Faculty reviews最新文献

In order to survive and thrive, organisms must adapt to constantly changing environmental pressures. When there are significant shifts in the environment, the brain and body engage a set of physiological and behavioral countermeasures collectively known as the "stress response". These responses, which include changes at the cellular, systems, and organismal level, are geared toward protecting homeostasis and adapting physiological operating parameters so as to enable the organism to overcome short-term challenges. It is the shift of these well-organized acute responses to dysregulated chronic responses that leads to pathologies. In a sense, the protective measures become destructive, causing the myriad health problems that are associated with chronic stress. To further complicate the situation, these challenges need not be purely physical in nature. Indeed, psychosocial stressors such as ruminating about challenges at work, resource insecurity, and unstable social environments can engage the very same emergency threat systems and eventually lead to the same types of pathologies that sometimes are described as "burnout" in humans. This short review focuses on very recent empirical work exploring the effects of chronic stress on key brain circuits, metabolism and metabolic function, and immune function.

Despite recent advances in the treatment of chronic heart failure, therapeutic options for acute heart failure (AHF) remain limited. AHF admissions are associated with significant multi-organ dysfunction, especially worsening renal failure, which results in significant morbidity and mortality. There are several aspects of AHF management: diagnosis, decongestion, vasoactive therapy, goal-directed medical therapy initiation and safe transition of care. Effective diagnosis and prognostication could be very helpful in an acute setting and rely upon biomarker evaluation with noninvasive assessment of fluid status. Decongestive strategies could be tailored to include pharmaceutical options along with consideration of utilizing ultrafiltration for refractory hypervolemia. Vasoactive agents to augment cardiac function have been evaluated in patients with AHF but have shown to only have limited efficacy. Post stabilization, initiation of quadruple goal-directed medical therapy-angiotensin receptor-neprilysin inhibitors, mineral receptor antagonists, sodium glucose type 2 (SGLT-2) inhibitors, and beta blockers-to prevent myocardial remodeling is being advocated as a standard of care. Safe transition of care is needed prior to discharge to prevent heart failure rehospitalization and mortality. Post-discharge close ambulatory monitoring (including remote hemodynamic monitoring), virtual visits, and rehabilitation are some of the strategies to consider. We hereby review the contemporary approach in AHF diagnosis and management.

The worldwide health-care burden of neurodegenerative diseases is on the rise-a crisis created through a combination of increased caseload and lack of effective treatments. The limitations of pharmacotherapy in these disorders have led to an urgent shift toward research and clinical trials for the development of novel compounds, interventions, and methods that target shared features across the spectrum of neurodegenerative diseases. Research targets include neuronal cell death, mitochondrial dysfunction, protein aggregation, and neuroinflammation. In the past few years, there has been a growth in understanding of the pathophysiologic mechanisms of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and Huntington's disease. This increase in knowledge has led to the discovery of numerous novel neuroprotective therapeutic targets. In this context, we reviewed and summarized recent advancements in neuroprotective strategies in neurodegenerative diseases.

Tumorigenesis has long been linked to the evasion of the immune system and the uncontrolled proliferation of transformed cells. The complement system, a major arm of innate immunity, is a key factor in the progression of cancer because many of its components have critical regulatory roles in the tumor microenvironment. For example, complement anaphylatoxins directly and indirectly inhibit antitumor T-cell responses in primary and metastatic sites, enhance proliferation of tumor cells, and promote metastasis and tumor angiogenesis. Many recent studies have provided evidence that cancer is able to hijack the immunoregulatory components of the complement system which fundamentally are tasked with protecting the body against abnormal cells and pathogens. Indeed, recent evidence shows that many types of cancer use C1q receptors (C1qRs) to promote tumor growth and progression. More importantly, most cancer cells express both C1q and its major receptors (gC1qR and cC1qR) on their surface which are essential for cell proliferation and survival. In this review, we discuss the ability of cancer to control and manipulate the complement system in the tumor microenvironment and identify possible therapeutic targets, including C1q and gC1qR.

Although much is known about the machinery that executes fundamental processes of gene expression in cells, much also remains to be learned about how that machinery works. A recent paper by O'Reilly et al. reports a major step forward in the direct visualization of central dogma processes at submolecular resolution inside bacterial cells frozen in a native state. The essential methodologies involved are cross-linking mass spectrometry (CLMS) and cryo-electron tomography (cryo-ET). In-cell CLMS provides in vivo protein interaction maps. Cryo-ET allows visualization of macromolecular complexes in their native environment. These methods have been integrated by O'Reilly et al. to describe a dynamic assembly in situ between a transcribing RNA polymerase (RNAP) and a translating ribosome - a complex known as the expressome - in the model bacterium Mycoplasma pneumoniae ¹. With the application of improved data processing and classification capabilities, this approach has allowed unprecedented insights into the architecture of this molecular assembly line, confirming the existence of a physical link between RNAP and the ribosome and identifying the transcription factor NusA as the linking molecule, as well as making it possible to see the structural effects of drugs that inhibit either transcription or translation. The work provides a glimpse into the future of integrative structural cell biology and can serve as a roadmap for the study of other molecular machineries in their native context.

