DCC, a potential target for controlling fear memory extinction and hippocampal LTP in male mice receiving single prolonged stress.

Post-traumatic stress disorder (PTSD) is a severe stress-dependent psychiatric disorder characterized by impairment of fear memory extinction; however, biological markers to determine impaired fear memory extinction in PTSD remain unclear. In male mice with PTSD-like behaviors elicited by single prolonged stress (SPS), 19 differentially expressed proteins in the hippocampus were identified compared with controls. Among them, a biological macromolecular protein named deleted in colorectal cancer (DCC) was highly upregulated. Specific overexpression of DCC in the hippocampus induced similar impairment of long-term potentiation (LTP) and fear memory extinction as observed in SPS mice. The impairment of fear memory extinction in SPS mice was improved by inhibiting the function of hippocampal DCC using a neutralizing antibody. Mechanistic studies have shown that knocking down or inhibiting µ-calpain in hippocampal neurons increased DCC expression and induced impairment of fear memory extinction. Additionally, SPS-triggered impairment of hippocampal LTP and fear memory extinction could be rescued through activation of the Rac1-Pak1 signaling pathway. Our study provides evidence that calpain-mediated regulation of DCC controls hippocampal LTP and fear memory extinction in SPS mice, which likely through activation of the Rac1-Pak1 signaling pathway.

Increased matrix stiffness in pituitary neuroendocrine tumors invading the cavernous sinus is activated by TAFs: focus on the mechanical signatures.

PURPOSE: Pituitary neuroendocrine tumors (PitNETs) with invasion of the cavernous sinus (CS) are particularly challenging to treat. Tumor associated fibroblasts (TAFs) are recognized for their pivotal role in reprogramming extracellular matrix (ECM). Herein, we aimed to explore the potential involvement of TAFs in ECM reprogramming and elucidate the underlying mechanism involved. METHODS: We applied dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to measure tumor vessel permeability and applied atomic force microscopy (AFM) to measure the matrix stiffness of PitNETs located in both CS and sella turcica (ST). Western blotting, immunofluorescence, immunohistochemistry, and quantitative RT-PCR were utilized to analyze the ECM components. Proteomic biochemical analysis was utilized to uncover potential mechanisms governing ECM dynamics. RESULTS: We found that PitNETs in the CS were stiffer than those in the ST. Increased ECM stiffness within the CS facilitated the acquisition of stem-like properties, enhanced proliferation, and induced epithelial-to-mesenchymal transition (EMT) of GH3 cells. Furthermore, the expression levels of lysyl oxidase (LOX), matrix metallopeptidase 2 (MMP2) and MMP9 in pituitary adenoma cells increased in the stiffer matrix. Proteomic analysis suggested TAFs were activated in the CS area and contributed enhanced matrix stiffness by secreting Col-1 and Col-3. Furthermore, mTOR pathway was activated under higher matrix stiffness and the migration and invasion of GH3 cells be repressed by mTOR inhibitor. CONCLUSION: These findings demonstrated that activated TAFs contributed to stiffer matrix and increased ECM stiffness stimulating mTOR pathway in pituitary tumor cells. Our study indicated that mTOR inhibitor was a promising treatment strategy from the standpoint of PitNET biomechanical properties.

Novel mechanisms of Anshen Dingzhi prescription against PTSD: Inhibiting DCC to modulate synaptic function and inflammatory responses.

