Related Human Diseases Research Articles

Recent progress of biocompatible carbon dots in hypoxia-related fields.

Almost all eukaryotes need oxygen to maintain regular physiological activities. When the organism is under hypoxic situation for a persistent or periodic, it will induce irreversible physiological disorders and even pathological results. Hypoxia is closely related to the pathogenesis of metabolic diseases, cancer, chronic heart disease and kidney disease, myocardial ischemia, as well as reproductive diseases like preeclampsia and endometriosis. Therefore, monitoring and treatment of hypoxia have important implications for the pathophysiology of human-related diseases. Carbon dots (CDs) are emerging nanomaterials developed after 2004 with excellent performance, and have broad application potential in variousdomains likeoptical, biomedicine, energy. Advanced hypoxia therapeutics should be integrated with monitoring and treatment, and CDs with excellent performance are good potential options when sensing is combined with various therapeutic methods. Some researchers have also begun to carry out research in related fields and achieved some results. This article aims to clarify the various applications of CDs in hypoxia-related fields in recent years, including hypoxia sensing and hypoxia tumor theranostics. Finally, the possible challenges and prospects for the application of CDs in hypoxia-related fields are discussed.

The combined use of photobiomodulation and curcumin-loaded iron oxide nanoparticles significantly improved wound healing in diabetic rats compared to either treatment alone

This experimental study examined the effects of curcumin-loaded iron oxide nanoparticles (CUR), photobiomodulation (PBM), and CUR + PBM treatments on mast cells (MC)s numbers and degranulation, inflammatory cells (macrophages, neutrophils), and wound strength in the last step of the diabetic wound repair process (maturation phase) in a rat model of type one diabetes mellitus (T1DM). T1DM was induced in 24 rats, and 1month later, an excisional wound was created on each rat's back skin. The rats were then distributed into four groups: (1) untreated diabetic control group (UDCG); (2) rats treated with CUR (CUR); (3) rats exposed to PBM (890nm, 80Hz, 0.2J/cm2) (PBM); (4) rats treated with CUR plus PBM (CUR + PBM). Fifteen days after surgery, skin tissue samples were taken for biomechanical and stereological evaluations. The biomechanical factor of maximum force was observed to be considerably improved in the CUR + PBM (p = 0.000), PBM (p = 0.014), and CUR (p = 0.003) groups compared to the UDCG. CUR + PBM, PBM, and CUR groups had significantly decreased total numbers of MC compared with the UDCG (all, p = 0.001). The results were significantly better in the CUR + PBM (p = 0.000) and PBM (p = 0.003) groups than in the CUR group. Inflammatory cell counts were significantly lower in the CUR + PBM, PBM, and CUR groups than in the UDCG (all, p = 0.0001). In all evaluating methods, the usage of CUR + PBM produced better results than the use of CUR or PBM alone (almost all tests, p = 0.0001). CUR + PBM, PBM, and CUR significantly improved the repair of diabetic skin wounds in type 1 DM rats through significant decreases of MC number, degranulation, and inflammatory cells as well as a noteworthy improvement in wound strength. The impact of CUR + PBM was superior to that of either PBM or CUR alone. It is suggested that CUR + PBM could be used as a MC stabilizer for the effective treatment of some related human diseases.

Antiresonant hollow-core fiber assisted photothermal spectroscopy for the detection of ammonia in human breath

• A nodeless five-ring nested antiresonant hollow-core fiber gas sensor is proposed. • The gas sensor suitable for the concentration of human exhaled NH3 in the near infrared band. • The sensitivity of the sensor is 1827.07 W/(m2⋅ppm) is by the photothermal spectroscopy. We propose a nodeless antiresonant hollow core fiber structure composed of five nested loops to detect the ammonia concentration of human body exhaled at 1527 nm in the near infrared. Based on the photothermal spectroscopy theory, the detection sensitivity of 1827.07 W/(m 2 ∙ppm) is obtained by simulating the detection of ammonia content within 5 s of breathing of different people, which divides the detection range of healthy people and patients with renal failure. Within the ±4.4 % tolerance allowed by optical fiber manufacturing, the sensor sensitivity error is only 0.82 %. The results of simulation theory are of great significance to the detection and prevention of human-related diseases.

