstract Background The SARS-CoV-2 (COVID-19) pandemic is a global event with unprecedented impact on individuals and communities around the world. The purpose of this study is to use a modified photo-elicitation methodology to examine the impact of the COVID-19 pandemic on the lives of medical students and their communities around the world. Methods Participating medical students were asked to take photographs for 14 days. In lieu of an interview, which is customary for photo-elicitation projects, participants were asked to share a reflection (a paragraph or two) for each photograph they contributed to the study. Results Between April 27th, 2020 and May 11th, 2020 26 students from 19 medical schools across 13 countries shared photographs and reflections. Qualitative analysis of written reflections revealed that medical students felt the impact of the pandemic on several levels 1) individual, 2) interpersonal, 3) educational, and 4) societal. Conclusions The COVID-19 pandemic has impacted the lives of medical students on multiple levels. As individuals, students felt emotional distress but found resilience through physical activity and the establishment of new routines. Many students felt isolated as their interpersonal relationships were confined due to social distancing measures. These feelings could be combated with new educational initiatives focused on group collaboration. Lastly, students reflecting on the larger societal implications were concerned with the economic ramifications of the virus and its impact on their future. This study brought together students from several different countries to engage in an applied learning program as a model for equitable global health research.

scholarly journals Melanization in Cryptococcus neoformans Requires Complex Regulation

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Radames J. B. Cordero ◽  
Emma Camacho ◽  
Arturo Casadevall
Keyword(s):  
Cryptococcus Neoformans ◽  
Defense Mechanisms ◽  
Environmental Stressors ◽  
Antimicrobial Compounds ◽  
Human Pathogen ◽  
Content Type ◽  
Signaling Mechanisms ◽  
Complex Regulation ◽  
Multiple Levels ◽  
Melanin Binding

ABSTRACT The fungal human pathogen Cryptococcus neoformans undergoes melanization in response to nutrient starvation and exposure to exogenous melanin precursors. Melanization protects the fungus against host defense mechanisms such as oxidative damage and other environmental stressors (e.g., heat/cold stress, antimicrobial compounds, ionizing radiation). Conversely, the melanization process generates cytotoxic intermediates, and melanized cells are potentially susceptible to overheating and to certain melanin-binding drugs. Despite the importance of melanin in C. neoformans biology, the signaling mechanisms regulating its synthesis are poorly understood. The recent report by D. Lee, E.-H. Jang, M. Lee, S.-W. Kim, et al. [mBio 10(5):e02267-19, 2019, https://doi.org/10.1128/mBio.02267-19] provides new insights into how C. neoformans regulates melanization. The authors identified a core melanin regulatory network consisting of transcription factors and kinases required for melanization under low-nutrient conditions. The redundant and epistatic connections of this melanin-regulating network demonstrate that C. neoformans melanization is complex and carefully regulated at multiple levels. Such complex regulation reflects the multiple functions of melanin in C. neoformans biology.

Abstract 3691: Deletion of Suppressor Of Cytokine Signaling-1 in a Murine Model of Atherosclerosis Results in a Lethal Systemic Inflammation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Christina Grothusen ◽  
Harald Schuett ◽  
Stefan Lumpe ◽  
Andre Bleich ◽  
Silke Glage ◽  
...  
Keyword(s):  
Foam Cell ◽  
Low Density Lipoprotein ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
The Impact

Introduction: Atherosclerosis is a chronic inflammatory disease of the cardiovascular system which may result in myocardial infarction and sudden cardiac death. While the role of pro-inflammatory signaling pathways in atherogenesis has been well characterized, the impact of their negative regulators, e.g. suppressor of cytokine signaling (SOCS)-1 remains to be elucidated. Deficiency of SOCS-1 leads to death 3 weeks post-partum due to an overwhelming inflammation caused by an uncontrolled signalling of interferon-gamma (IFNγ). This phenotype can be rescued by generating recombination activating gene (rag)-2, SOCS-1 double knock out (KO) mice lacking mature lymphocytes, the major source of IFNγ. Since the role of SOCS-1 during atherogenesis is unknown, we investigated the impact of a systemic SOCS-1 deficiency in the low-density lipoprotein receptor (ldlr) KO model of atherosclerosis. Material and Methods: socs-1 −/− /rag-2 −/− deficient mice were crossed with ldlr-KO animals. Mice were kept under sterile conditions on a normal chow diet. For in-vitro analyses, murine socs-1 −/− macrophages were stimulated with native low density lipoprotein (nLDL) or oxidized (ox)LDL. SOCS-1 expression was determined by quantitative PCR and western blot. Foam cell formation was determined by Oil red O staining. Results: socs-1 −/− /rag-2 −/− /ldlr −/− mice were born according to mendelian law. Tripel-KO mice showed a reduced weight and size, were more sensitive to bacterial infections and died within 120 days (N=17). Histological analyses revealed a systemic, necrotic, inflammation in Tripel-KO mice. All other genotypes developed no phenotype. In-vitro observations revealed that SOCS-1 mRNA and protein is upregulated in response to stimulation with oxLDL but not with nLDL. Foam cell formation of socs-1 −/− macrophages was increased compared to controls. Conclusion: SOCS-1 seemingly controls critical steps of atherogenesis by modulating foam cell formation in response to stimulation with oxLDL. SOCS-1 deficiency in the ldlr-KO mouse leads to a lethal inflammation. These observations suggest a critical role for SOCS-1 in the regulation of early inflammatory responses in atherogenesis.