ETHNOPHARMACOLOGICAL RELEVANCE: Anshen Dingzhi prescription (ADP), documented in "Yi Xue Xin Wu", is a famous prescription for treating panic-related mental disorders such as post-traumatic stress disorder (PTSD). However, the underlying mechanism remains unclear. AIM OF THE STUDY: This study aimed to investigate the mechanisms by which ADP intervened in PTSD-like behaviors. METHODS: A mouse model of single prolonged stress (SPS) was established to evaluate the ameliorative effects and mechanisms of ADP on PTSD. Behavioral tests were used to assess PTSD-like behaviors in mice; transmission electron microscopy was used to observe changes in the ultrastructure of hippocampal synapses, and western blot, immunofluorescence, and ELISA were used to detect the expression of hippocampal deleted in colorectal cancer (DCC) and downstream Ras-related C3 botulinum toxin substrate 1 (Rac1) - P21-activated kinase 1 (PAK1) signal, as well as levels of synaptic proteins and inflammatory factors. Molecular docking technology simulated the binding of potential brain-penetrating components of ADP to DCC. RESULTS: SPS induced PTSD-like behaviors in mice and increased expression of hippocampal netrin-1 (NT-1) and DCC on the 14th day post-modeling, with concurrent elevation in serum NT-1 levels. Simultaneously, SPS also decreased p-Rac1 level and increased p-PAK1 level, the down-stream molecules of DCC. Lentiviral overexpression of DCC induced or exacerbated PTSD-like behaviors in control and SPS mice, respectively, whereas neutralization antibody against NT-1 reduced DCC activation and ameliorated PTSD-like behaviors in SPS mice. Interestingly, downstream Rac1-PAK1 signal was altered according to DCC expression. Moreover, DCC overexpression down-regulated N-methyl-d-aspartate (NMDA) receptor 2A (GluN2A) and postsynaptic density 95 (PSD95), up-regulated NMDA receptor 2B (GluN2B) and increased neuroinflammatory responses. Administration of ADP (36.8 mg/kg) improved PTSD-like behaviors in the SPS mice, suppressed hippocampal DCC, and downstream Rac1-PAK1 signal, upregulated GluN2A and PSD95, downregulated GluN2B, and reduced levels of inflammatory factors NOD-like receptor protein 3 (NLRP3), nuclear factor kappa-B (NF-κB) and interleukin-6 (IL-6). Importantly, DCC overexpression could also reduce the ameliorative effect of ADP on PTSD. Additionally, DCC demonstrated a favorable molecular docking pattern with the potential brain-penetrating components of ADP, further suggesting DCC as a potential target of ADP. CONCLUSION: Our data indicate that DCC is a key target for the regulation of synaptic function and inflammatory response in the onset of PTSD, and ADP likely reduces DCC to prevent PTSD via modulating downstream Rac1-PAK1 pathway. This study provides a novel mechanism for the onset of PTSD and warrants the clinical application of ADP.

Comparison of Financial Hardship and Healthcare Utilizations Associated with Cancer in the United States Medicare Programs during the COVID-19 Pandemic.

BACKGROUND: In the United States, Medicare beneficiaries diagnosed with cancer often face significant financial challenges due to the expensive nature of cancer treatments and increased cost-sharing responsibilities. However, there is limited knowledge regarding the financial hardships and healthcare utilizations faced by those enrolled in Medicare Advantage (MA) compared to those in traditional fee-for-service Medicare (TM) during the COVID-19 pandemic. Our study aims to investigate the subjective financial hardships experienced by individuals enrolled in TM and MA and to determine whether these two Medicare programs exhibit differences in healthcare utilization during the pandemic. METHODS: We utilized data from the 2020-2022 National Health Interview Survey (NHIS), focusing on nationally representative samples of cancer survivors aged 65 or older. Financial hardship was categorized into three distinct groups: material (e.g., problems with medical bills), psychological (e.g., worry about paying), and behavioral (e.g., delayed care due to cost). Healthcare utilization included wellness visits (preventive care), emergency care services, hospitalizations, and telehealth. We used survey design-adjusted analysis to compare the study outcomes between MA and TM. RESULTS: Among a weighted sample of 4.4 million Medicare beneficiaries with cancer (mean age: 74.9), 76% were enrolled in MA plans. Cancer survivors with a college degree (59.3% vs. 49.8%) and high family income (38.2% vs. 31.1%) were more likely to enroll in MA plans. There were no significant differences in any material, psychological, or behavioral financial hardship domains between beneficiaries with MA and TM plans except forgone counseling due to cost. For healthcare utilization measures, cancer survivors in MA were more likely than those in TM to have flu vaccination (77.2% vs. 70.1%) and experience lower hospitalizations (16.0% vs. 20.0%). However, there were no differences in other health service utilizations between MA and TM. CONCLUSION: While no significant differences were observed in any materialized, psychological, or behavioral financial hardships, older cancer survivors enrolled in MA plans were more likely to receive vaccinations and lower hospitalization rates during COVID-19. Although other preventive or primary care visits (i.e., wellness visits) were higher, their difference did not reach statistical significance. As MA grows in popularity, it is essential to consistently monitor and evaluate the performance and outcomes of Medicare plans for cancer survivors as we navigate the post-pandemic landscape.