Therapeutic Strategies to Target the Androgen Receptor.

The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

A compact gas chromatography platform for detection of multicomponent volatile organic compounds biomarkers.

Some human exhaled volatile organic compounds (VOCs) can be employed to diagnose related human endogenous diseases as characteristic biomarkers, which is expected to be applied to rapid screening and grading because of their non-invasive and cost-effective advantages. In this study, we developed a compact gas chromatography (GC) platform mainly composed of an integrated silicon-based micro-column chip using micro-electromechanical system techniques and a miniaturized metal oxide semiconductor gas detector. In addition, the sampling/switching valve with related components and embedded microcontrollers was used for airflow control. The fabricated system selectively detected the five VOCs (pentane, acetone, toluene, octane, and decane) considered the typical endogenous disease biomarkers. In the experiments, the functional parameters of the system were investigated, and the optimum temperature conditions of the system for separation were determined. The results show that the system can successfully test the studied five VOCs as low as 1 ppm. In addition, the influence of interfering gas (carbon dioxide and ammonia) on the system for the VOC mixture is also investigated. Moreover, to prove the possibility of breath analysis of the fabricated system, the detection performance of isoprene and acetone at the ppb level is studied. Then, the concentration changes of the isoprene at the ppb concentration for human breath are successfully detected in the system. Therefore, we believe that the prepared compact GC system has potential applications in the human endogenous disease diagnosis for the VOC biomarkers.

Cholesterol crystals activate NLRP3 inflammasomes and promote gallstone formation by increasing mucin secretion

ABSTRACT Cholesterol crystals participate in cholesterol nucleation; however, the role of cholesterol crystals in gallstone development is unknown. Mucin secretion contributes to increased size of gallstones. Cholesterol crystals activate inflammasomes and participate in many sterile inflammation related human diseases. We investigated the role of cholesterol crystals and mucins in sterile inflammation and gallstone enlargement. We found that expression of mucin 5AC (MUC5AC), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) and interleukin-1b (IL-1b) was increased significantly in tissues adjacent to gallstones. Experiments in vitro showed that cholesterol crystals promote MUC5AC secretion; they also increase expression of NLRP3, NLR family CARD domain-containing 4 (NLRC4), apoptosis-associated speck-like protein containing caspase recruitment domain (ASC), and cleaved caspase-1 in biliary epithelial cells. Inhibition of Inflammasomes by NLRP3, ASC or caspase-1 small interfering RNAs reduced MUC5AC secretion. Also, the IL-1 receptor antagonist, IL1RA, and caspase-1 inhibitor, Ac-YVAD, both inhibited MUC5AC secretion induced by cholesterol crystals. We found that inflammasome activation participates in cholesterol crystal induced mucin secretion and gallstone development.

Actin-Associated Proteins and Small Molecules Targeting the Actin Cytoskeleton.

Actin-associated proteins (AAPs) act on monomeric globular actin (G-actin) and polymerized filamentous actin (F-actin) to regulate their dynamics and architectures which ultimately control cell movement, shape change, division; organelle localization and trafficking. Actin-binding proteins (ABPs) are a subset of AAPs. Since actin was discovered as a myosin-activating protein (hence named actin) in 1942, the protein has also been found to be expressed in non-muscle cells, and numerous AAPs continue to be discovered. This review article lists all of the AAPs discovered so far while also allowing readers to sort the list based on the names, sizes, functions, related human diseases, and the dates of discovery. The list also contains links to the UniProt and Protein Atlas databases for accessing further, related details such as protein structures, associated proteins, subcellular localization, the expression levels in cells and tissues, mutations, and pathology. Because the actin cytoskeleton is involved in many pathological processes such as tumorigenesis, invasion, and developmental diseases, small molecules that target actin and AAPs which hold potential to treat these diseases are also listed.

