Project description:Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1 triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.
Project description:As voice-user interfaces (VUIs), such as smart speakers like Amazon Alexa or social robots like Jibo, enter multi-user environments like our homes, it is critical to understand how group members perceive and interact with these devices. VUIs engage socially with users, leveraging multi-modal cues including speech, graphics, expressive sounds, and movement. The combination of these cues can affect how users perceive and interact with these devices. Through a set of three elicitation studies, we explore family interactions (N = 34 families, 92 participants, ages 4-69) with three commercially available VUIs with varying levels of social embodiment. The motivation for these three studies began when researchers noticed that families interacted differently with three agents when familiarizing themselves with the agents and, therefore, we sought to further investigate this trend in three subsequent studies designed as a conceptional replication study. Each study included three activities to examine participants' interactions with and perceptions of the three VUIS in each study, including an agent exploration activity, perceived personality activity, and user experience ranking activity. Consistent for each study, participants interacted significantly more with an agent with a higher degree of social embodiment, i.e., a social robot such as Jibo, and perceived the agent as more trustworthy, having higher emotional engagement, and having higher companionship. There were some nuances in interaction and perception with different brands and types of smart speakers, i.e., Google Home versus Amazon Echo, or Amazon Show versus Amazon Echo Spot between the studies. In the last study, a behavioral analysis was conducted to investigate interactions between family members and with the VUIs, revealing that participants interacted more with the social robot and interacted more with their family members around the interactions with the social robot. This paper explores these findings and elaborates upon how these findings can direct future VUI development for group settings, especially in familial settings.
Project description:Hypertriglyceridemia (HTG) is commonly encountered in lipid and cardiology clinics. Severe HTG warrants treatment because of the associated increased risk of acute pancreatitis. However, the need to treat, and the correct treatment approach for patients with mild to moderate HTG are issues for ongoing evaluation. In the past, it was felt that triglyceride does not directly contribute to development of atherosclerotic plaques. However, this view is evolving, especially for triglyceride-related fractions and variables measured in the non-fasting state. Our understanding of the etiology, genetics and classification of HTG states is also evolving. Previously, HTG was considered to be a dominant disorder associated with variation within a single gene. The old nomenclature includes the term "familial" in the names of several hyperlipoproteinemia (HLP) phenotypes that included HTG as part of their profile, including combined hyperlipidemia (HLP type 2B), dysbetalipoproteinemia (HLP type 3), simple HTG (HLP type 4) and mixed hyperlipidemia (HLP type 5). This old thinking has given way to the idea that genetic susceptibility to HTG results from cumulative effects of multiple genetic variants acting in concert. HTG most is often a "polygenic" or "multigenic" trait. However, a few rare autosomal recessive forms of severe HTG have been defined. Treatment depends on the overall clinical context, including severity of HTG, concomitant presence of other lipid disturbances, and the patient's global risk of cardiovascular disease. Therapeutic strategies include dietary counselling, lifestyle management, control of secondary factors, use of omega-3 preparations and selective use of pharmaceutical agents.
Project description:The current understanding of what infants see varies greatly among healthcare and education specialists. Even among ophthalmologists and pediatric neurologists in charge of clinical examinations of infants, opinions vary on what infants perceive, recognize, and use for communication and learning. It is, therefore, of interest to review publications from several specialties to learn whether new information is available on the development of visual functions and use of vision. Ten percent of total publications on this subject are reviewed here based on the usefulness of their content for improving early diagnosis and intervention of vision disorders in infants.
Project description:Primary biliary cholangitis (PBC) causes chronic and persistent cholestasis in the liver, eventually resulting in cirrhosis and hepatic failure without appropriate treatment. PBC mainly develops in middle-aged women, but it is also common in young women and men. PBC is considered a model of autoimmune disease because of the presence of diseasespecific autoantibodies, that is, antimitochondrial antibodies (AMAs), intense infiltration of mononuclear cells into the bile ducts, and a high prevalence of autoimmune diseases such as comorbidities. Histologically, PBC is characterized by degeneration and necrosis of intrahepatic biliary epithelial cells surrounded by a dense infiltration of mononuclear cells, coined as chronic non-suppurative destructive cholangitis, which leads to destructive changes and the disappearance of small- or medium-sized bile ducts. Since 1990, early diagnosis with the detection of AMAs and introduction of ursodeoxycholic acid as first-line treatment has greatly altered the clinical course of PBC, and liver transplantation-free survival of patients with PBC is now comparable to that of the general population.
Project description:The gut microbiome is widely accepted to have a significant impact on human health yet, despite years of research on this complex ecosystem, the contributions of different forces driving microbial population structure remain to be fully elucidated. The viral component of the human gut microbiome is dominated by bacteriophage, which are known to play crucial roles in shaping microbial composition, driving bacterial diversity, and facilitating horizontal gene transfer. Bacteriophage are also one of the most poorly understood components of the human gut microbiome, with the vast majority of viral sequences sharing little to no homology to reference databases. If we are to understand the dynamics of bacteriophage populations, their interaction with the human microbiome and ultimately their influence on human health, we will depend heavily on sequence based approaches and in silico tools. This is complicated by the fact that, as with any research field in its infancy, methods of analyses vary and this can impede our ability to compare the outputs of different studies. Here, we discuss the major findings to date regarding the human virome and reflect on our current understanding of how gut bacteriophage shape the microbiome. We consider whether or not the virome field is built on unstable foundations and if so, how can we provide a solid basis for future experimentation. The virome is a challenging yet crucial piece of the human microbiome puzzle. In order to develop our understanding, we will discuss the need to underpin future studies with robust research methods and suggest some solutions to existing challenges.
