Progress in Molecular Biology and Translational Science最新文献

Cell death is a crucial evolutionary adaptation for multicellular organisms through which they can systematically eliminate cells that are no longer needed, potentially harmful, or are damaged beyond repair. Over the past few decades, our understanding of the cell death mechanisms has expanded significantly revealing a diverse, and interconnected array of regulated cell death (RCD) pathways that includes apoptosis, necroptosis, pyroptosis, cuproptosis etc. While the complexities of these pathways have incrementally increased with the evolution of multicellularity, many core components associated with cell death have remained conserved. This points towards the essential function of cell death in maintenance of homeostasis at the cellular, organismal and individual level. It is thus not a surprise that their dysregulation can manifest in the form of several pathologies. Therefore, the ability to accurately detect and distinguish different forms of cell death is essential not only for advancing our understanding of the fundamental cellular and molecular processes but also for elucidating their role in disease pathogenesis, where their dysregulation contributes to various pathological conditions. However, detecting and differentiating various forms of cell death is a challenging task. Since there are multiple cell death modalities, many of their characteristics overlap, such as a condensed nucleus being observed in both secondary necrosis and apoptosis. Further, a cell can undergo more than one kind of cell death simultaneously, a process known as "cell death continuum" further complicating detection and classification. This chapter provides an overview of the conventional methods used for detecting cell death, highlighting both probe-based and non-probe-based techniques. Recent advancements in high-throughput strategies, AI based predictive modelling and other such novel techniques that offer greater specificity in cell death characterization are particularly emphasized.

The intricate interplay involving Type I interferon (IFN), anti-interferon antibodies, and COVID-19 elucidates a complex symphony within the immune system. This chapter thoroughly explores the dynamic landscape of Type I IFN, delineating its pivotal role as the guardian of the immune response. As SARS-CoV-2 engages the host, the delicate balance of IFN induction and signaling pathways is disrupted, resulting in a nuanced impact on the severity and pathogenesis of COVID-19. Clinical studies illuminate a critical link between impaired IFN response and severe outcomes, uncovering genetic factors contributing to susceptibility. Furthermore, the emergence of anti-interferon antibodies proves to be a disruptive force, compromising the immune arsenal and correlating with disease severity. Our chapter encompasses diagnostic and prognostic implications, highlighting the importance of assays in identifying levels of IFN and anti-interferon antibodies. This chapter examines the possible incorporation of interferon-related biomarkers in COVID-19 diagnostics, offering predictive insights into disease progression. On the therapeutic front, efforts to manipulate the IFN pathway undergo scrutiny, encountering complexities in light of anti-interferon antibodies. This chapter concludes by outlining prospective avenues for precision medicine, emphasizing the imperative need for a comprehensive comprehension of the IFN landscape and its intricate interaction with COVID-19.

Proteins are responsible for a vast majority of various cellular effector processes. α-crystallin is one of the most important proteins in the lens of the eye, which acts as a molecular chaperone that keeps the lens transparent and refractive. α-crystallin is categorized as an intrinsically disordered protein (IDP), devoid of a stable three-dimensional structure, in contrast to conventional globular proteins. Because of its structural flexibility, it can stop denatured proteins from aggregating and building up within the lens over time. α-crystallin's dynamic quaternary structure, which allows it to exist in a variety of oligomeric forms, from dimers to massive assemblies, improves its chaperone function and flexibility. Its intrinsically disordered nature enables it to interact with a variety of client proteins due to its large non-polar and polar residue content and lack of a hydrophobic core. Furthermore, under physiological stress, osmolytes like sorbitol, TMAO, and urea are essential in regulating the stability and function of α-crystallin. Post-translational modifications (PTMs) such as glycation, in which reducing sugars combine with amino groups on the protein to generate advanced glycation end-products, impair α-crystallin's ability to function. These AGEs can cross-link α-crystallin molecules to prevent protein aggregation, changing their structure and decreasing their chaperone action. Because of their raised blood glucose levels, diabetics have an increased chance of developing cataracts as a result of this process. Comprehending how glycation and other PTMs affect α-crystallin is crucial for formulating treatment plans to maintain lens transparency and fight cataracts linked to aging and metabolic disorders.

The formation of membraneless organelles is vital for the intracellular organization of macromolecules and in regulating many cellular processes. The membraneless organelles are formed by liquid-liquid phase separation (LLPS) mainly constituted of proteins and polynucleotides. The primary factor driving the liquid demixing into two phases is the multivalency of the proteins involved, a general characteristic of intrinsically disordered proteins (IDPs) or proteins with intrinsically disordered regions (IDRs). This chapter discusses the role of IDP/IDRs in biomolecular condensate formation and the physical characteristics of these states. Further, the LLPS formation of individual proteins induced by molecular crowding and its relevance to physiological conditions are presented. The studies on the effects of small molecular osmolytes and a hydrotrope, ATP on the phase separation temperature, protein concentration, and reentrant behavior are discussed. The advancements and limitations of the computational methods to predict the phase separation behavior of IDPs, and to analyze the interactions and dynamics of the proteins in condensates are presented. The roles of phase separation in cancer, neurological disorders, and cardiovascular diseases are highlighted.