Gender Identification and Classification of Drosophila melanogaster Flies Using Machine Learning Techniques.

Drosophila melanogaster is an important genetic model organism used extensively in medical and biological studies. About 61% of known human genes have a recognizable match with the genetic code of Drosophila flies, and 50% of fly protein sequences have mammalian analogues. Recently, several investigations have been conducted in Drosophila to study the functions of specific genes exist in the central nervous system, heart, liver, and kidney. The outcomes of the research in Drosophila are also used as a unique tool to study human-related diseases. This article presents a novel automated system to classify the gender of Drosophila flies obtained through microscopic images (ventral view). The proposed system takes an image as input and converts it into grayscale illustration to extract the texture features from the image. Then, machine learning (ML) classifiers such as support vector machines (SVM), Naive Bayes (NB), and K-nearest neighbour (KNN) are used to classify the Drosophila as male or female. The proposed model is evaluated using the real microscopic image dataset, and the results show that the accuracy of the KNN is 90%, which is higher than the accuracy of the SVM classifier.

M-CSFR/CSF1R signaling regulates myeloid fates in zebrafish via distinct action of its receptors and ligands

AbstractMacrophage colony-stimulating factor receptor (M-CSFR/CSF1R) signaling is crucial for the differentiation, proliferation, and survival of myeloid cells. The CSF1R pathway is a promising therapeutic target in many human diseases, including neurological disorders and cancer. Zebrafish are commonly used for human disease modeling and preclinical therapeutic screening. Therefore, it is necessary to understand the proper function of cytokine signaling in zebrafish to reliably model human-related diseases. Here, we investigate the roles of zebrafish Csf1rs and their ligands (Csf1a, Csf1b, and Il34) in embryonic and adult myelopoiesis. The proliferative effect of exogenous Csf1a on embryonic macrophages is connected to both receptors, Csf1ra and Csf1rb, however there is no evident effect of Csf1b in zebrafish embryonic myelopoiesis. Furthermore, we uncover an unknown role of Csf1rb in zebrafish granulopoiesis. Deregulation of Csf1rb signaling leads to failure in myeloid differentiation, resulting in neutropenia throughout the whole lifespan. Surprisingly, Il34 signaling through Csf1rb seems to be of high importance as both csf1rbΔ4bp-deficient and il34Δ5bp-deficient zebrafish larvae lack granulocytes. Our single-cell RNA sequencing analysis of adult whole kidney marrow (WKM) hematopoietic cells suggests that csf1rb is expressed mainly by blood and myeloid progenitors, and the expression of csf1ra and csf1rb is nonoverlapping. We point out differentially expressed genes important in hematopoietic cell differentiation and immune response in selected WKM populations. Our findings could improve the understanding of myeloid cell function and lead to the further study of CSF1R pathway deregulation in disease, mostly in cancerogenesis.

DNA damage and repair in the hematopoietic system.

Although hematopoietic stem cells (HSCs) in the bone marrow are in a state of quiescence, they harbor the self-renewal capacity and the pluripotency to differentiate into mature blood cells when needed, which is key to maintain hematopoietic homeostasis. Importantly, HSCs are characterized by their long lifespan ( e. g., up to 60 months for mice), display characteristics of aging, and are vulnerable to various endogenous and exogenous genotoxic stresses. Generally, DNA damage in HSCs is endogenous, which is typically induced by reactive oxygen species (ROS), aldehydes, and replication stress. Mammalian cells have evolved a complex and efficient DNA repair system to cope with various DNA lesions to maintain genomic stability. The repair machinery for DNA damage in HSCs has its own characteristics. For instance, the Fanconi anemia (FA)/BRCA pathway is particularly important for the hematopoietic system, as it can limit the damage caused by DNA inter-strand crosslinks, oxidative stress, and replication stress to HSCs to prevent FA occurrence. In addition, HSCs prefer to utilize the classical non-homologous end-joining pathway, which is essential for the V(D)J rearrangement in developing lymphocytes and is involved in double-strand break repair to maintain genomic stability in the long-term quiescent state. In contrast, the base excision repair pathway is less involved in the hematopoietic system. In this review, we summarize the impact of various types of DNA damage on HSC function and review our knowledge of the corresponding repair mechanisms and related human genetic diseases.

