Advances in experimental medicine and biology最新文献

The characterization of a protein complex by mass spectrometry can be conducted at different levels. Initial steps regard the qualitative composition of the complex and subunit identification. After that, quantitative information such as stoichiometric ratios and copy numbers for each subunit in a complex or super-complex is acquired. Peptide-based LC-MS/MS offers a wide number of methods and protocols for the characterization of protein complexes. This chapter concentrates on the applications of peptide-based LC-MS/MS for the qualitative, quantitative, and structural characterization of protein complexes focusing on subunit identification, determination of stoichiometric ratio and number of subunits per complex as well as on cross-linking mass spectrometry and hydrogen/deuterium exchange as methods for the structural investigation of the biological assemblies.

The pathogenesis of atopic dermatitis (AD) is complex and multifactorial. However, recent advancements in the genetics and pathophysiology of AD suggest that epidermal barrier dysfunction is paramount in the development and progression of the condition (Boguniewicz M, Leung DYM, Immunol Rev 242(1):233-246, 2011). In addition to standard therapy for AD, there are a plethora of nonprescription treatment modalities which may be employed. Over-the-counter treatments for atopic dermatitis can come in the form of topical corticosteroids, moisturizers/emollients, and oral antihistamines. Though these treatments are beneficial, prescription treatments may be quicker acting and more efficacious in patients with moderate to severe disease or during flares. OTC agents are best used for maintenance between flares and to prevent progression of mild disease. Alternative and complementary treatments lack strong efficacy evidence. However, wet wraps, bleach baths, and other treatments appear to be promising when used in conjunction with conventional treatments. With the financial burden of atopic dermatitis ranging from 364 million to 3.8 billion dollars each year in the United States, we suspect this topic will gain further research attention.

Erythroid Krüppel-like factor (KLF1), first discovered in 1992, is an erythroid-restricted transcription factor (TF) that is essential for terminal differentiation of erythroid progenitors. At face value, KLF1 is a rather inconspicuous member of the 26-strong SP/KLF TF family. However, 30 years of research have revealed that KLF1 is a jack of all trades in the molecular control of erythropoiesis. Initially described as a one-trick pony required for high-level transcription of the adult HBB gene, we now know that it orchestrates the entire erythroid differentiation program. It does so not only as an activator but also as a repressor. In addition, KLF1 was the first TF shown to be directly involved in enhancer/promoter loop formation. KLF1 variants underlie a wide range of erythroid phenotypes in the human population, varying from very mild conditions such as hereditary persistence of fetal hemoglobin and the In(Lu) blood type in the case of haploinsufficiency, to much more serious non-spherocytic hemolytic anemias in the case of compound heterozygosity, to dominant congenital dyserythropoietic anemia type IV invariably caused by a de novo variant in a highly conserved amino acid in the KLF1 DNA-binding domain. In this chapter, we present an overview of the past and present of KLF1 research and discuss the significance of human KLF1 variants.

Intestinal epithelium constitutes a barrier to the unrestricted movement of pathogens, and other detrimental substances from the external world (gut lumen) into the interstitial environment. Intestinal epithelial cells obstruct harmful substances passing through the epithelium as a physical and chemical barrier; Moreover, the epithelial cells can express Toll-like receptors (TLRs) and cytokines to exert innate immune function. In addition, high levels of immunoglobulin A (IgA) and other antibodies exist in the intestinal mucosa, maintaining intestinal immune homeostasis in conjunction with intestinal probiotics. Traditionally, these antibodies have been deemed to be secreted by submucosal plasma cells. Nonetheless, in recent years, it has been demonstrated that intestinal epithelial cells produce a substantial amount of Igs, especially IgA or free Ig light chains, which are involved in intestinal immune homeostasis and the survival of normal epithelial cells. Furthermore, mounting evidence affirms that many human carcinoma cells, including colorectal cancer (CRC), can overexpress Igs, particularly IgG. Cancer-derived Igs exhibit a unique V(D)J rearrangement pattern distinct from B cell-derived Ig; moreover, this cancer cell-derived IgG also has a unique sialic acid modification on the 162 site of CH1 domain (SIA-IgG). The SIA-IgG plays a crucial role in promoting cancer initiation, progression, metastasis, and tumour immune escape. Simultaneously, CRC cells can also express free Ig light chains, which promote colitis, colitis-associated colon carcinogenesis, and CRC progression. Therefore, Igs expressed by CRC cells could be a potential target for diagnosing and preventing the transformation of inflammation into cancer, as well as treating CRC.

Cytokine storm syndromes (CSSs) are caused by a dysregulated host immune response to an inciting systemic inflammatory trigger. This maladaptive and harmful immune response culminates in collateral damage to host tissues resulting in life-threatening multisystem organ failure. Knowledge of the various immune cells that contribute to CSS pathogenesis has improved dramatically in the past decade. Monocytes, dendritic cells, and macrophages, collective known as monocytic phagocytes, are well-positioned within the immune system hierarchy to make key contributions to the initiation, propagation, and amplification of the hyperinflammatory response in CSS. The plasticity of monocytic phagocytes also makes them prime candidates for mediating immunoregulatory and tissue-healing functions in patients who recover from cytokine storm-mediated immunopathology. Therefore, approaches to manipulate the myriad functions of monocytic phagocytes may improve the clinical outcome of CSS.

