Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.

Amyloid oligomers: A joint experimental/computational perspective on Alzheimer's disease, Parkinson's disease, type II diabetes, and amyotrophic lateral sclerosis

On cervical spondylotic myelopathy

Hereditary Spastic Paraplegia

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure. Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport. Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1. In motor neurons, this can disrupt transport of mitochondria to areas of metabolic need, resulting in damage to cells and can elicit a neuroinflammatory response leading to further neuronal damage. Recently, eight independent human genetics studies have uncovered a link between TANK-binding kinase 1 (TBK1) mutations and ALS. TBK1 belongs to the IKK-kinase family of kinases that are involved in innate immunity signaling pathways; specifically, TBK1 is an inducer of type-1 interferons. TBK1 also has a major role in autophagy and mitophagy, chiefly the phosphorylation of autophagy adaptors. Several other ALS genes are also involved in autophagy, including p62 and OPTN. TBK1 is required for efficient cargo recruitment in autophagy; mutations in TBK1 may result in impaired autophagy and contribute to the accumulation of protein aggregates and ALS pathology. In this review, we focus on the role of TBK1 in autophagy and the contributions of this process to the pathophysiology of ALS.

/pdf/tbk1-a-new-player-in-als-linking-autophagy-and-43o7mjk89z.pdf

TBK1: a new player in ALS linking autophagy and neuroinflammation

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons comprising the corticospinal tract and lower motor neurons arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement. In this review, we focus on the key cellular players of neuroinflammation during the pathogenesis of ALS by discussing not only their detrimental roles but also their immunomodulatory actions. We will summarize the pharmacological therapies for ALS that target neuroinflammation, as well as recent advances in the field of stem cell therapy aimed at modulating the inflammatory environment to preserve the remaining motor neurons in ALS patients and animal models of the disease.

/pdf/role-of-neuroinflammation-in-amyotrophic-lateral-sclerosis-59jys9m7r4.pdf

Role of Neuroinflammation in Amyotrophic Lateral Sclerosis: Cellular Mechanisms and Therapeutic Implications

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease affecting motor neurons with an incidence of about 1/100,000. Most ALS cases are sporadic, but 5-10% of the cases are familial ALS. Both sporadic and familial ALS (FALS) are associated with degeneration of cortical and spinal motor neurons. The etiology of ALS remains unknown. However, mutations of superoxide dismutase 1 have been known as the most common cause of FALS. In this study, we provide a comprehensive review of ALS. We cover all aspects of the disease including epidemiology, comorbidities, environmental risk factor, molecular mechanism, genetic factors, symptoms, diagnostic, treatment, and even the available supplement and management of ALS. This will provide the reader with an advantage of receiving a broad range of information about the disease.

A comprehensive review of amyotrophic lateral sclerosis.

Revisiting the utility of technical performance scores following tetralogy of Fallot repair

Zoografting-A History of Xenografts in Burn Treatment and Care.

Biliary diseases such as cholelithiasis, choledocholithiasis, and cholecystitis all rely on imaging modalities to help make diagnoses. In modern times, ultrasound, computer tomography, and nuclear medicine scans help precisely visualize biliary and hepatic anatomy and pathology. The predecessor of these imaging modalities was the cholecystogram. This involved administration of contrast media that reliably had hepatic uptake and biliary excretion without causing significant side effects followed by radiograms of the abdomen. In the 1950s, iopanoic acid, known as telepaque, was a novel oral contrast, developed and clinical trialed for the use in diagnosing biliary pathology. A small, off-white colored powder available in a pill form, telepaque was readily available, conveniently administered by physicians at the bedside and produced beautiful cholangiograms within hours of administration. This paper briefly discusses the advent, physiology, and use of this novel compound that helped surgeons for many decades.

Diagnostics in a Surgeon's Pocket-The History of Telepaque and Oral Cholecystograms.

Vascular catheterization procedures are performed on millions of patients in the United States annually. Diagnostic and therapeutic, these procedures allow for the detection and treatment of diseased vessels. The use of catheters, however, is no new phenomenon. Ancient Egyptians, Greeks, and Romans constructed tubes from hollow reeds and palm leaves to be tunneled through the vasculature of cadavers to study cardiovascular system function, while eighteenth century English physiologist Stephen Hales used a brass pipe cannula to perform the first central vein catheterization on a horse. In 1963, American surgeon Thomas Fogarty developed a balloon embolectomy catheter, while in 1974, German cardiologist Andreas Grüntzig developed a more refined angioplasty catheter using polyvinyl chloride with improved rigidity. Vascular catheter material has since continued to evolve and is tailored to the specific needs of the procedure but would not have been possible without its rich and diverse history of development.

Daud Lodin

Papers

A comprehensive review of amyotrophic lateral sclerosis.

Revisiting the utility of technical performance scores following tetralogy of Fallot repair

Zoografting-A History of Xenografts in Burn Treatment and Care.

Diagnostics in a Surgeon's Pocket-The History of Telepaque and Oral Cholecystograms.

From Palm Leaves to Thermoplastic Polyurethanes-The History of Vascular Catheter Development and Use.