ProfKin: A comprehensive web server for structure-based kinase profiling.

Protein kinases are central mediators of signal-transduction cascades and attractive drug targets for therapeutic intervention. Since kinases are structurally and mechanistically related to each other, kinase inhibitor selectivity is often investigated by kinase profiling and considered as an important index for drug discovery. We here describe a versatile web server termed ProfKin for structure-based kinase profiling, which is based on a kinase-ligand focused database (KinLigDB). It provides all ready-to-use 3D structure coordinates of 4219 kinase-ligand complex structures covering 297 human kinases and the associated information, particularly including binding site type, binding ligand type, interaction fingerprints, downstream molecules and related human diseases. The web server works via predicting possible binding modes for the query molecule, prioritizing the binding modes guided by an interaction fingerprint analysis method, and giving a list of ranked kinases by a comprehensive index. Users can freely select entire or part of the KinLigDB database, e.g. via subfamily and binding site type, to customize the profiling contents. The superimpositions of the predicted binding poses of the query molecule with reference binding modes can be visually inspected on the website. The additional classification attributes and phylogenetic tree are also given for each top-ranked kinase.

Mammalian hibernation: a unique model for medical research

Abstract Hibernation is an adaptive behavior for some small animals to survive cold winter. Hibernating mammals usually down-regulate their body temperature from ~37°C to only a few degrees. During the evolution, mammalian hibernators have inherited unique strategies to survive extreme conditions that may lead to disease or death in humans and other non-hibernators. Hibernating mammals can not only tolerant deep hypothermia, hypoxia and anoxia, but also protect them against osteoporosis, muscle atrophy, heart arrhythmia and ischemia-reperfusion injury. Finding the molecular and regulatory mechanisms underlying these adaptations will provide novel ideas for treating related human diseases.

Nucleic Acids Analytical Methods for Viral Infection Diagnosis: State-of-the-Art and Future Perspectives.

The analysis of viral nucleic acids (NA), DNA or RNA, is a crucial issue in the diagnosis of infections and the treatment and prevention of related human diseases. Conventional nucleic acid tests (NATs) require multistep approaches starting from the purification of the pathogen genetic material in biological samples to the end of its detection, basically performed by the consolidated polymerase chain reaction (PCR), by the use of specialized instruments and dedicated laboratories. However, since the current NATs are too constraining and time and cost consuming, the research is evolving towards more integrated, decentralized, user-friendly, and low-cost methods. These will allow the implementation of massive diagnoses addressing the growing demand of fast and accurate viral analysis facing such global alerts as the pandemic of coronavirus disease of the recent period. Silicon-based technology and microfluidics, in this sense, brought an important step up, leading to the introduction of the genetic point-of-care (PoC) systems. This review goes through the evolution of the analytical methods for the viral NA diagnosis of infection diseases, highlighting both advantages and drawbacks of the innovative emerging technologies versus the conventional approaches.

Therapeutic potential of melatonin and melatonergic drugs on K18‐hACE2 mice infected with SARS‐CoV‐2

As the COVID‐19 pandemic grows, several therapeutic candidates are being tested or undergoing clinical trials. Although prophylactic vaccination against SARS‐CoV‐2 infection has been shown to be effective, no definitive treatment exists to date in the event of infection. The rapid spread of infection by SARS‐CoV‐2 and its variants fully warrants the continued evaluation of drug treatments for COVID‐19, especially in the context of repurposing of already available and safe drugs. Here, we explored the therapeutic potential of melatonin and melatonergic compounds in attenuating COVID‐19 pathogenesis in mice expressing human ACE2 receptor (K18‐hACE2), strongly susceptible to SARS‐CoV‐2 infection. Daily administration of melatonin, agomelatine, or ramelteon delays the occurrence of severe clinical outcome with improvement of survival, especially with high melatonin dose. Although no changes in most lung inflammatory cytokines are observed, treatment with melatonergic compounds limits the exacerbated local lung production of type I and type III interferons, which is likely associated with the observed improved symptoms in treated mice. The promising results from this preclinical study should encourage studies examining the benefits of repurposing melatonergic drugs to treat COVID‐19 and related diseases in humans.

