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Lysosome is closely linked to autophagy, which plays a vital role in pancreatic adenocarcinoma (PDAC) tumor biology. This study investigated whether lysosome storage dysfunction (LSD) contributes to PDAC development. Germline putative pathogenic variants (PPVs) in genes involved in lysosome functions were compared between PDAC patients (N=418) and healthy controls (N=845). Furthermore,Galc-knockout mouse pancreas organoids and human PDAC organoids were used to evaluate the consequences of PPV status in PDAC development and establishment. LSD PPVs were enriched in PDAC patients (Log2OR=1.65, P=3.08×10−3). PPV carriers diagnosed with PDAC were younger than non-carriers (61.5 vs. 65.3 years, P=0.031). Hampered autophagolysosome activity with increased autophagy flux and elevated Ki-67 index were observed following GALC downregulation. RNA sequencing of human PDAC organoids revealed upregulation of metabolism related to LSD. Genetically defined lysosome dysfunction is frequently observed in young-age onset PDACs. Lysosome dysfunction might contribute to PDAC development via altered metabolism and impaired autophagolysosome activity.

Hepatocellular carcinoma (HCC) is an aggressive and incurable cancer. Although understanding of the molecular pathogenesis of HCC has greatly advanced, therapeutic options for the disease remain limited. In this study, we demonstrated that SETD5 expression is positively associated with poor prognosis of HCC and that SETD5 depletion decreased HCC cell proliferation and invasion while inducing cell death. Transcriptome analysis revealed that SETD5 loss downregulated the interferon-mediated inflammatory response in HCC cells. In addition, SETD5 depletion downregulated the expression of a critical glycolysis gene, PKM (pyruvate kinase M1/2), and decreased glycolysis activity in HCC cells. Finally, SETD5 knockdown inhibited tumor growth in xenograft mouse models. These results collectively suggest that SETD5 is involved in the tumorigenic features of HCC cells and that targeting SETD5 may suppress HCC progression.

Oxygen deprivation (hypoxia), which frequently occurs in the tumour microenvironment, is a strong driver of the phenotypic transition of cancer cells. An increase in metastatic potential such as cell invasion is a well-known phenotypical change induced in hypoxia. The present study demonstrated that lysine demethylase 3A (KDM3A), a Jumonji C domain-containing KDM, is involved in the hypoxia-induced invasion of MCF7 breast cancer cells. KDM3A depletion inhibits the induction of cell invasion without affecting MCF7 cell survival rate or proliferation under hypoxic conditions, whereas KDM3A overexpression enhances MCF7 cell invasion even under normoxic conditions. KDM3A suppresses E-cadherin expression, which is associated with epithelial-to-mesenchymal transition (EMT)-mediated cell invasion in hypoxia. In addition, KDM3A promotes the expression of Slug, an EMT transcription factor that negatively regulates E-cadherin expression. Consistent with this finding, the removal of the repressive transcription marker, dimethylated histone H3 at lysine 9 from the Slug promoter is dependent on hypoxia-induced recruitment of KDM3A. Collectively, the results of the present study suggest that KDM3A is a crucial transcriptional coactivator of Slug expression to induce MCF7 breast cancer cell invasion in hypoxia, and that inhibition of KDM3A may efficaciously prevent metastatic cancer development.

Oxygen deprivation induces a range of cellular adaptive responses that enable to drive cancer progression. Here, we report that lysine‐specific demethylase 1 (LSD1) upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia‐inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen‐independent degradation of HIF‐1α. This ability of LSD1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide (FAD), a metabolic cofactor of LSD1, causing HIF‐1α downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF‐1α stability, indicating a rate‐limiting role for FAD in LSD1‐mediated HIF‐1α regulation. Transcriptomic analyses of patient tissues show that the HIF‐1 signature is highly correlated with the expression of LSD1 target genes as well as the enzymes of FAD biosynthetic pathway in triple‐negative breast cancers, reflecting the significance of FAD‐dependent LSD1 activity in cancer progression. Together, our findings provide a new insight into HIF‐mediated hypoxia response regulation by coupling the FAD dependence of LSD1 activity to the regulation of HIF‐1α stability.

Additional file 3: Supplemental Table 3. Results of short tandem repeat (STR) profiling (HPBIO, Inc., Seoul, South Korea).

Additional file 1: Supplemental Table 1. RT-PCR primer list.

Additional file 2: Supplemental Table 2. Information of metastatsis tissue from a human colon cancer tissue array (CDA3-G, SuperBioChips).

