Biological Rhythms in the Skin

Circadian rhythms, ≈24 h oscillations in behavior and physiology, are reflected in all cells of the body and function to optimize cellular functions and meet environmental challenges associated with the solar day. This multi-oscillatory network is entrained by the master pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, which directs an organism’s rhythmic expression of physiological functions and behavior via a hierarchical system. This system has been highly conserved throughout evolution and uses transcriptional–translational autoregulatory loops. This master clock, following environmental cues, regulates an organism’s sleep pattern, body temperature, cardiac activity and blood pressure, hormone secretion, oxygen consumption and metabolic rate. Mammalian peripheral clocks and clock gene expression have recently been discovered and are present in all nucleated cells in our body. Like other essential organ of the body, the skin also has cycles that are informed by this master regulator. In addition, skin cells have peripheral clocks that can function autonomously. First described in 2000 for skin, this review summarizes some important aspects of a rapidly growing body of research in circadian and ultradian (an oscillation that repeats multiple times during a 24 h period) cutaneous rhythms, including clock mechanisms, functional manifestations, and stimuli that entrain or disrupt normal cycling. Some specific relationships between disrupted clock signaling and consequences to skin health are discussed in more depth in the other invited articles in this IJMS issue on Sleep, Circadian Rhythm and Skin

Peritraumatic distress: A review and synthesis of 15 years of research

ContextAlthough the subjective trauma exposure criterion was removed from the DSM‐5 criteria set for posttraumatic stress disorder (PTSD), emerging literature suggests that peritraumatic distress may be useful in predicting outcomes after exposure to a stressful event.MethodWe conducted a comprehensive review of the literature examining the association between peritraumatic distress and PTSD and other psychiatric outcomes. The 57 studies herein varied in both experimental design and target populations.ResultsForty‐eight studies found associations between peritraumatic distress and PTSD outcome measures, 23 found associations between peritraumatic distress and other psychiatric outcomes, and three found associations between peritraumatic distress and PTSD‐related symptoms or other psychiatric outcomes after non‐Criterion A stressful events by DSM‐5 criteria.ConclusionPeritraumatic distress is associated with PTSD symptom severity, other psychiatric symptoms, and severity of PTSD‐related symptoms after exposure to non‐Criterion A events, suggesting that peritraumatic distress is a risk factor for various psychiatric outcomes and furthering our understanding of the impact of subjective experience on trauma psychopathology.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146284/1/jclp22612.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146284/2/jclp22612_am.pd

Interactions between the NR2B receptor and CaMKII modulate synaptic plasticity and spatial learning.

The NR2B subunit of the NMDA receptor interacts with several prominent proteins in the postsynaptic density, including calcium/calmodulin-dependent protein kinase II (CaMKII). To determine the function of these interactions, we derived transgenic mice expressing a ligand-activated carboxy-terminal NR2B fragment (cNR2B) by fusing this fragment to a tamoxifen (TAM)-dependent mutant of the estrogen receptor ligand-binding domain LBD(G521R). Here, we show that induction by TAM allows the transgenic cNR2B fragment to bind to endogenous CaMKII in neurons. Activation of the LBD(G521R)-cNR2B transgenic protein in mice leads to the disruption of CaMKII/NR2B interactions at synapses. The disruption decreases Thr286 phosphorylation of alphaCaMKII, lowers phosphorylation of a key CaMKII substrate in the postsynaptic membrane (AMPA receptor subunit glutamate receptor 1), and produces deficits in hippocampal long-term potentiation and spatial learning. Together our results demonstrate the importance of interactions between CaMKII and NR2B for CaMKII activity, synaptic plasticity, and learning

Identification and validation of the dopamine agonist bromocriptine as a novel therapy for high-risk myelodysplastic syndromes and secondary acute myeloid leukemia

Myelodysplastic syndromes (MDS) represent a broad spectrum of diseases characterized by their clinical manifestation as one or more cytopenias, or a reduction in circulating blood cells. MDS is predominantly a disease of the elderly, with a median age in the UK of around 75. Approximately one third of MDS patients will develop secondary acute myeloid leukemia (sAML) that has a very poor prognosis. Unfortunately, most standard cytotoxic agents are often too toxic for older patients. This means there is a pressing unmet need for novel therapies that have fewer side effects to assist this vulnerable group. This challenge was tackled using bioinformatic analysis of available transcriptomic data to establish a gene-based signature of the development and progression of MDS. This signature was then used to identify novel therapeutic compounds via statistically-significant connectivity mapping. This approach suggested re-purposing an existing and widely-prescribed drug, bromocriptine as a novel potential therapy in these disease settings. This drug has shown selectivity for leukemic cells as well as synergy with current therapies

A zebrafish model of conditional targeted podocyte ablation and regeneration

Podocytes are specialized cells that contribute critically to the normal structure and function of the glomerular filtration barrier. Their depletion plays an important role in the pathogenesis of glomerulosclerosis. Here, we report generation of a genetic model of conditional podocyte ablation and regeneration in zebrafish using a bacterial nitroreductase strategy to convert a prodrug, Metronidazole, into a cytotoxic metabolite. A transgenic zebrafish line was generated that expresses a green fluorescence protein (GFP) and the nitroreductase fusion protein under the control of the podocin promoter Tg(podocin:nitroreductase-GFP). Treatment of these transgenic zebrafish with Metronidazole results in podocyte apoptosis, a loss of nephrin and podocin expression, foot process effacement, and a leaky glomerular filtration barrier. Following Metronidazole washout, proliferating cells were detected in the glomeruli of recovering transgenic fish with a restoration of nitroreductase-GFP fluorescence, nephrin and podocin expression, a reestablishment of normal foot process architecture and glomerular barrier function. Thus, our studies show that zebrafish podocytes are capable of regenerating following depletion and establish the Tg(podocin:NTR-GFP) fish as a new model to study podocyte injury and repair

Outbreak of H7N8 Low Pathogenic Avian Influenza in Commercial Turkeys with Spontaneous Mutation to Highly Pathogenic Avian Influenza

Highly pathogenic avian influenza (HPAI) subtype H7N8 was detected in commercial turkeys in January 2016. Control zone surveillance discovered a progenitor low pathogenic avian influenza (LPAI) virus in surrounding turkey flocks. Data analysis supports a single LPAI virus introduction followed by spontaneous mutation to HPAI on a single premises

Outbreak of H7N8 Low Pathogenic Avian Influenza in Commercial Turkeys with Spontaneous Mutation to Highly Pathogenic Avian Influenza

Highly pathogenic avian influenza (HPAI) subtype H7N8 was detected in commercial turkeys in January 2016. Control zone surveillance discovered a progenitor low pathogenic avian influenza (LPAI) virus in surrounding turkey flocks. Data analysis supports a single LPAI virus introduction followed by spontaneous mutation to HPAI on a single premises