Osteoarthritis (OA) is a chronic musculoskeletal disease with a polygenic and heterogeneous nature. In addition, when clinical manifestations appear, the evolution of the disease is usually already irreversible. Therefore, the efforts on OA research are focused mainly on the discovery of therapeutic targets and reliable biomarkers that permit the early identification of different OA-related parameters such as diagnosis, prognosis, or phenotype identification. To date, potential candidate protein biomarkers have been associated with different aspects of the disease; however, there is currently no gold standard. In this sense, genomic data could act as complementary biomarkers of diagnosis and prognosis or even help to identify therapeutic targets of the disease. In this review, we will describe the most recent advances in genetic biomarkers in OA over the past three years.

Huntington's disease (HD) is a neurodegenerative disease that results in motor and cognitive dysfunction, leading to early death. HD is caused by an expansion of CAG repeats in the huntingtin gene (HTT). Here, we review the mouse models of HD. They have been used extensively to better understand the molecular and cellular basis of disease pathogenesis as well as to provide non-human subjects to test the efficacy of potential therapeutics. The first and best-studied in vivo rodent model of HD is the R6/2 mouse, in which a transgene containing the promoter and exon 1 fragment of human HTT with 150 CAG repeats was inserted into the mouse genome. R6/2 mice express rapid, robust behavioral pathologies and display a number of degenerative abnormalities in neuronal populations most vulnerable in HD. The first conditional full-length mutant huntingtin (mHTT) mouse model of HD was the bacterial artificial chromosome (BAC) transgenic mouse model of HD (BACHD), which expresses human full-length mHTT with a mixture of 97 CAG-CAA repeats under the control of endogenous HTT regulatory machinery. It has been useful in identifying the role of mHTT in specific neuronal populations in degenerative processes. In the knock-in (KI) model of HD, the expanded human CAG repeats and human exon 1 are inserted into the mouse Htt locus, so a chimera of the full-length mouse protein with the N-terminal human portion is expressed. Many of aspects of the pathology and behavioral deficits in the KI model better mimic disease characteristics found in HD patients than other models. Accordingly, some have proposed that these mice may be preferable models of the disease over others. Indeed, as our understanding of HD advances, so will the design of animal models to test and develop HD therapies.

At present, there are no US Food and Drug Administration-approved treatments for cocaine use disorders. One consideration for this lack of treatment efficacy stems from the appropriate use of animal models. The premise of this commentary is that social behavior needs to be incorporated in animal models of cocaine use disorder. The goal of this commentary is to describe some of the strengths and limitations of recent preclinical animal models of cocaine abuse which have incorporated social behavior. There are many ways to include social variables into preclinical research, and the study design will depend on the questions asked. Four general types of studies incorporating social factors are described: those involving aggression (that is, maternal neglect and social defeat), modeling, social reward, and social housing, including social isolation. The inclusion of social variables into preclinical research will help identify biobehavioral markers that may lead to an individualized treatment approach that more effectively decreases cocaine use. These studies will aid in the development of novel pharmacotherapies as well as non-pharmacological interventions (for example, punishment, alternative reinforcers, and environmental enrichment) that would be critical for informing policy decisions.

Over the past 20 years, Nipah virus (NiV) has emerged as a significant, highly pathogenic bat-borne paramyxovirus causing severe respiratory disease and encephalitis in humans, and human-to-human transmission has been demonstrated in multiple outbreaks. In addition to causing serious illness in humans, NiV is a zoonotic pathogen capable of infecting a wide range of other mammalian species, including pigs and horses. While NiV has caused less than 700 human cases since its discovery in 1998/1999, the involvement of intermediate agricultural hosts can result in significant economic consequences. Owing to the severity of disease, capacity for human-to-human transmission, zoonotic potential, and lack of available approved therapeutic treatment options, NiV has been listed by the World Health Organization in their Blueprint list of priority pathogens as one of the eight most dangerous pathogens to monitor and prepare countermeasures to prevent a pandemic. Here, we discuss progress towards the development of therapeutic measures for the treatment of NiV infection and disease.

Supergenes are regions of suppressed recombination that may span hundreds of genes and can control variation in key ecological phenotypes. Since genetic analysis is made impossible by the absence of recombination between genes, it has been difficult to establish how individual genes within these regions contribute to supergene-controlled phenotypes. The white-throated sparrow is a classic example in which a supergene controls behavioral differences as well as distinct coloration that determines mate choice. A landmark study now demonstrates that differences between supergene variants in the promoter sequences of a hormone receptor gene change its expression and control changes in behavior. To unambiguously establish the link between genotype and phenotype, the authors used antisense oligonucleotides to alter the level of gene expression in a focal brain region targeted through a cannula. The study showcases a powerful approach to the functional genomic manipulation of a wild vertebrate species.