Identification of the causative gene of a transparent phenotype of juvenile red sea bream Pagrus major.

Deformities in cultured fish species may be genetic, and identifying causative genes is essential to expand production and maintain farmed animal welfare. We previously reported a genetic deformity in juvenile red sea bream, designated a transparent phenotype. To identify its causative gene, we conducted genome-wide linkage analysis and identified two single nucleotide polymorphisms (SNP) located on LG23 directly linked to the transparent phenotype. The scaffold on which the two SNPs were located contained two candidate genes, duox and duoxa, which are related to thyroid hormone synthesis. Four missense mutations were found in duox and one in duoxa, with that in duoxa showing perfect association with the transparent phenotype. The mutation of duoxa was suggested to affect the transmembrane structure and thyroid-related traits, including an enlarged thyroid gland and immature erythrocytes, and lower thyroxine (T4) concentrations were observed in the transparent phenotype. The transparent phenotype was rescued by T4 immersion. Loss-of-function of duoxa by CRISPR-Cas9 induced the transparent phenotype in zebrafish. Evidence suggests that the transparent phenotype of juvenile red sea bream is caused by the missense mutation of duoxa and that this mutation disrupts thyroid hormone synthesis. The newly identified missense mutation will contribute to effective selective breeding of red sea bream to purge the causative gene of the undesirable phenotype and improve seed production of red sea bream as well as provide basic information of the mechanisms of thyroid hormones and its related diseases in fish and humans.

Improving Cd risk managements of rice cropping system by integrating source-soil-rice-human chain for a typical intensive industrial and agricultural region

Cadmium (Cd) accumulation in rice (Oryza sativa L.) leads to a large number of human health risks. To better understand the critical processes of Cd-related health risks and to inform mitigation policies, an assessment method was integrated by coupling source-soil-rice-human systems with anthropogenic Cd sources historical survey, regional soil Cd concentration surveyed data and an extensive literature review of Cd related human diseases. This method was subsequently applied to a rapid developing industrial and agricultural area in China. Results indicated that Cd emission sources increased fourfold from 1990 to 2007, and remained high value about 140 × 103 kg yr−1 after 2008 in the study region. The Cd fluxes in 1990–2017 varied from 3.93 to 73.49 mg m−2. Raw coal consumption contributed to approximately 50% of total Cd fluxes. During 2003–2013, the annual increasing rate of soil Cd varied from −2.34 μg kg−1yr−1 to 7.94 μg kg−1yr−1 with an average 5.14 μg kg−1yr−1. Under the current industry and agriculture developing trends, farmland soil in 2030 will face significant Cd pollution risks and the average soil Cd concentration will increase to 0.35 mg kg−1 which is 1.75 times higher than that of 2003. Consequently, higher Cd concentrations were predicted in rice grain and human blood. About 3.43% of adults may have obesity and hypertension, and approximately 4.96% of children will also be the risk of physical, cognitive neurobehavioral development. The mitigation strategies of Cd source reduction and phytoremediation technology in rice system can significantly decrease Cd-related health risks. These strategies are far less effective in already heavily polluted soils. This study provides critical information on Cd emission factors, Cd related human diseases, and a novel useful tool for policy-makers on metals pollution management.

Expression Characteristics of microRNA in Pig Umbilical Venous Blood and Umbilical Arterial Blood.