Project description:Gliomatosis cerebri (GC) is a rare, extensively infiltrating glioma involving multiple contiguous lobes of the brain. This lethal disease affects all age groups, and the majority of patients have a poor outcome despite aggressive treatment. Despite its initial recognition in 1938, GC remains a controversial entity with little consensus in its definition, histology, or treatment. The majority of GC tumors are astrocytic, although mixed phenotypes have been identified. Treatment of GC is challenging as surgery is generally not an option due to the extensive areas of brain involved, the benefit of radiation therapy is unclear, and no chemotherapy has proven efficacy. Due to the rarity of the disease and its heterogeneity, both at histopathological and molecular levels, it is difficult to conduct clinical trials tailored for this diagnosis. This review summarizes our current knowledge, examines clinical studies focusing on the treatment of GC, highlights ongoing challenges, and discusses the recent molecular insights into adult and pediatric GC. We conclude that, although no longer recognized as a distinct pathological entity, GC represents a unique disease phenotype. Given the histologic and molecular overlap with other diffuse gliomas, the research emphasis should be on investigating its unique invasive biology.
Project description:In the past, most scientists conducted their inquiries of nature via inductivism, the patient accumulation of "pieces of information" in the pious hope that the sum of the parts would clarify the whole. Increasingly, modern biology employs the tools of bioinformatics and systems biology in attempts to reveal the "big picture." Most successful laboratories engaged in the pursuit of the secrets of embryonic development, particularly those whose research focus is craniofacial development, pursue a middle road where research efforts embrace, rather than abandon, what some have called the "pedestrian" qualities of inductivism, while increasingly employing modern data mining technologies. The secondary palate has provided an excellent paradigm that has enabled examination of a wide variety of developmental processes. Examination of cellular signal transduction, as it directs embryogenesis, has proven exceptionally revealing with regard to clarification of the "facts" of palatal ontogeny-at least the facts as we currently understand them. Herein, we review the most basic fundamentals of orofacial embryology and discuss how functioning of TGFbeta, BMP, Shh, and Wnt signal transduction pathways contributes to palatal morphogenesis. Our current understanding of palate medial edge epithelial differentiation is also examined. We conclude with a discussion of how the rapidly expanding field of epigenetics, particularly regulation of gene expression by miRNAs and DNA methylation, is critical to control of cell and tissue differentiation, and how examination of these epigenetic processes has already begun to provide a better understanding of, and greater appreciation for, the complexities of palatal morphogenesis.
Project description:Asthma is a heterogeneous lung disease with variable phenotypes (clinical presentations) and distinctive endotypes (mechanisms). Over the last decade, considerable efforts have been made to dissect the cellular and molecular mechanisms of asthma. Aberrant T helper type 2 (Th2) inflammation is the most important pathological process for asthma, which is mediated by Th2 cytokines, such as interleukin (IL)-5, IL-4, and IL-13. Approximately 50% of mild-to-moderate asthma and a large portion of severe asthma is induced by Th2-dependent inflammation. Th2-low asthma can be mediated by non-Th2 cytokines, including IL-17 and tumor necrosis factor-α. There is emerging evidence to demonstrate that inflammation-independent processes also contribute to asthma pathogenesis. Protein kinases, adapter protein, microRNAs, ORMDL3, and gasdermin B are newly identified molecules that drive asthma progression, independent of inflammation. Eosinophils, IgE, fractional exhaled nitric oxide, and periostin are practical biomarkers for Th2-high asthma. Sputum neutrophils are easily used to diagnose Th2-low asthma. Despite progress, more studies are needed to delineate complex endotypes of asthma and to identify new and practical biomarkers for better diagnosis, classification, and treatment.
Project description:Chordoma is a low-grade notochordal tumor of the skull base, mobile spine and sacrum which behaves malignantly and confers a poor prognosis despite indolent growth patterns. These tumors often present late in the disease course, tend to encapsulate adjacent neurovascular anatomy, seed resection cavities, recur locally and respond poorly to radiotherapy and conventional chemotherapy, all of which make chordomas challenging to treat. Extent of surgical resection and adequacy of surgical margins are the most important prognostic factors and thus patients with chordoma should be cared for by a highly experienced, multi-disciplinary surgical team in a quaternary center. Ongoing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (e.g., platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (e.g., phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury-a transcription factor expressed ubiquitously in chordoma but not in other tissues-and the fibroblast growth factor [FGF]/mitogen-activated protein kinase kinase [MEK]/extracellular signal-regulated kinase [ERK] pathway. In this review article, the pathophysiology, diagnosis and modern treatment paradigms of chordoma will be discussed with an emphasis on the ongoing research and advances in the field that may lead to improved outcomes for patients with this challenging disease.