A longitudinal approach to understanding boredom during pandemics: The predictive roles of trauma and emotion dysregulation.

Research during the COVID-19 pandemic and prior outbreaks suggest that boredom is linked to poor compliance with critical lifesaving social distancing and quarantine guidelines, as well as to numerous mental health difficulties. As such, continued understanding on what contributes to boredom is imperative. Extending beyond the roles of constraint, monotony, and trait dispositions (e.g., individual differences in boredom propensity), and informed by prior theories on the emotional contributors of boredom, the current longitudinal study examined the predictive role of "pandemic trauma" on people's boredom, with a focus on how emotion dysregulation mediates this relationship. Community participants (N = 345) completed questionnaires three times across an average of 3 1/2 weeks, rating their pandemic trauma, emotion dysregulation, and boredom over the past week each time. Pandemic trauma was assessed with items querying exposure to coronavirus, as well as the financial, resource-related, and interpersonal pandemic stressors that participants experienced. Emotion dysregulation was assessed with the Difficulties in Emotion Regulation Scale. Boredom was assessed with the short-form Multidimensional State Boredom Scale. The results of a theory-informed mediation model showed that participants' pandemic trauma at Time 1 positively and modestly predicted their boredom at Time 3 and that this relationship was partially and moderately mediated by participants' lack of emotional clarity and difficulties with engaging in goal-directed behaviors at Time 2. When people experience pandemic-related trauma, they subsequently struggle to understand their feelings and engage in goal-oriented actions, and, in turn, feel more bored. Theoretical and clinical implications as related to the emotional underpinnings of boredom are discussed.

Examining the Longitudinal Associations between Adjustment Disorder Symptoms and Boredom during COVID-19.

The COVID-19 pandemic has led to a myriad of stressors, underscoring the relevance of adjustment disorder during these extraordinary times. Boredom-as a feeling and as a dispositional characteristic-is an equally pertinent experience during the pandemic that has been cross-sectionally linked to various mental health difficulties. The current longitudinal study expanded on this work, examining the associations between adjustment disorder symptoms and boredom (both as a feeling and as a trait) over time during the COVID-19 pandemic. Community participants completed questionnaires three times, rating their trait boredom at Time 1 and their feelings of boredom and adjustment disorder symptoms (preoccupation with a pandemic stressor and failure to adapt) over the past week at Times 1-3. Latent growth curve analyses found that an increase in feelings of boredom was significantly associated with increased preoccupation with a pandemic stressor and increased difficulties with adapting over time. Additionally, trait boredom significantly predicted changes in preoccupation and the failure to adapt, such that participants high in trait boredom increasingly struggled with these symptoms over time. Our results suggest that increased feelings of boredom and a trait disposition towards boredom can be detrimental to people's ability to adjust over time to the stressors associated with the pandemic. Boredom, as an aversive state and as a chronic difficulty, may be important to address in treatment approaches for adjustment disorder symptoms during COVID-19.

One-cell zygote transfer from diabetic to nondiabetic mouse results in congenital malformations and growth retardation in offspring.

Fetuses of type 1 and 2 diabetic women experience higher incidences of malformations and fetal death as compared with nondiabetics, even when they achieve adequate glycemic control during the first trimester. We hypothesize that maternal diabetes adversely affects the earliest embryonic stage after fertilization and programs the fetus to experience these complications. To test this hypothesis, we transferred either one-cell mouse zygotes or blastocysts from either streptozotocin-induced diabetic or control mice into nondiabetic pseudopregnant female recipients. We then evaluated the fetuses at embryonic d 14.5 to assess fetal growth and the presence or absence of malformations. We found that fetuses from the diabetic mice transferred at the blastocyst stage but also as early as the one-cell zygote stage displayed significantly higher rates of malformations consistent with neural tube closure problems and abdominal wall and limb deformities. In addition, both these groups of fetuses were significantly growth retarded. To determine if this phenomenon was due to high glucose concentrations, two-cell embryos were cultured to a blastocyst stage in 52 mm D-glucose or L-glucose as an osmotic control, transferred into nondiabetic pseudopregnant mice, and examined at embryonic d 14.5. These embryos did not demonstrate any evidence of malformations, however, they did experience significantly higher rates of resorptions, lower implantation rates, and they were significantly smaller at embryonic d 14.5. In summary, exposure to maternal diabetes during oogenesis, fertilization, and the first 24 h was enough to program permanently the fetus to develop significant morphological changes.

