Nordic partnership choices in a fierier security environment: Towards more alignment

Nordic states’ partnership choices in security and defence are more aligned than they were a decade ago. When Danish, Finnish, Norwegian and Swedish government officials now identify key security challenges and partners, and reflect on the potential for Nordic cooperation, they have the same reference points and use similar wording. Since 2014, the toolbox for Nordic defence cooperation has also solidified and different formal affiliations with NATO and the EU seem to matter less than before. Furthermore, an array of multi- and minilateral cooperation structures have emerged across and beyond the EU and NATO, expanding the possibilities for Nordic cooperation under a larger Euro-Atlantic umbrella. However, two limitations remain: First, Nordic security and defence cooperation still remains subordinate to and a supplement rather than an alternative to NATO. Second, putting Nordic response mechanisms into practice remains dependent not only on the context and issue at stake, but also on the political appetite of the individual Nordic governments to choose a Nordic solution.publishedVersio

Viral dynamics of acute SARS-CoV-2 infection and applications to diagnostic and public health strategies.

SARS-CoV-2 infections are characterized by viral proliferation and clearance phases and can be followed by low-level persistent viral RNA shedding. The dynamics of viral RNA concentration, particularly in the early stages of infection, can inform clinical measures and interventions such as test-based screening. We used prospective longitudinal quantitative reverse transcription PCR testing to measure the viral RNA trajectories for 68 individuals during the resumption of the 2019-2020 National Basketball Association season. For 46 individuals with acute infections, we inferred the peak viral concentration and the duration of the viral proliferation and clearance phases. According to our mathematical model, we found that viral RNA concentrations peaked an average of 3.3 days (95% credible interval [CI] 2.5, 4.2) after first possible detectability at a cycle threshold value of 22.3 (95% CI 20.5, 23.9). The viral clearance phase lasted longer for symptomatic individuals (10.9 days [95% CI 7.9, 14.4]) than for asymptomatic individuals (7.8 days [95% CI 6.1, 9.7]). A second test within 2 days after an initial positive PCR test substantially improves certainty about a patient's infection stage. The effective sensitivity of a test intended to identify infectious individuals declines substantially with test turnaround time. These findings indicate that SARS-CoV-2 viral concentrations peak rapidly regardless of symptoms. Sequential tests can help reveal a patient's progress through infection stages. Frequent, rapid-turnaround testing is needed to effectively screen individuals before they become infectious

Dopaminergic Activation of Estrogen Receptors Induces Fos Expression within Restricted Regions of the Neonatal Female Rat Brain

Steroid receptor activation in the developing brain influences a variety of cellular processes that endure into adulthood, altering both behavior and physiology. Recent data suggests that dopamine can regulate expression of progestin receptors within restricted regions of the developing rat brain by activating estrogen receptors in a ligand-independent manner. It is unclear whether changes in neuronal activity induced by dopaminergic activation of estrogen receptors are also region specific. To investigate this question, we examined where the dopamine D1-like receptor agonist, SKF 38393, altered Fos expression via estrogen receptor activation. We report that dopamine D1-like receptor agonist treatment increased Fos protein expression within many regions of the developing female rat brain. More importantly, prior treatment with an estrogen receptor antagonist partially reduced D1-like receptor agonist-induced Fos expression only within the bed nucleus of the stria terminalis and the central amygdala. These data suggest that dopaminergic activation of estrogen receptors alters neuronal activity within restricted regions of the developing rat brain. This implies that ligand-independent activation of estrogen receptors by dopamine might organize a unique set of behaviors during brain development in contrast to the more wide spread ligand activation of estrogen receptors by estrogen

SKF 38393-induced Fos expression within the BST and mPoA.

<p>Photomicrographs of SKF 38393-induced Fos expression within the BST and mPOA. The right column shows schematics of the regions pictured. Shaded area indicates regions examined. 3V, third ventricle; ac, anterior commissure; BST, bed nucleus of the stria terminalis; LV, lateral ventricle; mPOA, medial preoptic area.</p

Photomicrographs of SKF 38393-induced Fos expression partially blocked by PSK 3668 within the bed nucleus of the stria terminalis.

<p>A schematic of this region is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002177#pone-0002177-g002" target="_blank">Figure 2</a>. ac, anterior commissure; LV, lateral ventricle.</p

Effect of SKF 38393 on Fos expression within the developing female rat brain.

<p>SKF 38393 increased Fos expression within the AVPV, CPu, BST, mPOA, CeA, VMH, Arc, and Hb, but not within the PVP. Data are shown as mean±standard error. * indicates p<0.05.</p

Photomicrographs of SKF 38393-induced Fos expression within the mPOA.

<p>PSK 3668 did not block SKF 38393-induced Fos expression within this region. A schematic of this region is shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0002177#pone-0002177-g002" target="_blank">Figure 2</a>. 3V, third ventricle.</p

AHR Regulates Metabolic Reprogramming to Promote SIRT1-Dependent Keratinocyte Differentiation

Activation of the transcription factor, AHR, in normal human epidermal keratinocytes increased AHR binding in the gene regions of the glucose transporter, SLC2A1, and the glycolytic enzyme, ENO1. This increased chromatin binding corresponded with AHR-dependent decreases in levels of SLC2A1 and ENO1 mRNA, protein, and activities. Studies of the ENO1 promoter showed activation of the AHR decreases the transcription of ENO1. Glycolysis was lowered by activation of the AHR as measured by decreases in glucose uptake and the production of pyruvate and lactate. Levels of ATP were also decreased. Downregulation of glucose metabolism, either by activation of the AHR, inhibition of glycolysis, inhibition of glucose transport, or inhibition of enolase, increased SIRT1 protein levels in normal human epidermal keratinocytes and the immortalized keratinocyte cell line, N/TERT-1. This increase in SIRT1 was abrogated by the addition of exogenous pyruvate. Moreover, keratinocyte differentiation in response to downregulation of glycolysis, either by activation of the AHR, inhibition of glucose transport, or inhibition of enolase, was dependent on SIRT1. These results indicate that regulation of glycolysis controls keratinocyte differentiation, and that activation of the AHR, by lowering the expression of SLC2A1 and ENO1, can determine this fate

NRF2 regulates core and stabilizing circadian clock loops, coupling redox and timekeeping in mus musculus

Diurnal oscillation of intracellular redox potential is known to couple metabolism with the circadian clock, yet the responsible mechanisms are not well understood. We show here that chemical activation of NRF2 modifies circadian gene expression and rhythmicity, with phenotypes similar to genetic NRF2 activation. Loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver also altered circadian rhythms, suggesting that NRF2 stoichiometry and/or timing of expression are important to timekeeping in some cells. Consistent with this concept, activation of NRF2 at a circadian time corresponding to the peak generation of endogenous oxidative signals resulted in NRF2-dependent reinforcement of circadian amplitude. In hepatocytes, activated NRF2 bound specific enhancer regions of the core clock repressor gene Cry2, increased Cry2 expression and repressed CLOCK/BMAL1-regulated E-box transcription. Together these data indicate that NRF2 and clock comprise an interlocking loop that integrates cellular redox signals into tissue-specific circadian timekeeping

Cutaneous effects of in utero and lactational exposure of C57BL/6J mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin

To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 _g TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDDexposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects