Can Chrono-Nutrition Help Prevent Diabetes?

This editorial aimed to put forward a question if chrono-nutrition can help prevent diabetes through optimizing circadian rhythms of glucose metabolism. With the advancing mechanization, eating behavior (timing, sequence, and frequency) has changed. People are now more willing to eat fast foods at suboptimal times of the circadian period. Growing evidence suggests that untimely eating and lack of exercise can interfere with optimal physiological rhythms of glucose and insulin metabolism that can lead to diabetes. Type 2 diabetes mellitus (T2D) is a foremost metabolic disorder worldwide occurring largely due to suboptimal eating timing and lifestyle. Consuming less sugars and carbohydrates during evening and overnight may help optimize human chrono-physiology. Chrono-nutrition via optimizing the timing of meals is a growing science that needs to be well practiced to help prevent or possibly reduce risks of T2D in today’s complicated life.

Green notes: The rhythms of cyanobacteria exoelectrogenesis as de-composed by the Hilbert-Huang transform

Electrons from cyanobacteria photosynthetic and respiratory systems are implicated in current generated in biophotovoltaic (BPV) devices. However, the pathway that electrons follow to electrodes remains largely unknown, limiting progress of applied research. Here we use Hilbert-Huang transforms to decompose Synechococcus elongatus sp. PCC7942 BPV current density profiles into physically meaningful oscillatory components, and compute their instantaneous frequencies. We develop hypotheses for the genesis of the oscillations via repeat experiments with iron-depleted and 20% CO2 enriched biofilms. The oscillations exhibit rhythms that are consistent with the state of the art cyanobacteria circadian model, and putative exoelectrogenic pathways. In particular, we observe oscillations consistent with: rhythmic D1:1 (photosystem II core) expression; circadian-controlled glycogen accumulation; circadian phase shifts under modified intracellular %ATP; and circadian period shortening in the absence of the iron-sulphur protein LdpA. We suggest that the extracted oscillations may be used to reverse-identify proteins and/or metabolites responsible for cyanobacteria exoelectrogenesis.

Arabidopsis thaliana PRR7 Provides Circadian Input to the CCA1 Promoter in Shoots but not Roots

The core of the plant circadian clock involves multiple interlocking gene expression loops and post-translational controls along with inputs from light and metabolism. The complexity of the interactions is such that few specific functions can be ascribed to single components. In previous work, we reported differences in the operation of the clocks in Arabidopsis shoots and roots, including the effects of mutations of key clock components. Here, we have used luciferase imaging to study prr7 mutants expressing CCA1::LUC and GI::LUC markers. In mature shoots expressing CCA1::LUC, loss of PRR7 radically altered behaviour in light:dark cycles and caused loss of rhythmicity in constant light but had little effect on roots. In contrast, in mature plants expressing GI::LUC, loss of PRR7 had little effect in light:dark cycles but in constant light increased the circadian period in shoots and reduced it in roots. We conclude that most or all of the circadian input to the CCA1 promoter in shoots is mediated by PRR7 and that loss of PRR7 has organ-specific effects. The results emphasise the differences in operation of the shoot and root clocks, and the importance of studying clock mutants in both light:dark cycles and constant light.

Regional genetic diversity in circadian period in Boechera stricta populations is high relative to the global range of diversity in Arabidopsis

Circadian clocks manifest adaptations to predictable 24-h fluctuations in the exogenous environment, but it has yet to be determined why the endogenous circadian period length in the wild varies genetically around the hypothesized optimum of 24 h. We quantified genetic variation in circadian period in leaf movement in 30 natural populations of the Arabidopsis relative Boechera stricta sampled within only 1° of latitude but across an elevational gradient spanning 2460−3300 m in the Rocky Mountains. Measuring over 3800 plants from 473 maternal families (7−20 per population), we found genetic variation that was of similar magnitude among vs. within populations, with population means varying between 21.9−24.9 h and maternal family means within populations varying by up to ~6 h. After statistically factoring out spatial autocorrelation at the habitat extremes, we found that elevation explained a significant proportion of genetic variation in circadian period such that higher-elevation populations had shorter mean period lengths and less within-population variation. Environmental data indicate that these spatial trends could be related to steep regional climatic gradients in temperature, precipitation, and their intra-annual variability. Our findings provide evidence that spatially fine-grained environmental heterogeneity contributes to naturally occurring genetic diversity in circadian traits in wild populations.