scholarly journals Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1267-1279 ◽  
Author(s):  
Jessica Caprioli ◽  
Marina Noris ◽  
Simona Brioschi ◽  
Gaia Pianetti ◽  
Federica Castelletti ◽  
...  
Keyword(s):  
Disease Recurrence ◽  
Factor H ◽  
Response To Therapy ◽  
Regulatory Proteins ◽  
Response To Treatment ◽  
Complement Factor ◽  
Genetic Studies ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
The Impact

Abstract Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non–Shiga toxin–associated HUS (non-Stx–HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx–HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCP-mutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments.

scholarly journals Tumor evolution selectively inactivates the core microRNA machinery for immune evasion

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tian-Yu Song ◽  
Min Long ◽  
Hai-Xin Zhao ◽  
Miao-Wen Zou ◽  
Hong-Jie Fan ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Human Cancer ◽  
Mirna Biogenesis ◽  
Cytokine Signaling ◽  
Tumor Evolution ◽  
Mouse Tumor ◽  
The Core ◽  
The Impact

AbstractCancer cells acquire genetic heterogeneity to escape from immune surveillance during tumor evolution, but a systematic approach to distinguish driver from passenger mutations is lacking. Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system. We find that the core microRNA (miRNA) biogenesis and targeting machinery maintains the sensitivity of cancer cells to PD-1-independent T cell-mediated cytotoxicity. Genetic inactivation of the machinery or re-introduction of ANKRD52 frequent patient mutations dampens the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells, largely by abolishing miR-155-targeted silencing of suppressor of cytokine signaling 1 (SOCS1). Expression of each miRNA machinery component strongly correlates with intratumoral T cell infiltration in nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway can be exploited by cancer cells to escape from T cell-mediated elimination and immunotherapy.

scholarly journals E-Government services in Moldova: Value and opportunities

2018 ◽  
Vol 325 ◽  
pp. 347-358
Author(s):  
Mihai Grecu ◽  
Ilie Costaş ◽  
Artus Reaboi
Keyword(s):  
High Performance ◽  
Electronic Government ◽  
Government Services ◽  
Telecommunications Infrastructure ◽  
Technology Changes ◽  
Multiple Levels ◽  
The Government ◽  
The One ◽  
Short Time ◽  
The Impact

Technological progress in ICT has created conditions for a new government paradigm - from a government that leads to a government providing services to society. Technology changes the nature of the connection between government and citizens: governance becomes more participatory and citizens' interests prevail. The impact of e-Government solutions is complex, on multiple levels, depending on the maturity of the models applied and the capacity of citizens and business to assimilate e-Government services. In a short time, electronic government services in Moldova have evolved from simple information services to integrated transactional services. On the one hand, this is due to high performance telecommunications infrastructure (broadband, 2G, 3G and 4G technology) and, on the other hand, to citizens' expectations that boosted recently and determined the government to accelerate the implementation of new e-services, increasingly complex and a better quality. The paper addresses the issue of e-Government services in terms of the value that it gives to the government and to citizens' lives and analyzes opportunities to develop e-Government services in the new technological and social realities.

A Mechanistic Motor-Clutch Model That Explains Cell Shape Dynamics to Cyclic Stretch

2022 ◽  
Author(s):  
Benjamin W. Scandling ◽  
Jia Gou ◽  
Jessica Thomas ◽  
Jacqueline Xuan ◽  
Chuan Xue ◽  
...  
Keyword(s):  
Computational Model ◽  
Computational Models ◽  
The Body ◽  
Cyclic Stretch ◽  
Substrate Stiffness ◽  
Cell Alignment ◽  
Cellular Mechanisms ◽  
Actin Bundles ◽  
The Impact

Many cells in the body experience cyclic mechanical loading, which can impact cellular processes and morphology. In vitro studies often report that cells reorient in response to cyclic stretch of their substrate. To explore cellular mechanisms involved in this reorientation, a computational model was developed by utilizing the previous computational models of the actin-myosin-integrin motor-clutch system developed by others. The computational model predicts that under most conditions, actin bundles align perpendicular to the direction of applied cyclic stretch, but under specific conditions, such as low substrate stiffness, actin bundles align parallel to the direction of stretch. The model also predicts that stretch frequency impacts the rate of reorientation, and that proper myosin function is critical in the reorientation response. These computational predictions are consistent with reports from the literature and new experimental results presented here. The model suggests that the impact of different stretching conditions (stretch type, amplitude, frequency, substrate stiffness, etc.) on the direction of cell alignment can largely be understood by considering their impact on cell-substrate detachment events, specifically whether detachment occurs during stretching or relaxing of the substrate.

Hu Resources Replaces Human Resources in Health Care

2012 ◽  
pp. 1392-1407
Author(s):  
Emmett Davis
Keyword(s):  
Health Care ◽  
Human Resources ◽  
Healthcare Professionals ◽  
Healthcare Industry ◽  
Behavioral Skills ◽  
Intelligent Software ◽  
The Social ◽  
Multiple Levels ◽  
And Performance ◽  
The Impact

Intelligent technologies are exponentially approaching the stage where healthcare professionals must begin to plan for the management of “hu” (human, software, and robotic) resources, replacing management of human resources alone in isolation from other intelligences. The healthcare industry in multiple levels and ways must begin to plan for human resources in health care to extend existing and to develop new conceptual and behavioral skills in order for humans, intelligent software, and robots to optimally partner with each other. The interaction among hu resources will be active and carried out in multiple modes and intellectual and emotional intensities. Healthcare professionals, who shape the social and cultural institutions around intelligence and active knowledge, can optimize the impact and performance of this intelligence partnership.

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