This paper explores the trajectories of black manhood and fatherhood in modern and contemporary American literature and literary criticism and contemplates a possible space for “good” black fathers. As we investigate how earlier discourses and discussions on black manhood have been constructed, and have remained and developed, there certainly is a change or progress in reading and creating different types of representations of black men — without focusing too much on body and sexuality — in American literature and literary criticism, starting from a ragged image considered problematic, violent, dangerous, or bereft, and under institutionalized destitution. This denigration of the black male has intensified and solidified myths of the black family — a black matriarchal family that lacks a desirable father figure, consequently leading to the effeminized, castrated black masculine presence in their communities — but has come to be questioned, leading to a somewhat hopeful, positive, and even philosophical depiction by questioning the core of defining good and bad under the dire circumstances within which African American men find themselves. By scrutinizing innocuous, caregiving father figures dwelling at home in African American novels, this paper looks back at how literary criticism and literature itself have exercised creative power in order to give birth to the “good” black men, who were deemed nonexistent or insufficient before, through re -reading, re -tracing, and re -looking at black fathers/men in novels written by renowned literary figures from Richard Wright, Ralph Ellison, James Baldwin, and Toni Morrison to contemporary — and relatively young — authors such as Leonard Pitts Jr. and Bernice L. McFadden.

Sherman Alexie’s 2007 young adult fiction, The Absolutely True Diary of a Part-Time Indian, depicts the life of a young Spokane Indian boy named Arnold Spirit Jr., and the writer tries to show how this young protagonist deals with his identity issues both on the reservation and at a white school. Off the poor reservation where limitations make him a loser, he needs to balance his Indian identity and agency with the white American identity he has come into contact with. The final answer, outcome, or resolution of his long search and struggle is to become a nomad (an old-time Indian way of life) or to become Nomad (an alternative superhero identity of Captain America). Following Junior’s track, Alexie implies that there should be a new form of identity for the young generation, because obviously there is none, for them, available now. Giving them a reachable, accessible form of identity and heroic figure would lead young readers like Junior to dreams of being someone important.

The purpose of this study is to analyze the performance of the flow control oil pump for automatic transmission. The numerical model for analysis the performance of the flow control oil pump was develop and the characteristics of the internal flow, discharge flow rate, displacement of outer ring, driving torque, generation of cavitation was investigated according to rotating speed. As a result, the cavitation generation increased as the rotating speed increased. The volumetric efficiency was 90% for 2200 rpm and it decreased rapidly, then it decreased about 81% for 5000 rpm. Besides, the cavitation generation was 20%∼30% for inlet of suction part, but it reduced below 13% owing to the compression. However, it shows higher cavitation generation for high rotating speed like 5000 rpm.

Understanding one's pet has been an interest among animal owners for a long time. Dogs take up 90% of animals that are kept as pets and dog owners are interested in understanding their dogs in order to form a closer bond. Communication with one's dog is not only important for a healthy relationship, but it can also prevent possible harms that dogs can do. There are already proceeding works on understanding dogs based on body language, but for ordinary pet owners, the signs that their dogs give can only be vague and confusing. This paper proposes a device that offers a more subjective and easier way to interpret a dog's emotion by monitoring its heart rate. Heart rate is a possible indication for emotion, and it has been found that heart rate variability patterns are consistently the most dynamic and reflective of changes in one's emotional state. By measuring a canine's heartbeat and analyzing it, it would be possible to induce their emotions. By using photograph to capture the situation that makes the dog's heartbeat change will make it easier for owners to understand what makes the dog undergo emotional changes.

Epithelial-mesenchymal transition (EMT) is an important process implicated in tumor invasion and metastasis. Twist1 is a transcription factor that induces EMT, including E-cadherin suppression and cancer cell migration and invasion; hence it promotes cancer metastasis. Twist1 directly or indirectly regulates the expression of various genes and cellular functions involved in cancer progression. However, the underlying mechanisms remain largely unknown. In this study, we investigated the molecular basis for Twist1-mediated invasion and EMT. In human cancer cells, Twist1 was found to directly upregulate transcription of the mesenchymal gene integrin α5 in an E-box-independent, but activating protein-1 (AP-1) element-dependent, manner. Twist1 activated the integrin α5 promoter by interacting with and activating the transcription factor AP-1, composed of c-Jun and activating transcription factor-2 (ATF-2); it also enhanced the nuclear presence of ATF-2. AP-1 was critical for Twist1-induced cancer cell invasion, primarily through the induction of integrin α5, which activated c-Jun N-terminal kinase and focal adhesion kinase-signaling activities. Using data from The Cancer Genome Atlas, we found that Twist1 expression positively correlates with integrin α5 expression in human colorectal cancers. These findings suggest that cooperation between Twist1 and AP-1 represents a novel mechanism for EMT and tumor invasiveness. This study supports further investigation into the molecular basis underlying the diverse Twist1-mediated functions that occur during tumor progression.