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\"In 1974, a group of determined, young high-school actors started doing plays under the name of Steppenwolf Theatre Company, eventually taking residence in the basement of a church in Highland Park, a suburb of Chicago. Thus began their unlikely journey to become on of the most prominent theatre companies in the world. Steppenwolf Theatre Company has changed the face of American Theatre with its innovative approach that blends dynamic ensemble performance, honest, straightforward acting, and bold, thought-provoking stories to create compelling theatre. This is the first book to chronicle this iconic theatre company, offering an account of its early years and development, its work, and the methodologies that have made it one of the most influential ensembles in theatres today. Through extensive, in-depth interviews conducted by the author with ensemble members, this book reveals the story of Steppenwolf's miraculous rose from basement to Broadway and beyond. Interviewees include co-founder Jeff Perry, Gary Sinise, and Terry Kinney, along with a myriad of ensemble, staff, board members, and others.\" -- Page 4 of cover.

Key Points Insulin therapy has been the cornerstone of diabetes treatment for nearly a century, and numerous commercial alternatives are available to control blood glucose. Nonetheless, insulin therapy remains sub-optimal, as manifested by infrequent normalization of blood glucose and the risk of experiencing dangerously low blood glucose levels. Numerous novel insulin analogues and formulations are in development with the goal of further optimizing the time–action profile. Several once-weekly candidates that might minimize the requirement for daily injection in certain patients are currently in early clinical trials. Alternative methods to subcutaneous injection of insulin delivery should improve the convenience of treatment and should probably lead to enhanced diabetic care, especially in patients that resist using injectable therapy despite treatment failure on oral medications. Oral and inhalable insulin formulations currently represent the most promising prospects in non-injectable delivery and constitute a priority area in the refinement of insulin therapy. Substantial interest persists in the development of glucose-sensitive therapy that is responsive to real-time changes in blood glucose. Direct and indirect methods to render insulin therapy less prone to life-threatening hypoglycaemia are being aggressively pursued. Most notably, the combination of insulin and incretin therapy has delivered superior clinical results as measured by improvements in mean plasma glucose concentration (HbA 1C ), with fewer occurrences of hypoglycaemia and less body weight gain. Separately, advances in glucagon therapy move the field closer to achieving closed-loop insulin pump therapy. Advances in insulin synthesis have stimulated a renewed interest in structural analogues that enhance pharmacodynamic properties, through tissue targeting (hepatospecific), supplemental pharmacology (insulin sensitizers) or selective action only in hyperglycaemia. Given the seminal importance of insulin as a drug we anticipate the continued pursuit of perfect insulin. Normalization of glucose control without the risk of hypoglycaemia and delivery in a patient-friendly form remain the central objectives. Insulin continues to represent a cornerstone therapy for diabetes, but its use is limited by its narrow therapeutic index. Here, DiMarchi and colleagues provide an overview of the history of the development and use of insulin as an antidiabetic agent, focusing on recent approaches to improve the efficacy, safety and convenience of insulin therapy. Insulin remains indispensable in the treatment of diabetes, but its use is hampered by its narrow therapeutic index. Although advances in peptide chemistry and recombinant DNA-based macromolecule synthesis have enabled the synthesis of structurally optimized insulin analogues, the growing epidemics of obesity and diabetes have emphasized the need for diabetes therapies that are more efficacious, safe and convenient. Accordingly, a broad set of drug candidates, targeting hyperglycaemia plus other disease abnormalities, is now progressing through the clinic. The development of an insulin therapy that is responsive to glucose concentration remains an ultimate goal, with initial prototypes now reaching the proof-of-concept stage. Simultaneously, the first alternatives to injectable delivery have progressed to registration.

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.

In 1896 the Great Brain of Adenville, Utah, is almost twelve years old and more mischievous than ever in his practical jokes and schemes against everyone in town.