Syntaxin 4 expression affects glucose transporter 8 translocation and embryo survival.

Target-soluble N-ethylmaleimide-sensitive factor attachment protein receptors (t-SNAREs) are receptors that facilitate vesicle and target membrane fusion. Syntaxin 4 is the t-SNARE critical for insulin-stimulated glucose transporter 4 (GLUT4)-plasma membrane fusion in adipocytes. GLUT8 is a novel IGF-I/insulin-regulated glucose transporter expressed in the mouse blastocyst. Similar to GLUT4, GLUT8 translocates to the plasma membrane to increase glucose uptake at a stage in development when glucose serves as the main substrate. Any decrease in GLUT8 cell surface expression results in increased apoptosis and pregnancy loss. Previous studies have also shown that disruption of the syntaxin 4 (Stx4a) gene results in early embryonic lethality before embryonic d 7.5. We have now demonstrated that syntaxin 4 protein is localized predominantly to the apical plasma membrane of the murine blastocyst. Stx4a inheritance, as detected by protein expression, occurs with the expected Mendelian frequency up to embryonic d 4.5. In parallel, 22% of the blastocysts from Stx4a+/- matings had no significant insulin-stimulated translocation of GLUT8 whereas 77% displayed either partial or complete translocation to the apical plasma membrane. This difference in GLUT8 translocation directly correlated with one-third of blastocysts from Stx4a+/- mating having reduced rates of insulin-stimulated glucose uptake and 67% with wild-type rates. These data demonstrate that the lack of syntaxin 4 expression results in abnormal movement of GLUT8 in response to insulin, decreased insulin-stimulated glucose uptake, and increased apoptosis. Thus, syntaxin 4 functions as the necessary t-SNARE protein responsible for correct fusion of the GLUT8-containing vesicle with the plasma membrane in the mouse blastocyst.

GLUT9 is differentially expressed and targeted in the preimplantation embryo.

During preimplantation development in the mouse, it is crucial that glucose metabolism not be compromised. Any decrease in glucose uptake at this stage in development can compromise the developing embryo. We have cloned another member of the glucose transporter family, GLUT9, which is expressed embryonically. Three different isoforms were identified. We have shown that two of the mouse GLUT9 isoforms transport glucose at a rate significantly greater than controls. Expression analysis of the preimplantation blastocyst identifies only the presence of the shorter GLUT9 isoform, RT-PCR and Western immunoblot confirmed this finding. A differential pattern of expression was seen with GLUT9 present at the plasma membrane in one- and two-cell zygotes and in an intracellular compartment in trophectoderm cells at a blastocyst stage. Although blocking GLUT9 expression during preimplantation development had no effect on glucose transport or apoptosis, transfer of these embryos into pseudopregnant mice resulted in increased pregnancy loss, suggesting that GLUT9 is critical for early preimplantation development.

AMP kinase activation increases glucose uptake, decreases apoptosis, and improves pregnancy outcome in embryos exposed to high IGF-I concentrations.

Women with polycystic ovarian syndrome are at increased risk of miscarriage. Although evidence exists that metformin reduces this risk, the mechanism is unknown. This study tests the hypothesis that AMP kinase (AMPK) activation with metformin directly improves insulin signaling within the blastocyst, leading to improved pregnancy outcomes. Murine embryos were exposed to 200 nmol/l IGF-I, similar to the concentrations that can occur during polycystic ovary syndrome (PCOS). Resulting blastocysts were compared with embryos cocultured with excess IGF-I plus metformin and embryos cultured in control medium for the following: AMPK phosphorylation, insulin-stimulated glucose uptake, and apoptosis. Study and control blastocysts were also transferred into control animals. On embryonic day (E) 14.5, resulting fetuses were examined for size and rates of fetal implantation and resorption. Compared with control blastocysts, blastocysts exposed to high concentrations of IGF-I showed a decrease in AMPK activation and insulin-stimulated glucose uptake and an increase in the number of apoptotic nuclei. Blastocysts cocultured in metformin and excess IGF-I performed as well as controls in all studies. 5-Aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside, another AMPK activator, also prevented the effects of excess IGF-I on blastocysts. Implantation rates and fetal size at day 14.5 were significantly lower among IGF-I-exposed embryos transferred into control mothers compared with control embryos transferred into control mothers. Both of these parameters were reversed by co-incubation with metformin and IGF-I before transfer. Activation of embryonic AMPK may be the mechanism responsible for the improved pregnancy outcomes seen in PCOS patients taking metformin.

Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts.

The phosphatidylinositol 3-kinase (PI3K) signal transduction pathway is a well known mediator of cell growth, proliferation, and survival signals. Whereas the expression and function of this pathway has been documented during mammalian development, evidence demonstrating the physiologic importance of this pathway in murine preimplantation embryos is beginning to emerge. This study demonstrates that inhibition of the PI3K pathway leads to the induction of apoptosis in both murine blastocysts and trophoblast stem cells. The apoptosis induced in both model systems correlates with a decrease in the expression of the glucose transporter GLUT1 at the plasma membrane. In addition, blastocysts cultured in the presence of the PI3K inhibitor LY-294002 display a decrease in both 2-deoxyglucose uptake and hexokinase activity as compared with control blastocysts. To determine the impact of PI3K inhibition on pregnancy outcome, embryo transfer experiments were performed. Blastocysts cultured in the presence of LY-294002 demonstrate a dramatic increase in fetal resorptions as compared with control embryos. Finally, we demonstrate that impairment of glucose metabolism via iodoacetate, a glyceraldehyde-3-phosphate dehydrogenase inhibitor, is sufficient to induce apoptosis in both blastocysts and trophoblast stem cells. Moreover, blastocysts treated with iodoacetate result in poor pregnancy outcome as determined by embryo transfer experiments. Taken together these data demonstrate the critical importance of the PI3K pathway in preimplantation embryo survival and pregnancy outcome and further emphasize the importance of glucose utilization and metabolism in cell survival pathways.

The PI3K/Akt pathway is present and functional in the preimplantation mouse embryo.

The PI3K/Akt signal transduction pathway is a well-known mediator of growth promoting and cell survival signals. While the expression and function of this pathway have been documented during early and late stages of the reproductive process, currently, there is no evidence demonstrating either the presence or function of the PI3K/Akt pathway in murine preimplantation embryos. We found, using confocal immunofluorescent microscopy and Western blot analysis, that the p 85 and p110 subunits of PI3K and Akt are expressed from the 1-cell through the blastocyst stage of murine preimplantation embryo development. These proteins were localized predominantly at the cell surface from the 1-cell through the morula stage. At a blastocyst stage, both PI3K and Akt exhibited an apical staining pattern in the trophectoderm cells. Interestingly, phosphorylated Akt was detected throughout murine preimplantation development, and its presence at the plasma membrane is a reflection of its activation status. Inhibition of Akt activity had significant effects on the normal physiology of the blastocyst. Specifically, inhibition of this pathway resulted in a reduction in insulin-stimulated glucose uptake. In addition, inhibiting Akt activity resulted in a significant delay in blastocyst hatching, a developmental step facilitating implantation. Finally, we established the presence of this pathway in trophoblast stem (TS) cells, a potentially useful in vitro model to study this signaling cascade. Taken together, these data are the first to demonstrate the presence and function of the PI3K/Akt pathway in mammalian preimplantation embryos.

TRAIL and KILLER are expressed and induce apoptosis in the murine preimplantation embryo.

TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) and KILLER are a death-inducing ligand and receptor pair that belong to the TNF and TNF-receptor superfamilies, respectively. To date, only one apoptosis-inducing TRAIL receptor (murine KILLER [MK]) has been identified in mice, and it is a homologue of human Death Receptor 5. Whereas the expression of other death receptors, such as Fas and TNF receptor 1 have been documented in mammalian preimplantation embryos, no evidence currently demonstrates either the presence or the function of TRAIL and its corresponding death receptor, MK. Using reverse transcription-polymerase chain reaction and confocal immunofluorescent microscopy, we found that both TRAIL and MK are expressed from the 1-cell through the blastocyst stage of murine preimplantation embryo development. These proteins are localized mainly at the cell surface from the 1-cell through the morula stage. At the blastocyst stage, both TRAIL and MK exhibit an apical staining pattern in the trophectoderm cells. Finally, using the TUNEL assay, we demonstrated that MK induces apoptosis in blastocysts sensitized to TRAIL via actinomycin D. Taken together, these data are the first to demonstrate the presence and function of TRAIL and MK, a death-inducing ligand and its receptor, in mammalian preimplantation embryos.