Circular RNAs (circRNAs) are unique transcript isoforms characterized by back splicing of exon ends to form a covalently closed loop or circular conformation. These transcript isoforms are now known to be expressed in a variety of organisms across the kingdoms of life. Recent studies have shown the role of circRNAs in a number of diseases and increasing evidence points to their potential application as biomarkers in these diseases. We have created a comprehensive manually curated database of circular RNAs associated with diseases. This database is available at URL The Database lists more than 1300 circRNAs associated with 150 diseases and mapping to 113 International Statistical Classification of Diseases (ICD) codes with evidence of association linked to published literature. The database is unique in many ways. Firstly, it provides ready-to-use primers to work with, in order to use circRNAs as biomarkers or to perform functional studies. It additionally lists the assay and PCR primer details including experimentally validated ones as a ready reference to researchers along with fold change and statistical significance. It also provides standard disease nomenclature as per the ICD codes. To the best of our knowledge, circad is the most comprehensive and updated database of disease associated circular RNAs.
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Like any other software, the Windows operating system keeps getting updated to new versions. And while the transitions maintain program compatibility during direct upgrades, things start getting murkier across multiple versions.
In the early 1970s, the neural structure responsible for synchronizing circadian rhythms in mammals was localized to the suprachiasmatic nucleus (SCN), a small structure located in the brain's hypothalamus. This structure was first identified in studies in which the SCN was lesioned. SCN lesions, resulted in behavior that no longer occurred at regular, near-24-hour intervals but instead was arrhythmic. After the SCN was identified, additional studies in which the electrical activity of the SCN was recorded revealed that part of the brain has a 24-hour cyclicity in electrical activity. A series of elegant studiesin which the SCN from mutant animals was transplanted into SCN-lesioned wild-type animals, and vice versa, resulted in the host animals exhibiting the circadian characteristics of the donor animals, further evidence of the role of the SCN as the circadian pacemaker. Since that time, further studies have demonstrated that the near-24-hour pattern of electrical activity is a property of individual SCN neurons.
The primary source of environmental information to this internal pacemaker is the light-dark cycle, which is transmitted along a mono-synaptic pathway (the retinohypothalamic tract, or RHT) from the retina to the SCN. There are other, non-photic, rhythmic factors from the environment that have been shown to provide information to the circadian pacemaker in some species, including cycles in environmental temperature or food availability. Rhythmic alterations in behavior can also provide timing information to the circadian system in certain situations.
Circadian rhythms are endogenously generated, and not simply a reflection of daily changes in light and darkness, ambient temperature, or patterns of rest and activity. As such, circadian rhythms continue to be expressed when the organism is studied in constant conditions, although the exact period (cycle length) of the rhythm is usually no longer precisely 24 hours, but instead is slightly shorter or longer than 24 hours. The actual cycle length of a circadian rhythm when studied under constant environmental conditions is termed the free-running period. Under normal conditions, these non-24-hour rhythms are synchronized to the 24-hour day by periodic exposure to signals from the environment, a process called entrainment. For most mammals, regular exposure to the light-dark (LD) cycle entrains the circadian timing system to the 24-hour solar day. In order to maintain entrainment, an organism with a slightly shorter than 24-hour circadian period must have its circadian system reset slightly later each day, while an organism with a longer than 24-hour period must have its circadian system reset earlier each day.
The time of a particular event within the circadian cycle is referred to as the phase of that event. For example, the nadir of the endogenous circadian rhythm of core body temperature is often used as a circadian phase marker. The time at which the core body temperature phase occurs can then be compared with respect to the timing of the sleep-wake cycle, can be compared between individuals, or can be compared before and after an intervention. Thus, the term phase refers to a reference point within the near-24-hour rhythm.
Another key feature of the circadian timing system is that it typically has a phase-dependent response to many types of stimuli. This means that the time within the circadian cycle that a stimulus is applied will affect the magnitude and direction of the response to that stimulus. For example, the resetting response of the circadian system of most organisms to light is phase-dependent. A light stimulus applied in the early night will cause a phase delay shift of the animal's circadian rhythms (the timing will be shifted to a later hour), a light stimulus applied in the late night will cause a phase advance shift (to an earlier hour), and a light stimulus applied in the middle of the day will cause a very small change in phase. The phase-dependent response of the circadian system to a stimulus is typically summarized in a phase-response curve (PRC).
Under entrained conditions, the phase of a circadian rhythm has a fixed relationship to the signal from the environment (in most cases, thelight-dark cycle) that synchronizes, or entrains, the circadian timing system to the 24-hour day. This phase relationship is termed the phase-angle of entrainment.
While circadian rhythms are endogenously (internally) generated, they can also be directly affected by changes in the environment or by changes in behavior. For example, nocturnal rodents typically are inactive during the light portion of the light-dark cycle. If bright lights were turned on during the animal's normal dark time (when it would typically be active), the animal may cease activity. Thus, the endogenous component of the animal's circadian activity rhythm is acutely altered by exposure to light. This can also occur when human circadian rhythms are studied, and the endogenous circadian component of many physiologic and behavioral rhythms can be affected by things such as ambient light, activity, sleep-wake state, food intake, postural change, and emotional state. Thus, it is important that studies of circadian rhythmicity be conducted under controlled conditions in which the endogenous component of circadian rhythms can be measured.
Studies of circadian rhythms in humans began as early as the 1930s. Nathaniel Kleitman studied human subjects in Mammoth Cave in Kentucky, an environment where temperature, humidity, and darkness were constant. While the experimental subjects in those studies were allowed access to artificial lighting, Kleitman's studies revealed that humans, like other organisms, continue to exhibit near-24-hour physiological rhythms even when living in constant conditions. In the 1960s, JÎrgen Aschoff and colleagues began a series of circadian rhythm studies in Germany. They studied their subjects in underground bunkers, which, like the cave used by Kleitman, were shielded from information from the external environment. In the 1970s and later, special laboratories were developed for the study of circadian rhythms in humans. Those laboratory study rooms were typically shielded from outdoor light, were soundproof, and contained no obvious means of telling the time of day (e.g., they did not have clocks, radios, televisions).
Results of studies from humans living in those special laboratory conditions have revealed that there are circadian rhythms in many aspects of human behavior and physiology. Those rhythms include daily oscillations of hormone levels (including such hormones as cortisol, melatonin, thyroid stimulating hormone, and prolactin); core body temperature; EEG activity; alertness and vigilance; sleep tendency; and many aspects of performance. Neuroanatomical studies have also found that the same structures that comprise the circadian timing system in mammals, the SCN and RHT, are present in the human brain.
The particular methods used for studying human circadian rhythms depend on the aspect of circadian physiology that is of interest. The constant routine is an effective protocol to assess phase, amplitude, or the effect of a particular stimulus on the endogenous output of the human circadian system. In this protocol, subjects' circadian rhythms are measured for at least one complete circadian cycle while they remain awake, in a constant posture, in constant dim light, and with food and fluid intake distributed across day and night. In constant routine studies, often multiple variables controlled by the circadian timing system are measured simultaneously, so the phase and amplitude of each of those rhythms can be assessed. In studies in which the influence on the circadian timing system of a particular stimulus is of interest, an initial assessment of circadian phase and amplitude is made, the stimulus is applied, and then a reassessment of phase is done. Thus, the change in phase and amplitude as a result of the stimulus can be estimated. 2ff7e9595c
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