Simple SummaryUmbilical cord blood is an important biological resource for research on fetal development and treatment of related diseases. To further explore the biological functions of umbilical cord blood, we sequenced the small RNAs in porcine umbilical venous blood and umbilical arterial blood and analyzed them through two differential expression analysis methods. Through comparative analysis, it is found that highly expressed miRNAs in umbilical venous blood and umbilical artery blood perform similar functions, but there may be differences in immunity and angiogenesis. Because miRNAs are highly conserved and have the ability to transmit across species, they have great potential in the treatment of human-related diseases. Further analysis shows that cord venous blood miRNA may be helpful in the treatment of muscle-related diseases, while cord arterial blood miRNA may be beneficial in the treatment of liver- and brain-related diseases. This research helps to analyze the biological functions of cord blood miRNA and provides a reference for the development and application of porcine cord blood miRNA-related products. At the same time, it provides new insights for the further development of value-added products in the animal husbandry industry and the treatment of human diseases.As the medium of material exchange between mother and fetus, umbilical cord blood is closely connected with fetal development. microRNA (miRNA) has a wide range of biological functions and has high flow characteristics. Small RNA sequencing of pig umbilical venous blood (UVB) and umbilical arterial blood (UAB) revealed that a total of 302 miRNAs were identified, and 106 and 22 miRNAs were specifically expressed in the UVB and UAB, respectively. Using the two methods of differential expression multiple and differential expression percentage, it is found that only 35% of the highly expressed miRNAs in the UVB by the two analysis modes overlap, but 56.25% of the enriched signal pathways are the same. Only 20% of the highly expressed miRNAs in the UAB overlap, but 62.07% of the signal pathways are the same. Further analysis revealed that miR-423 can be used as a characteristic miRNA of UVB and has the potential to treat muscle-related diseases. miR-122-5p can be used as a characteristic miRNA of UAB and may help to improve liver- and brain-related diseases. In summary, these results enrich understanding of miRNA in mother–fetal communication and provide a reference for the development and application of porcine cord blood products.

Mechanism of Ligand Recognition by Human ACE2 Receptor.

Angiotensin converting enzyme 2 (ACE2) plays a key role in renin–angiotensin system regulation and amino acid homeostasis. Human ACE2 acts as the receptor for severe acute respiratory syndrome coronaviruses SARS-CoV and SARS-CoV-2. ACE2 is also widely expressed in epithelial cells of the lungs, heart, kidney, and pancreas. It is considered an important drug target for treating SARS-CoV-2 as well as pulmonary diseases, heart failure, hypertension, renal diseases, and diabetes. Despite the critical importance, the mechanism of ligand binding to the human ACE2 receptor remains unknown. Here, we have addressed this challenge through all-atom simulations using a novel ligand Gaussian accelerated molecular dynamics (LiGaMD) method. Microsecond time scale LiGaMD simulations have unprecedentedly captured multiple times of spontaneous binding and unbinding of a potent inhibitor MLN-4760 in the ACE2 receptor. With ligand far away in the unbound state, the ACE2 receptor samples distinct Open, Partially Open, Closed, and Fully Closed conformations. Upon ligand binding to the active site, conformational ensemble of the ACE2 receptor is biased toward the Closed state as observed in the X-ray experimental structure. The LiGaMD simulations thus suggest a conformational selection mechanism for ligand recognition by the highly flexible ACE2 receptor, which is expected to facilitate rational drug design targeting human ACE2 against coronaviruses and other related human diseases.

Structural feature of TRAFs, their related human diseases and therapeutic intervention.

Several studies have been conducted over the years to unravel the structural information on the receptors that bind to tumor necrosis factor receptor-associated factor (TRAF) and the driving forces for the TRAF/receptor complex. In addition, studies have also been performed to highlight the influence of TRAF malfunctioning and mutations on the development of human disease. However, a holistic study that systematically summarizes the available information and the existing clinical trends towards development of the TRAF-targeting drugs has not been conducted to date. Herein, I reviewed existing research that focused on the structural information of various receptors recognized by the different members of the TRAF family. I also reviewed studies on the different human diseases that occur due to TRAF malfunctioning or mutations as well as the clinical trials undertaken to treat TRAF-associated diseases.