Key Points Ubiquitin is a highly conserved 76 amino-acid protein that covalently attaches to protein substrates targeted for degradation by the 26S proteasome. The coordinated effort of a series of enzymes, including an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3), uses ATP to ultimately form an isopeptide bond between ubiquitin and a substrate. Another class of enzymes called deubiquitylating enzymes (DUBs) deconstruct these linkages and also have an essential role in ubiquitin function. In addition, ubiquitin-like proteins (UBLs), including NEDD8, SUMO and ISG15, share a characteristic three-dimensional fold with ubiquitin but have their own dedicated enzyme cascades and distinct (although sometimes overlapping) biological functions. The ubiquitin–proteasome system (UPS) and UBL conjugation pathways have important roles in various human diseases, including numerous types of cancer, cardiovascular disease, viral diseases and neurodegenerative disorders. The proteasome inhibitor bortezomib (Velcade; Millennium Pharmaceuticals) is the first clinically validated drug to target the UPS and is approved for the treatment of multiple myeloma. This suggests that other diseases may conceivably be targeted by modulating components of the UPS and UBL conjugation pathways using small-molecule inhibitors. A significant hurdle to identifying drug-like inhibitors of enzyme targets within the UPS and UBL conjugation pathways is the limited understanding of the molecular mechanisms and biological consequences of UBL conjugation. Here, we provide an overview of the enzyme classes in the UPS and UBL pathways that are potential therapeutic targets, and highlight considerations that are important for drug discovery. We also discuss the progress in the development of small-molecule inhibitors, and review developments in understanding of the role of the components of the UPS and the UBL pathways in disease and their potential for therapeutic intervention. The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis, and their functional importance in various diseases, including cancer, cardiovascular disease and neurodegenerative disorders, is now beginning to emerge. Brownell and colleagues review developments in understanding of the role of the components of the UPS and the UBL pathways in disease and their potential for therapeutic intervention. The ubiquitin–proteasome system (UPS) and ubiquitin-like protein (UBL) conjugation pathways are integral to cellular protein homeostasis. The growing recognition of the fundamental importance of these pathways to normal cell function and in disease has prompted an in-depth search for small-molecule inhibitors that selectively block the function of these pathways. However, our limited understanding of the molecular mechanisms and biological consequences of UBL conjugation is a significant hurdle to identifying drug-like inhibitors of enzyme targets within these pathways. Here, we highlight recent advances in understanding the role of some of these enzymes and how these new insights may be the key to developing novel therapeutics for diseases including immuno-inflammatory disorders, cancer, infectious diseases, cardiovascular disease and neurodegenerative disorders.

The exploits of the Great Brain of Adenville, Utah are described by his younger brother, frequently the victim of the Great Brain's schemes for gaining prestige or money.

Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ -shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ -shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation. Through structural and functional analyses, this work defines the molecular mechanisms underlying the activation of the insulin receptor (IR) involving multisite insulin binding, paving the way for the eventual therapeutic intervention for diseases caused by aberrant activation of IR.

هذا الكتاب الحيوي يوضح بجلاء أهمية الشخصية والأحكام التي يصدرها أحدنا على الآخر، يستعرض مؤلف الكتاب جون دي ماير مجموعة واسعة من الأبحاث الكلاسيكية والحديثة جنبا إلى جنب، مع بعض القصص الشخصية الممتعة لتقديم حجة مقنعة لدعم نظريته المبتكرة عن الذكاء الشخصي، حيث يأخذنا في رحلة شاملة عبر نظريته وعلى طول الطريق يظهر مدى أهمية الذكاء الشخصي في فهم أنفسنا إلى جانب الإبحار في عالمنا الاجتماعي، إن فهم الآخرين مهارة أساسية ويبين لنا كتاب الذكاء الشخصي كيف نستخدمها ومتى نستخدمها وسبب أهميتها.

Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin’s action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases. Genetic mutations of insulin receptor (IR) cause severe insulin resistance syndromes with no current treatment or cure. Here, the authors present that insulin-independent IR activation mechanism by peptide agonist which activate non-functional IR mutants that cause the insulin resistance syndromes.