What is the relationship between mitochondria of granulosa cells (GCs) and age and ovarian function in the patients under the POSEIDON classification? Our results revealed obvious abnormal mitochondrial-related changes in low prognosis IVF population, where age and the function of ovarian reserve exerted a divergent effect on mitochondrial content and function. Mitochondria have an important role in the cross-talk between GCs and oocytes. However, factors affecting mitochondria of GCs and related mechanisms are still poorly understood. GCs samples were obtained from 119 infertile women undergoing IVF from September 2020 to February 2021. Six groups were investigated by the POSEIDON stratification: young with normal prognosis (C1), aging with normal prognosis (C2), young and low prognosis group with normal ovarian reserve (NOR) (G1), aging and low prognosis group with NOR (G2), young and low prognosis group with diminished ovarian reserve (DOR) (G3), and aging and low prognosis group with DOR (G4). The morphology of GC mitochondria was observed by transmission electron microscopy. MtDNA copy number and mitochondrial replication-related genes were detected by real-time quantitative PCR (qPCR). Mitochondrial membrane potential (MMP) and cytosolic reactive oxygen species (ROS) were detected by confocal microscopy. Cellular glycolysis and aerobic respiratory capacity were analyzed by Seahorse XFe96 Analyzer, and related gene expression and protein levels were assessed by qPCR and Western blot. Compared to the normal prognosis groups, mitochondrial morphology was impaired in the low prognosis groups, where the young groups (G1, G3) with low prognosis showed phenotypes undergoing oxidative stress (round, vacuolated, swollen with decreased matrix density) and the aging groups (G2, G4) revealed typical aging characteristics (an irregular shape with heterogeneous matrix density and cord-like cristae). Additionally, the degree of corresponding change and damage was more obvious in patients with DOR (G3, G4) regardless of age. For mitochondrial content, the mtDNA copy number in GCs was significantly negatively correlated with age in the low prognosis groups (β = −0.373, P = 0.005). Interestingly, the relationship between mtDNA copy number and anti-Mullerian hormone score differed between the two age groups with low prognosis, with a negative correlation in the young groups (β = −0.639, P = 0.049) and a positive correlation in the aging groups (β = 0.505, P = 0.039). In addition, significantly reduced mitochondrial activity (MMP, ROS) and cell metabolism (both glycolysis and OXPHOS) were observed in the low prognosis groups, with the most obvious decrease being observed in the DOR population. However, the metabolism of the GCs in normal prognosis aging women (C2) shifted from OXPHOS to anaerobic glycolysis. Owing to the difficulties involved in primary GC collection and culture, the sample size was limited. Mitochondrial abnormality is closely linked to the low prognostic outcome in IVF patients. Supplementing the functional mitochondrial content or improving mitochondrial function by autologous mitochondrial transfer or mitochondrial-related regulating drugs may help improve the clinical outcomes in patients with a low prognosis, especially for those with DOR. This work was supported by the National Natural Science Foundation of China (No. 21737001), the Peking University Clinical Medicine + X Youth Project (PKU2020LCXQ011), the Research and Development Program of Peking University People’s Hospital (No. RDH2017-03; No. RDX2019-06) and the Application of Clinical Features of Capital Special Subject (Z171100001017130). There were no competing interests. This study was registered with the Chinese Clinical Trial Register (Clinical Trial Number: ChiCTR2100045531).

Diminished interest constitutes a core behavioral deficit across multiple neuropsychiatric conditions, yet its neural mechanism remains poorly understood. Here, we identify projection-biased and transcriptionally distinct subsets of glutamatergic neurons in the ventromedial prefrontal cortex (vmPFC) that preferentially innervate the anterior piriform cortex (APC) and posterior piriform cortex (PPC). By establishing a behavioral paradigm that selectively captures interest-related behaviors, we reveal that the vmPFC^glu-PPC, but not the vmPFC^glu-APC, circuit governs interest-related engagement without affecting olfactory function. This regulation is encoded by AMPAR-dependent burst firing in PPC neurons. Chronic stress selectively weakens this cortico-cortical pathway, reducing glutamatergic transmission and impairing burst firing in PPC neurons, thereby leading to deficits in interest-related behavior in mice. Targeted reactivation of the vmPFC^glu-PPC circuit rescues these behavioral impairments. Collectively, our findings uncover a previously unrecognized cortical pathway dedicated to interest encoding and establish a circuit-level framework for explaining the selective vulnerability of interest under chronic stress.

Background/Objectives: This paper describes the use of physiologically based biopharmaceutics modelling (PBBM) to predict the effect of food on diclofenac and ibuprofen absorption from ultra-rapid-release Surge Dose^® tablets. Methods: Fasted-state diclofenac pharmacokinetics (PK) were used with published IV data and biorelevant dissolution data for the diclofenac tablets to develop a mechanistic PBBM model which could be used to predict absorption. Results: The resultant model that best fitted the PK data showed that, in vivo, the ultra-rapid-release tablets behaved like a solution with a median time to peak plasma concentration (T_max) of 20 min. Incorporating a well-established model for gastric emptying in the fed state, the fed T_max for these tablets was predicted to be 21 min, similar to that seen in fasted subjects. Use of a PBBM model to predict absorption of ibuprofen in the fasted and fed states again showed that ultra-rapid-release tablets produced fast and consistent absorption independent of the presence of food. Predicted mean T_max values were 31.8 and 35.4 min in the fasted and fed states, respectively. Conclusions: Therefore, even if Surge Dose^® formulations are taken after food, as frequently recommended for NSAIDs, the speed of absorption and subsequent onset of action should not be impacted.