Motivation A fundamental interest in chronobiology is to compare patterns between groups of rhythmic data. However, many existing methods are ill-equipped to derive statements concerning the statistical significance of differences between rhythms that may be visually apparent. This is attributed to both the form of data used (longitudinal versus cross-sectional) and the limitations of the statistical tests used to draw conclusions. Results To address this problem, we propose that a cosinusoidal curve with a particular parametrization be used to model and compare data of two sets of observations collected over a 24-h period. The novelty of our test is in the parametrization, which allows the explicit estimation of rhythmic parameters [mesor (the rhythm-adjusted mean level of a response variable around which a wave function oscillates), amplitude and phase], and simultaneously testing for statistical significance in all three parameters between two or more groups of datasets. A statistically significant difference between two groups, regarding each of these rhythmic parameters, is indicated by a P-value. The method is evaluated by applying the model to publicly available datasets, and is further exemplified by comparison to the currently recommended method, DODR. The results suggest that the method proposed may be highly sensitive to detect rhythmic differences between groups in phase, amplitude and mesor. Availability and implementation https://github.com/RWParsons/circacompare/

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 - 15% of the liver transcriptome as rhythmic in control and T3 groups, but only 4% of the liver transcriptome (1,033 genes) were rhythmic across both conditions - amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

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Learning, memory consolidation, and retrieval are processes known to be modulated by the circadian (circa: about; dies: day) system. The circadian regulation of memory performance is evolutionarily conserved, independent of the type and complexity of the learning paradigm tested, and not specific to crepuscular, nocturnal, or diurnal organisms. In mammals, long-term memory (LTM) formation is tightly coupled to de novo gene expression of plasticity-related proteins and posttranslational modifications and relies on intact cAMP/protein kinase A (PKA)/protein kinase C (PKC)/mitogen-activated protein kinase (MAPK)/cyclic adenosine monophosphate response element-binding protein (CREB) signaling. These memory-essential signaling components cycle rhythmically in the hippocampus across the day and night and are clearly molded by an intricate interplay between the circadian system and memory. Important components of the circadian timing mechanism and its plasticity are members of the Period clock gene family (Per1, Per2). Interestingly, Per1 is rhythmically expressed in mouse hippocampus. Observations suggest important and largely unexplored roles of the clock gene protein PER1 in synaptic plasticity and in the daytime-dependent modulation of learning and memory. Here, we review the latest findings on the role of the clock gene Period 1 (Per1) as a candidate molecular and mechanistic blueprint for gating the daytime dependency of memory processing.

Introduction Lutetium‐177‐PSMA (LuPSMA) is a targeted systemic radioligand treatment for metastatic castration‐resistant prostate cancer (mCRPC). LuPSMA is considered as an experimental treatment not yet used in routine practice. Here, we report our experience following the introduction of LuPSMA therapy at our institution. Methods Referred mCRPC patients were assessed for treatment suitability including Gallium‐68‐PSMA PET/CT and blood tests. Suitable patients underwent up to four cycles of LuPSMA treatment. Response to treatment was assessed by changes in serum prostate‐specific antigen (PSA) levels. Toxicity was assessed by recording of adverse events. Results In an 18 month period, 50 patients underwent 132 cycles of LuPSMA therapy. Patients underwent a median of three cycles each (range: 1–4) and the mean administered amount of activity per cycle was 5.9 GBq (range: 3.5–8.2 GBq). PSA decline could be calculated for 49 patients, with a best PSA decline of ≥ 50% observed in 22 patients (44.9%). Adverse events were reported across 45 of 132 LuPSMA cycles. Most adverse events were grade I (42/45) and the remaining three events were grade II. Conclusion Initial experience at our site supports the use of LuPSMA as an emerging safe and effective treatment for mCRPC. Since introducing LuPSMA therapy at our institution, 44.9% of patients have experienced a decline in PSA level ≥ 50% with low or minimal toxicity. This is an important finding as these patients had previously exhausted all available treatment options. Overall, we have found patients and their primary care doctors have eagerly accepted LuPSMA as another line of defence against mCRPC.