Hemophagocytic lymphohistiocytosis (HLH) comprises a broad spectrum of life-threatening cytokine storm syndromes, classified into primary (genetic) or secondary (acquired) HLH. The latter occurs in a variety of medical conditions, including infections, malignancies, autoimmune and autoinflammatory diseases, acquired immunodeficiency, and metabolic disorders. Despite recent advances in the field, the pathogenesis of secondary HLH remains incompletely understood. Considering the heterogeneity of triggering factors and underlying diseases in secondary HLH, a large diversity of animal models has been developed to explore pivotal disease mechanisms. To date, over 20 animal models have been described that each recapitulates certain aspects of secondary HLH. This review provides a comprehensive overview of the existing models, highlighting relevant findings, discussing the involvement of different cell types and cytokines in disease development and progression, and considering points of interest toward future therapeutic strategies.

Cytokine storm syndromes (CSS) include different entities such as macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis (HLH), and multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. An effective management strategy is critical in CSS. While biologics have become an essential part of CSS treatment, hematopoietic stem cell transplantation (HSCT) has changed the fate of primary HLH patients. This chapter will focus on the available alternative immunomodulatory therapies in CSS, which include corticosteroids, cyclosporine A, intravenous immunoglobulin, interleukin 18 binding protein, therapeutic plasmapheresis, HSCT, and mesenchymal stromal cell-based therapies.

While viruses are considered the most common infectious triggers for cytokine storm syndromes (CSS), a growing list of bacterial pathogens, particularly intracellular organisms, have been frequently reported to be associated with this syndrome. Both familial and sporadic cases of CSS are often precipitated by acute infections. It is also important to note that an underlying precipitating infection might not be clinically obvious as the CSS clinical picture can mimic an infectious process or an overwhelming septicemia. It is important to detect such an underlying treatable condition. In addition, infections can also be acquired during the course of CSS due to the concurrent immune suppression with treatment. Optimal CSS outcomes require treating bacterial infections when recognized.CSS should always be suspected in patients presenting with a sepsis-like or multi-organ dysfunction picture. There are many criteria proposed to diagnose CSS in general, with HLH-2004 being the most commonly used. Alternatively, criteria have been proposed for CSS occurring in specific underlying conditions such as systemic lupus erythematosus (SLE) or systemic juvenile idiopathic arthritis (sJIA). However, waiting for many of these criteria to be fulfilled could lead to significant delay in diagnosis, and the physician needs a high index of suspicion for CSS in critically ill febrile hospitalized patients in order to properly recognize the condition. Thus, there should be diagnostic equipoise between CSS and infections, including bacterial, in this population. In this chapter, we discuss the more common bacterial precipitants of CSS with many of the cases being discussed in the pediatric age group.

Lockdown restrictions and social distancing regulations enforced by governments worldwide to prevent COVID-19 transmission have caused momentous disruption to the global education sector. Educators and students across all institutions and levels had to suddenly adapt to a new reality where in-person teaching was replaced by hybrid or remote learning activities. This chapter aims to evaluate the impact of the pandemic on teaching, learning and assessment in higher education. It discusses the challenges presented by the shift to online teaching and the pedagogical strategies developed to foster student engagement and assess their progress in a remote learning setting. Moreover, this chapter explores the impact of the pandemic on wellbeing and mental health of students and academic staff. The last section draws on the lessons learned from the pandemic to identify areas of good practice that are likely to positively shape the post-pandemic higher education panorama.

Chronic conditions or diseases are defined as persistent conditions lasting ≥ 1 year requiring either ongoing medical attention or limiting daily living or both (Agency for Healthcare Research and Quality (AHRQ) in Programs: SHARE approach workshop, Agency for Healthcare Research and Quality (AHRQ) (2016) Programs: SHARE approach workshop 2016. https://www.ahrq.gov/professionals/education/curriculum-tools/shareddecisionmaking/workshop/index.html . Accessed 20 Jan 2017). Physical chronic conditions, including diabetes, hypertension, heart disease, arthritis, and stroke, are prevalent, especially in the older population. Over 90% of older adults have at least 1 and 77% have ≥ 2 chronic conditions (American Diabetes Association (ADA) in Statistics about diabetes, American Diabetes Association (ADA) (2023) Statistics about diabetes. https://diabetes.org/about-us/statistics/about-diabetes . Accessed 20 Apr 2023). Chronic conditions account for $4.1 trillion of the nation's annual healthcare expenditure (Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion in Health and economic costs of chronic conditions, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion. Health and Economic Costs of Chronic Conditions (2022). https://www.cdc.gov/chronicdisease/about/costs/index.htm . Accessed 7 Jan 2023). There are marked disparities based on age, color, and income, with older people, people of color, and lower-income people having higher treatment costs or even lost wages in response to having chronic conditions. Chronic conditions are the on-the-top leading causes for death with diabetes being the top 7th in the USA in 2019 (Ferguson in Metabolic Syndrome Related Dis, Ferguson et al., Metab Syndr Relat Disord 21:177-187, 2023).