The fact that protein universe is enriched in intrinsic disorder is an accepted truism now. It is also recognized that the phenomenon of protein intrinsic disorder contains keys to answer numerous questions that do not have obvious solutions within the classic "lock-and-key"-based structure-function paradigm. In fact, reality is much more complex than the traditional "one-gene - one-protein - one-function" model, as many (if not most) proteins are multifunctional. This multifunctionality is commonly rooted in the presence of the intrinsically disordered or structurally flexible regions in a protein. Here, in addition to various events at the DNA (genetic variations), mRNA (alternative splicing, alternative promoter usage, alternative initiation of translation, and mRNA editing), and protein levels (post-translational modifications), intrinsic disorder and protein functionality are crucial for generation of proteoforms, which are functionally and structurally different protein forms produced from a single gene. Therefore, since a given protein exists as a dynamic conformational ensemble containing multiple proteoforms characterized by a broad spectrum of structural features and possessing various functional potentials, "protein structure-function continuum" model represents a more realistic way to correlate protein structure and function.

CRISPR-Cas (clustered regularly interspaced short palindromic repeats and associated proteins) is a novel genome editing technology with potential applications in treating diseases. Currently, its use in humans is restricted to clinical trials, although its growth rate is significant, and some have received initial FDA approval. It is crucial to examine and address the challenges for this technology to be implemented in clinical settings. This review aims to identify and explore new research ideas to increase of CRISPR's efficiency in treating genetic diseases and cancer, as well as its future prospects. Given that a substantial amount of previous research has focused on CRISPR-Cas delivery strategies and materials, this overview introduces specific conditions and strategies. It also discusses some of the challenges and opportunities in this field, offering a unique perspective.

In the face of advancements in health care and a shift towards healthy lifestyle, diabetes mellitus (DM) still presents as a global health challenge. This chapter explores recent advancements in the areas of genetic and molecular underpinnings of DM, addressing the revolutionary potential of CRISPR-based genome editing technologies. We delve into the multifaceted relationship between genes and molecular pathways contributing to both type1 and type 2 diabetes. We highlight the importance of how improved genetic screening and the identification of susceptibility genes are aiding in early diagnosis and risk stratification. The spotlight then shifts to CRISPR-Cas9, a robust genome editing tool capable of various applications including correcting mutations in type 1 diabetes, enhancing insulin production in T2D, modulating genes associated with metabolism of glucose and insulin sensitivity. Delivery methods for CRISPR to targeted tissues and cells are explored, including viral and non-viral vectors, alongside the exciting possibilities offered by nanocarriers. We conclude by discussing the challenges and ethical considerations surrounding CRISPR-based therapies for DM. These include potential off-target effects, ensuring long-term efficacy and safety, and navigating the ethical implications of human genome modification. This chapter offers a comprehensive perspective on how genetic and molecular insights, coupled with the transformative power of CRISPR, are paving the way for potential cures and novel therapeutic approaches for DM.

CRISPR-Cas technologies have drastically revolutionized genetic engineering and also dramatically changed the potential for treating inherited disorders. The potential to correct genetic mutations responsible for numerous hereditary disorders from single-gene disorders to complex polygenic diseases through precise DNA editing is feasible. The tactic now employed in CRISPR-Cas systems for treating inherited disorders is the usage of particular guide RNAs to target and edit disease-causing mutations in the patient's genome. Several methods such as CRISPR-Cas9, CRISPR-Cas12, and CRISPR-Cas13 are being thoroughly researched and optimized to increase effectiveness, accuracy, and safety in gene editing. Additionally, it is predicted that CRISPR-based therapies will be able to treat complex genetic illnesses such as cancer predisposition syndromes, neurological disorders, and cardiovascular conditions in addition to single-gene disorders. The available editing tools and creation of base editing technology facilitate the simultaneous correction of many mutations or accurate nucleotide changes leading to further advances in the development of multiplex editing tools and base editing technology fiction. When combined with other paradigms such as gene therapy using stem cell treatment, CRISPR-Cas promises improved efficacy. Patient treatment and lowering side effects significantly in individual genetic profiles will guide CRISPR-based treatments. These procedures will undoubtedly lead to therapies that are both efficient and curative of a wide range of genetic diseases, ushering in a new era of precision medicine. This chapter discusses about CRISPR Cas9 mechanism and its significance in the treatment of Hereditary disorders.

The SARS-CoV-2 outbreak in late 2019 triggered a major increase in activities related to immunobiology and immunotherapy to cope with and find solutions to end the COVID-19 pandemic. The unprecedented approach to research and development of drugs and vaccines against SARS-CoV-2 has substantially improved the understanding of immunobiology for COVID-19, which can also be applied to other infectious diseases. Major efforts were dedicated to the repurposing of existing antiviral drugs and the development of novel ones. For this reason, numerous approaches to evaluating interferons, immunoglobulins, and cytokine inhibitors have been conducted. Antibody-based therapies, especially employing monoclonal antibodies have also been on the agenda. Cell-based therapies involving dendritic cells, macrophages, and CAR T-cell approaches have been evaluated. Many existing antiviral drugs have been repurposed for COVID-19 and novel formulations have been tested. The extraordinarily rapid development of efficient vaccines led to the breakthrough of novel vaccine approaches such as mRNA-based vaccines saving millions of lives. Waning immunity of existing vaccines and emerging SARS-CoV-2 variants have required additional booster vaccinations and re-engineering of new versions of COVID-19 vaccines.