Elements of the NRF were activated in August 2021 to support the evacuation and relocation of Afghans who worked alongside NATO, together with their families. This response included the establishment of Task Force Noble, a task force coordinating hundreds of NRF troops from 20 Allied countries. These troops are supporting the evacuation in locations across Europe, including with transportation aircraft, construction equipment, ambulances, medical teams, civil affairs teams and security personnel.
After eccentric muscle damage, voluntary activation (and hence muscle force) may be reduced as a result of muscle pain and tenderness. Saxton & Donnelly (1996) used a type of twitch interpolation with nerve stimulation during isometric contraction of the elbow flexors in the days after eccentric exercise. They found inconsistent changes in the force added by tetanic stimulation. Using motor cortical stimulation to evoke force increments Löscher & Nordlund (2002) found some impairment of voluntary activation immediately after eccentric exercise, but this recovered within 5 min. Twitch interpolation using nerve stimulation after eccentric exercise of the elbow flexors also revealed an immediate reduction in voluntary activation (Michaut et al. 2002). In the latter two studies it was not possible to separate an acute effect of muscle fatigue from a longer-term effect related to muscle damage.
In addition to peripheral inflammation, central inflammation namely neuroinflammation, has also been found in stress condition (García-Bueno et al., 2008; Munhoz et al., 2008). Elevated pro-inflammatory cytokines, increased microglia activation and accumulation of peripherally-derived monocytes and macrophages were detected in the brain with psychological stress exposure (Johnson et al., 2005). As the brain-resident macrophages, microglia was considered to be the major pro-inflammatory cytokine source. Stress-elicited potentiate microglial activation is via both direct and indirect mechanisms. Microglia express both GC and mineralocorticoid receptors, thus microglia are likely to have direct response to corticosterone peak (Calcia et al., 2016). In addition, GC receptors also are highly present in the hippocampus and prefrontal cortex, so stress-induced corticosterone may have indirect effects on microglia. Besides this, a recent research display that CNS innate immune system can respond to an acute stressor, thereby releasing the danger signal high mobility group box-1 (HMGB-1) in the brain to prime microglia by acting on the NLRP3 inflammasome, in preparation for IL-1β secretion (Weber et al., 2015). Activated microglia display hypertrophic branch morphology with an enlarged soma and produce an exaggerated cytokine to recruit peripheral monocytes. Increased brain macrophages and circulating monocytes, contribute to elevated levels of pro-inflammatory cytokine production (i.e., IL-1β, TNFα, IL-6) in the brain (Wohleb and Delpech, 2016).
While the biological mechanisms of stress increasing CVD risk are not well-known, chronic low-grade inflammatory load may emerge as a possible link as it is both elevated by chronic stress and contributed to early process, progression and thrombotic complications of atherosclerosis. IL-6 and CRP, the two important biomarkers of systematic inflammation, are considered indicative and potentially predictive for atherosclerosis (Tsirpanlis, 2005; Nadrowski et al., 2016). Coincidently, these two inflammatory indicators were elevated in different types of life stress. For instance, severe levels of childhood abuse were associated with a more elevated acute stress-induced IL-6 response, possibly due to reduced methylation of the IL-6 promoter (Janusek et al., 2017). Adults who had greater childhood adversity was reported to have more depressive symptoms and elevated concentrations of CRP (Janusek et al., 2017). Recent studies have suggested that CRP and IL-6 are mechanisms by which early adversity may contribute to CVD (Ridker et al., 2002; Albert et al., 2006; Graham et al., 2006). Work-related stressors have also been mentioned to correlate with elevated CRP and IL-6 (von Känel et al., 2008). In a recent study applied in black and white men, greater stressor-evoked reduction in high-frequency heart rate variability (HF-HRV) and were correlated with higher CRP and IL-6. In animal stress models (social isolation, social disruption, cold stress, severe chronic unpredictable stress), increased plaque size, elevated serum IL-6, NPY levels were observed. However, when single supplied with GC after Adrenalectomy, plaque size and serum inflammatory factors were decreased or did not change. This suggested that the possible mechanisms of stress-related inflammation in CVD may include SNS-mediated increases in NE and NPY. Noisy communities as life stressor induces significant increase in urine epinephrine and NE leading to hypertension (Seidman and Standring, 2010). NE promoted the production of inflammatory factors by facilitating the phosphorylation of MAPKs through activation of NE α receptor (Huang et al., 2012). NPY could elicit TGF-β1 and TNFα production in macrophage-like cell line RAW264.7 via Y1 receptor (von Känel et al., 2008). NPY could also directly activate the HMGB1 release and cytoplasmic translocation from the macrophage (Zhou et al., 2013). Inflammation has also been shown to correlate with endothelial dysfunction and relate to the renin-angiotensin system (Li et al., 2012).
