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Simple Summary: Cancer arises through the accumulation of somatic mutations in key biological pathways. This paper aims to develop a probabilistic approach to delineate the temporal order of mutations during cancer development based on mutation profile data from a cohort of patients. A unique feature of our method is that it incorporates intra-tumor heterogeneity (ITH) information, which refers to the heterogeneous cell populations within a tumor and characterizes the evolutionary history of the tumor. We showed that by integrating ITH, pathways, and functional annotation information, our method yielded high accuracy in inferring the temporal order of pathway mutations during carcinogenesis. The development of cancer involves the accumulation of somatic mutations in several essential biological pathways. Delineating the temporal order of pathway mutations during tumorigenesis is crucial for comprehending the biological mechanisms underlying cancer development and identifying potential targets for therapeutic intervention. Several computational and statistical methods have been introduced for estimating the order of somatic mutations based on mutation profile data from a cohort of patients. However, one major issue of current methods is that they do not take into account intra-tumor heterogeneity (ITH), which limits their ability to accurately discern the order of pathway mutations. To address this problem, we propose PATOPAI, a probabilistic approach to estimate the temporal order of mutations at the pathway level by incorporating ITH information as well as pathway and functional annotation information of mutations. PATOPAI uses a maximum likelihood approach to estimate the probability of pathway mutational events occurring in a specific sequence, wherein it focuses on the orders that are consistent with the phylogenetic structure of the tumors. Applications to whole exome sequencing data from The Cancer Genome Atlas (TCGA) illustrate our method's ability to recover the temporal order of pathway mutations in several cancer types. [ABSTRACT FROM AUTHOR]

Simple Summary: Glycolysis and oxidative phosphorylation play important roles in the progression and growth of cancers. The development of natural products and their semisynthetic derivatives for cancer treatment is a longstanding focus of our research interests. We developed compounds known as diaminobutoxy-substituted isoflavonoids (DBIs) that effectively stimulated Adenosine 5′ Monophosphate-activated Protein Kinase (AMPK) and suppressed the growth of colorectal cancer cells by specifically targeting mitochondrial complex I. We now report a new DBI analog, namely, DBI-2, with promising properties for cancer treatment. The combination of DBI-2 and BAY-876, a glucose transporter 1 inhibitor, exhibited synergistic effects on colorectal cancer cells. Furthermore, the therapeutic effectiveness of DBI-2 in colorectal cancer cell xenograft mouse models was enhanced by implementing a ketogenic diet, an outcome that indicated this drug/diet combination is a potentially promising combination strategy for cancer therapy. Cancer cells undergo a significant level of "metabolic reprogramming" or "remodeling" to ensure an adequate supply of ATP and "building blocks" for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I. Furthermore, DBI-1 and a glucose transporter 1 (GLUT1) inhibitor, BAY-876, synergistically inhibited CRC cell growth in vitro and in vivo. We now report a study of the structure–activity relationships (SARs) in the isoflavonoid family in which we identified a new DBI-1 analog, namely, DBI-2, with promising properties. Here, we aimed to explore the antitumor mechanisms of DBIs and to develop new combination strategies by targeting both glycolysis and OXPHOS. We identified DBI-2 as a novel AMPK activator using an AMPK phosphorylation assay as a readout. DBI-2 inhibited mitochondrial complex I in the Seahorse assays. We performed proliferation and Western blotting assays and conducted studies of apoptosis, necrosis, and autophagy to corroborate the synergistic effects of DBI-2 and BAY-876 on CRC cells in vitro. We hypothesized that restricting the carbohydrate uptake with a KD would mimic the effects of GLUT1 inhibitors, and we found that a ketogenic diet significantly enhanced the therapeutic efficacy of DBI-2 in CRC xenograft mouse models, an outcome that suggested a potentially new approach for combination cancer therapy. [ABSTRACT FROM AUTHOR]

The implementation of China's rural homestead withdrawal policy has been a topic of great interest in recent years. However, little is known about its impact on farmers' homestead withdrawal behavior from the perspective of psychological resilience. This study aims to evaluate the impact of psychological resilience on farmers' homestead withdrawal behavior and to explore its mechanism and heterogeneity, as well as its impact on compensation choices. The research data was collected through a survey of 657 rural households in Shaanxi and Shandong provinces. The probit model and mediation effect model were used to analyze the data. The results demonstrate that psychological resilience positively affects farmers' homestead withdrawal behavior; this finding is robust. Specifically, the positive influence of stability and adaptability dimensions of psychological resilience is more significant. Moreover, the effect of psychological resilience varies across different family life cycles, and it has a stronger promoting effect on the homestead withdrawal behavior of child-raising families. Mechanism analysis indicates that psychological resilience can promote homestead withdrawal behavior by reducing farmers' land dependence consciousness and improving farmers' risk preferences. Finally, farmers with strong psychological resilience are more inclined to choose cash compensation. Based on these findings, this paper proposes targeted policy recommendations for rural homestead system reform. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has adversely impacted the agricultural supply chain, export of agricultural products, and overall food security. However, minimal exploration has been attempted of farmers' confidence in agricultural production recovery after the COVID-19 pandemic. Therefore, this study intends to explore the determinants of farmers' confidence in agricultural production recovery in China during the early stages of the COVID-19 pandemic. More specifically, we analyzed the relationship between risk expectation and social support on the farmers' confidence in agricultural production recovery by using the ordered probit model. Cross-sectional survey data were collected from February to March 2020 from 458 farm households in the 7 provinces of China to produce the findings. We found that the risk expectation of farmers had a significant negative impact on farmers' confidence in agricultural production recovery. Social support seemingly had a significant positive impact on the farmers' confidence in agricultural production recovery, and could play a supportive role in moderating the relationship between risk expectation and farmers' confidence in recovery. However, social support alleviates the adverse effect of risk expectation on farmers' confidence in agricultural production recovery to a certain extent. In addition, there were intergenerational differences in the effects of risk expectation and social support on farmers' confidence in agricultural production recovery. These results imply that policies establishing the risk early warning mechanisms for agricultural production and strengthening the social support from governments and financial institutions are likely to significantly impact agricultural development in the post-COVID-19 era. The formal and informal risk minimization mechanisms should extend their support to vulnerable sectors such as agribusiness. [ABSTRACT FROM AUTHOR]