Characterizing Genetic Mechanisms Involved in Measuring Day-length in Drosophila melanogaster

Many organisms are known to regulate seasonal behaviors and physiological processes in response to day length changes through photoperiodism. Extreme changes in photoperiods have detrimental effects on human health, which can impair development and serve as the origin of adult diseases. Since the seminal work by Bünning in 1936, there are studies supporting the view that organisms can measure the day length through an endogenous 24-hour cellular circadian clock. However, the mechanisms involved in measuring seasonal or day-length changes are not understood. In the current study, we performed a genome-wide association study (GWAS) on photoperiodism using the Drosophila Genetic Reference Panel. The GWAS identified 32 candidate genes responsible for photoperiodic regulations. The knockout mutants of the top four candidate genes (Protein Kinase C delta (Pkcdelta), Glucuronyltransferase-P (GlcAT-P), Brain-specific homeobox (Bsh), and Diuretic hormone 31 Receptor (Dh31-R1)) were analyzed for their photoperiod and circadian period phenotypes. PKCdelta and GlcAT-P mutants show a significantly different photoperiod response compared to that of the wild type strain, and also had an altered circadian period phenotype. Further molecular characterization revealed that the mutant two independent mutant alleles of PKCdelta with a defective catalytic domain had distinct photoperiod responses. Taken these data together, we concluded that there is overlap between the circadian clock and photoperiodic regulations in Drosophila, and PKCdelta is a component that is involved in both circadian and photoperiodic regulations. By identifying novel molecular components of photoperiod, the current study provides new insights into the genetic mechanisms of determining the seasonal changes.

A point mutation in Phytochromobilin Synthase alters the circadian clock and photoperiodic flowering of Medicago truncatula

Plants use seasonal cues to initiate flowering at an appropriate time of year to ensure optimal reproductive success. The circadian clock integrates these daily and seasonal cues with internal cues to initiate flowering. The molecular pathways that control the sensitivity of flowering to photoperiod (daylength) are well described in the model plant Arabidopsis. However, much less is known in crop species, such as the legume family species. Here we performed a flowering time screen of a TILLING population of Medicago truncatula and found a line with late-flowering and altered light-sensing phenotypes. Using RNA-sequencing, we identified a nonsense mutation in the Phytochromobilin Synthase (MtPΦBS) gene, which encodes an enzyme that carries out the final step in the biosynthesis of the chromophore required for phytochrome (PHY) activity. The analysis of the circadian clock in the MtpΦbs mutant revealed a shorter circadian period, which was shared with the phyA mutant. The MtpΦbs and MtphyA mutants showed downregulation of FT floral regulators MtFTa1, MtFTb1/b2 and a shift in phase for morning and night core clock genes. Our findings show that PHYA is necessary to synchronize the circadian clock and integration of light signaling to promote expression of the MtFT genes to precisely time flowering.

Structure-based design and classifications of small molecules regulating the circadian rhythm period

Circadian rhythm is an important mechanism that controls behavior and biochemical events based on 24 h rhythmicity. Ample evidence indicates disturbance of this mechanism is associated with different diseases such as cancer, mood disorders, and familial delayed phase sleep disorder. Therefore, drug discovery studies have been initiated using high throughput screening. Recently the crystal structures of core clock proteins (CLOCK/BMAL1, Cryptochromes (CRY), Periods), responsible for generating circadian rhythm, have been solved. Availability of structures makes amenable core clock proteins to design molecules regulating their activity by using in silico approaches. In addition to that, the implementation of classification features of molecules based on their toxicity and activity will improve the accuracy of the drug discovery process. Here, we identified 171 molecules that target functional domains of a core clock protein, CRY1, using structure-based drug design methods. We experimentally determined that 115 molecules were nontoxic, and 21 molecules significantly lengthened the period of circadian rhythm in U2OS cells. We then performed a machine learning study to classify these molecules for identifying features that make them toxic and lengthen the circadian period. Decision tree classifiers (DTC) identified 13 molecular descriptors, which predict the toxicity of molecules with a mean accuracy of 79.53% using tenfold cross-validation. Gradient boosting classifiers (XGBC) identified 10 molecular descriptors that predict and increase in the circadian period length with a mean accuracy of 86.56% with tenfold cross-validation. Our results suggested that these features can be used in QSAR studies to design novel nontoxic molecules that exhibit period lengthening activity.