Academic literature on the topic 'N-end rule like pathway'

We saw in the previous chapter how Otto Wallach’s early proposal regarding the structural origin of terpenoid natural products was later refined by the insightful work of Leopold Rudzicka, leading to the biogenetic isoprene rule and all that it implies. In a nearly parallel fashion, we find in our present chapter a second, unrelated class of naturally occurring compounds whose characteristic structural features prompted an initial innovative hypothesis by J. N. Collie near the turn of the 20th century. Collie proposed that certain natural compounds might arise from precursors containing repeated “ketide” (–CH2CO–) units which could then undergo subsequent condensations and other reactions typical of carbonyl compounds to produce some of the observed structures. Unfortunately, Collie’s work was more or less ignored and largely forgotten for nearly a half century, only to be reimagined and expanded in the middle of the century by A. J. Birch, another pioneer whose proposals met with considerable initial resistance. But unlike his predecessor, Birch ultimately prevailed by providing experimental results that supported a comprehensive theory of the biochemical origin of the group of compounds now universally known as “polyketide” natural products. This structurally diverse family includes some of the most useful medicinal agents now known to us, with many members possessing powerful antibacterial, antifungal, anticancer, immunosuppressant, and even cholesterol-lowering biological properties. As we see in Fig. 5.1, such structures range from the relatively simple to the exceedingly complex and may include large macrocyclic lactone rings (macrolides) such as erythromycin, polycyclic ethers such as monensin A, polycyclic structures which may be partly or mostly aromatic as in tetracycline, griseofulvin, or daunorubicin, or nonaromatic polycyclics such as tacrolimus and lovastatin. Some also contain noncyclic linear components that may be saturated, oxygenated, or unsaturated, as seen in different regions of amphotericin B which, like erythromycin, daunorubicin, and many other polyketides, also possesses an aglycone core which has been glycosylated with a carbohydrate component at a specific position. But in spite of this range of structures, many polyketide compounds share some common features that ultimately become more evident upon closer inspection; six-membered rings (either aromatic or nonaromatic) and multiple oxygens which tend to appear in a repeating 1,3-relationship to one another on both acyclic, cyclic, and aromatic structures.

Palliative care (PC) is holistic care that encompasses prevention, assessment, and treatment of symptoms, and addresses the psychological, social, and spiritual problems of ill people and their relatives with the goal of improving quality of life and, finally, dying. It is not an alternative but a supplement to curative treatment, making symptom alleviation and quality of life equally important goals for management and care as healing along the whole disease trajectory. The SENSE model describes elements of PC: Symptom management, dEcision-making, Networking, Support, and End-of-life care. People with heart disease, particularly those with advanced heart failure (HF), benefit from PC care. Pain, breathlessness, tiredness, depression, anxiety, and dry mouth are frequent symptoms among people with HF and could be effectively alleviated with PC. Many of these symptoms, almost constantly present in HF patients, are usually not specifically targeted by medical interventions. Preparedness for anticipatory death improves quality of life during dying for patients and their relatives, and improves satisfaction with care. The greatest challenge still lies in recognizing unmet PC needs and involving a PC team appropriately early, not simply in the very last hours of life. A number of specific issues, such as the modification of implantable cardioverter defibrillator activity or withdrawal of ventricular assist device support, can be addressed by preparing advance directives leading to protecting patients from unwished, usually futile, therapies when they become imminently dying and/or incompetent for decision-making. PC also gives support to cardiology teams in difficult communications on end-of-life issues. Modern PC manages or prevents suffering in people with advanced diseases, independent of diagnosis and prognosis and care for their relatives. It can be provided additionally to disease-specific management as a parallel care, or sometimes as the main care pathway in people close to death as end-of-life care. Parallel PC care should be needs driven; end-of-life care can additionally be prognosis driven. In the majority of cardiological patients PC can/should be delivered by the cardio team that has been treating the person to date and who applies the general PC rules (symptom and distress assessment and management). The PC specialist should ensure consultations in case of difficult/resistant problems, and take the lead in treatment only rarely, if needed. PC acknowledges four dimensions influencing a person’s quality of life: physical, psychological/emotional, spiritual, and social. Each of them needs to be addressed effectively which may require the involvement of a multidisciplinary team. A PC team can provide important support to the treatment team in analysing/solving complex management-related ethical issues.

Fatigue is a phenomenon, which needs to be considered in the present day’s vessel design. The welded joints are particularly affected by the fatigue damage due to high stress concentrations caused by the metallurgical discontinuities present in the weld. For oil tankers and bulk carriers adequate guidelines for the fatigue strength assessment have been established by the classification societies. But for navy vessel, like offshore patrol vessel, the design guidelines for the fatigue strength analysis are not widely available. In the present paper, an attempt has been made to calculate the fati