Although p53 has transcription-independent MOMP-inducing activities, its significance relative to transcription remains unknown. The apoptosis defect of the Puma knockout mouse and the p53 transactivation domain mutant mouse suggests that transcription is indispensable for apoptosis induction (Jeffers et al. 2003; Brady et al. 2011). A study aimed at addressing this question showed that a subset of cytosolic p53 is sequestered in an inactive complex by BclXL. Stress activation of p53 induces Puma expression, which forms Puma-BclXL complex and liberates the cytosolic p53 to activate Bax in the cytoplasm (Chipuk et al. 2005). Therefore, the transcription-dependent and independent p53 activities may cooperate to induce apoptosis.
Biochemically, p53 targets involved in cell-cycle and DNA repair often have high-affinity binding sites, whereas the binding sites on apoptosis targets are more variable in affinity (Weinberg et al. 2005). p53 binding to the degenerate weak sites is more dependent on cooperative binding through tetramerization of the core domain (Schlereth et al. 2010). As such, at low p53 concentration, the occupancy on cell-cycle target sites will be higher than apoptosis genes, whereas a high p53 level is needed for significant binding and activation of apoptosis genes. This is consistent with the chromatin immunoprecipitation analysis of p53 occupancy on these genes (Kaeser and Iggo 2002). Reporter gene assays also showed that cell-cycle target promoters are generally more responsive to p53 compared with apoptosis gene promoters (Qian et al. 2002). Furthermore, cell-cycle target-binding sites can act alone without adjacent sequences, whereas additional promoter sequences in the apoptotic gene promoters are needed for strong p53 response, indicating that other inputs are required to trigger apoptosis (Qian et al. 2002). Corroborating these findings, experiments using inducible p53 showed that, in the absence of DNA damage, low-level p53 induced arrest, whereas high-level p53 induced apoptosis (Chen et al. 1996).
An alternative strategy has been proposed to take advantage of the reversible cell-cycle arrest by MDM2 inhibitors. Blocking normal cells in G1 phase can protect them from drugs that target dividing cells (Carvajal et al. 2005; Kranz and Dobbelstein 2006). More than 50% of human tumors express mutant p53 and are not expected to respond to MDM2 inhibitors. For these patients, the MDM2 inhibitors may be useful for protecting normal tissues from chemotherapy toxicity by inducing arrest, while leaving their p53-defective tumors open to attack by the S/M phase-specific cancer drugs. However, for this strategy to be practical, the MDM2 inhibitors must display low toxicity to normal cells. The p53ERTAM mouse model showed that in the absence of MDM2, p53 is spontaneously activated and induces apoptosis in radio-sensitive organs (Ringshausen et al. 2006). Somatic knockout of MDM2 also causes apoptosis in both radio-sensitive and radio-insensitive tissues, resulting in organ damage and rapid death (Zhang et al. 2014). Clinical trials of MDM2 inhibitor RG7112 encountered toxicities consistent with the effects of p53 activation in the hematopoietic system, suggesting that the observations in mice may also be applicable to humans (Ray-Coquard et al. 2012). Clinical tests of additional classes of MDM2 inhibitors will be needed to determine the level of on-target toxicity in humans, and identify a safe therapeutic window.
The ability to sense and adapt to the environment is essential for survival in all organisms. For example, bacteria adapt to changes in osmotic force through the activation of mechanosensitive ion channels enabling them to survive when trapped in rainwater [4, 5]. In humans and other animals, somatic sensation arises from the body surface or internal organs and endow us with the sense of touch, proprioception, pain and temperature. These are vital functions allowing organisms to continuously adapt to changes in the external and internal environment.
PTEN, a negative regulator of PI3K pathway, acts as a direct antagonist of PI3K action through dephosphorylation of PIP3. Dimeric PTEN complexes have higher activity than PTEN monomers in PIP3 dephosphorylation and PI3K signaling regulation [19, 20]. PTEN is a well characterized tumor suppressor with growth, survival and metabolic regulatory functions, and its loss or inactivation of function is frequently observed in both heritable and sporadic malignances, including brain cancer, breast cancer, and prostate cancer [21,22,23]. Furthermore, it has been shown that small changes in PTEN expression contribute to major consequences for normal cellular function . In PTEN knock-in mice harboring two cancer-associated PTEN mutations, PTENC124S and PTENG129E inhibit the PTEN lipid-phosphatase activity in a dominant negative manner, leading to increased activity of PI3K signaling and tumorigenesis . Moreover, in PTEN-deficient cancer, the main carcinogenic driving force is the overactivation of AKT caused by the loss of PTEN lipid phosphatase function [20, 25]. 153554b96e