Naturally aged polylactic acid microplastics stunted pakchoi (Brassica rapa subsp. chinensis) growth with cadmium in soil.

Biodegradable microplastics (BMPs) and cadmium (Cd) are posing threats to agro-systems especially to plants and current studies mostly used virgin BMPs to explore their ecological effects. However, effects of naturally aged BMPs and their combined effects with Cd on pakchoi are yet to be unraveled. Therefore, this study incubated naturally aged polylactic acid (PLA) MPs through soil aging process and investigated the single and combined effects of Cd and PLA MPs (virgin and aged) on pakchoi (Brassica rapa subsp. chinensis) morphology, antioxidant systems and soil microbial activities. Our results found that after being deposited in soil for six months, aged PLA (PLAa) MPs formed with a fractured surface, demonstrating more detrimental effects on pakchoi than virgin ones. PLA/PLAa MPs and Cd stunted pakchoi growth, caused oxidative stress and altered the biophysical environment in soil, separately. Moreover, co-existence of PLA/PLAa MPs and Cd caused greater damages to pakchoi than applied alone. The co-presence of PLAa MPs and Cd inhibited pakchoi biomass accumulation rate by 92.2 % compared with the no-addition group. The results unraveled here emphasized BMPs, especially aged BMPs, could trigger negative effects on agro-systems with heavy metals. These findings will give reference to future holistic assessments of BMPs' ecological effects.

Fear of progression and its associated factors in parents of children undergoing cancer treatment: A cross-sectional study.

OBJECTIVE: Fear of progression (FoP) is a common psychosocial problem among adult cancer patients, but data on parents of children undergoing cancer treatment are scarce. This study aimed to determine the prevalence of FoP in parents of children undergoing cancer treatment and explore the associated factors. METHODS: Overall, 285 parents of children undergoing cancer treatment were recruited from three general hospitals in China. FoP in the parents was assessed using the Chinese version of the Fear of Progression Questionnaire-parent version (FoP-Q-SF/PR). Other questionnaires included the Self-Compassion Scale, Pittsburgh Sleep Quality Index, Posttraumatic Stress Disorder Checklist-Civilian Version, and items on socio-demographic and medical characteristics. Pearson correlation and multiple linear regression analysis were used to identify factors associated with FoP. RESULTS: A total of 75.1% of the participants showed dysfunctional levels of FoP. The mean FoP-Q-SF/PR score was 39.98 (standard deviation = 9.18). Parental FoP was significantly associated with a shorter time since diagnosis, lower levels of self-compassion, poor sleep quality, and severe posttraumatic stress symptoms (Adjusted R Squared = 0.369, F = 12.838, p < 0.01). CONCLUSIONS: FoP is a frequently reported problem among parents of children undergoing cancer treatment. In this cohort, parents of children with a shorter time since cancer diagnosis were at higher risk of suffering from FoP. Interventions to enhance self-compassion, improve sleep quality, and mitigate posttraumatic stress symptoms may help with the psychological adjustment and well-being of parents whose children are undergoing cancer treatment.

Introgressing the Aegilops tauschii genome into wheat as a basis for cereal improvement.

Increasing crop production is necessary to feed the world's expanding population, and crop breeders often utilize genetic variations to improve crop yield and quality. However, the narrow diversity of the wheat D genome seriously restricts its selective breeding. A practical solution is to exploit the genomic variations of Aegilops tauschii via introgression. Here, we established a rapid introgression platform for transferring the overall genetic variations of A. tauschii to elite wheats, thereby enriching the wheat germplasm pool. To accelerate the process, we assembled four new reference genomes, resequenced 278 accessions of A. tauschii and constructed the variation landscape of this wheat progenitor species. Genome comparisons highlighted diverse functional genes or novel haplotypes with potential applications in wheat improvement. We constructed the core germplasm of A. tauschii, including 85 accessions covering more than 99% of the species' overall genetic variations. This was crossed with elite wheat cultivars to generate an A. tauschii-wheat synthetic octoploid wheat (A-WSOW) pool. Laboratory and field analysis with two examples of the introgression lines confirmed its great potential for wheat breeding. Our high-quality reference genomes, genomic variation landscape of A. tauschii and the A-WSOW pool provide valuable resources to facilitate gene discovery and breeding in wheat.