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In this study, we developed a deep neural network (DNN) model with weight correlation descent (WCD) regularization to improve polygenic risk score predictions for complex diseases, specifically gender-specific cancers, using the UK Biobank dataset. Our DNN model with WCD outperformed both conventional PRS models and DNN models without WCD, demonstrating the importance of regularization techniques in enhancing model performance and capturing non-linear effects and interactions in genomic data. These findings contribute to a better understanding of genetic architecture, facilitating personalized interventions based on individual genetic profiles and ultimately benefiting patient care and health outcomes.

Although the primary purpose of signing players is to provide fans with the best on-field performance, players’ role in team branding is another important factor that needs to be considered. Furthermore, as teams are dedicating tremendous time and effort into scouting and with large talent pools available worldwide, teams can easily find players with similar on-field qualities but possess dissimilar brand personalities. Thus, the purpose of the current study is to investigate the role of player signing in team branding. Particularly, this study examined the effect of player-team brand personality alignment on team-related fan responses. The empirical evaluation was undertaken with data collected from an experimental study. The authors empirically demonstrated that player-team brand personality alignment positively affected overall team evaluation and customer-based team brand equity, with more pronounced result for unfamiliar teams. Our findings not only establish the vital role of players in teams’ branding strategies but also uncover when aligned brand personality is more influential in reinforcing brand meaning and shaping affective brand evaluations and customer-based brand equity. The results of the current study fill gaps in the literature and extend the body of knowledge in branding studies in general and sports team branding studies in particular.

Wild-type YAP does not enhance metastasis in zebrafish embryos.

Movie over 12 hours of a whole zebrafish embryo injected with YAP-AA over-expressing A375 cells

Movie of A375 cells over-expressing YAP-AA in the inter-segmental vessels (ISVs) over the course of ~3 hours.

The oncogene YAP has been shown previously to promote tumor growth and metastasis. However, how YAP influences the behavior of tumor cells traveling within the circulatory system has not been as well explored. Given that rate-limiting steps of metastasis are known to occur while tumor cells enter, travel through, or exit circulation, we sought to study how YAP influences tumor cell behavior within the circulatory system. Intravital imaging in live zebrafish embryos revealed that YAP influenced the distribution of tumor cells within the animal following intravenous injection. Control cells became lodged in the first capillary bed encountered in the tail, whereas cells overexpressing constitutively active YAP were able to travel through this capillary plexus, reenter systemic circulation, and seed in the brain. YAP controlled transit through these capillaries by promoting active migration within the vasculature. These results were corroborated in a mouse model following intravenous injection, where active YAP increased the number of circulating tumor cells over time. Our results suggest a possible mechanism whereby tumor cells can spread to organs beyond the first capillary bed downstream from the primary tumor. These results also show that a specific gene can affect the distribution of tumor cells within an animal, thereby influencing the global pattern of metastasis in that animal.Significance:These findings demonstrate that YAP endows tumor cells with the ability to move through capillaries, allowing them to return to and persist in circulation, thereby increasing their metastatic spread.See related commentary by Davidson, p. 3797

Movie of A375 control cells in the tail over the course of 12 hours following injection.

Movie showing blood flow through the Duct of Cuvier of a 2-day-old zebrafish embryo.

Movie over 12 hours of a whole zebrafish embryo injected with EV control A375 cells

Supplementary materials and methods

Movie of A375 EV control cells in the inter-segmental vessels (ISVs) over the course of ~3 hours.

Movie over 12 hours of the head of a zebrafish embryo injected with EV control A375 cells.

Legends for the supplemental figures and videos.

Movie over 12 hours of the head of a zebrafish embryo injected with YAP-AA-over-expressing A375 cells.

Movie of A375 cells over-expressing YAP-AA in the tail over the course of 12 hours following injection.

This empirical study investigated the perceived impacts of the PyeongChang 2018 Winter Olympics on emotional changes and support of residents hosting a mega-event. Pre- and post-event surveys with a homogeneous group were collected from 479 South Koreans who were residents or non-residents of the host region. A paired t-test was used to detect changes in satisfaction and positive affect from before to after the event. Additionally, a mixed linear modelling analyses were conducted where region and event attachment were treated as between-subject variables whereas time was treated as a within-subject variable. The results indicated a significant increase in residents' satisfaction with hosting the mega-event. For the results of positive affect, the levels of positive affect after the mega-event was significantly higher than before the mega-event. Specifically, the levels of host city residents' positive affect were significantly higher than non-host city residents' positive affect. Lastly, event attachment significantly predicted the levels of residents' positive affect, which indicates that people who were emotionally attached to the mega event experienced the higher levels of positive affect than their counterparts who were not emotionally attached.

Previous studies suggested that genetic, environmental factors and their interactions could affect body fat mass (BFM). However, studies describing these effects were performed at a single time point in a population. In this study, we investigated the interaction between genetic and environmental factors in affecting BFM and implicate the healthcare utilization of lifestyle modifications from a personalized and genomic perspective. We examined how nutritional intake or physical activity changes in the individuals affect BFM concerning the genetic composition. We conducted an observational study including 259 adult participants with single nucleotide polymorphism (SNP) genotyping and longitudinal lifestyle monitoring, including food consumption and physical activities, by following lifestyle modification guidance. The participants’ lifelog data on exercise and diet were collected through a wearable device for 3 months. Moreover, we measured anthropometric and serologic markers to monitor their potential changes through lifestyle modification. We examined the influence of genetic composition on body fat reduction induced by lifestyle changes using genetic risk scores (GRSs) of three phenotypes: GRS-carbohydrate (GRS-C), GRS-fat (GRS-F), and GRS-exercise (GRS-E). Our results showed that lifestyle modifications affected BFM more significantly in the high GRS class compared to the low GRS class, indicating the role of genetic factors affecting the efficiency of the lifestyle modification-induced BFM changes. Interestingly, the influence of exercise modification in the low GRS class with active lifestyle change was lower than that in the high GRS class with inactive lifestyle change (P = 0.022), suggesting the implication of genetic factors for efficient body fat control.

Retinal implants electrically stimulate surviving retinal neurons to restore vision in people blinded by outer retinal degeneration. Although the healthy retina is known to transmit a vast amount of visual information to the brain, it has not been studied whether prosthetic vision contains a similar amount of information. Here, we assessed the neural information transmitted by population responses arising in brisk transient (BT) and brisk sustained (BS) subtypes of ON and OFF retinal ganglion cells (RGCs) in the rabbit retina. To correlate the response heterogeneity and the information transmission, we first quantified the cell-to-cell heterogeneity by calculating the spike time tiling coefficient (STTC) across spiking patterns of RGCs in each type. Then, we computed the neural information encoded by the RGC population in a given type. In responses to light stimulation, spiking activities were more heterogeneous in OFF than ON RGCs (STTCAVG = 0.36, 0.45, 0.77 and 0.55 for OFF BT, OFF BS, ON BT, and ON BS, respectively). Interestingly, however, in responses to electric stimulation, both BT and BS subtypes of OFF RGCs showed remarkably homogeneous spiking patterns across cells (STTCAVG = 0.93 and 0.82 for BT and BS, respectively), whereas the two subtypes of ON RGCs showed slightly increased populational heterogeneity compared to light-evoked responses (STTCAVG = 0.71 and 0.63 for BT and BS, respectively). Consequently, the neural information encoded by the electrically-evoked responses of a population of 15 RGCs was substantially lower in the OFF than the ON pathway: OFF BT and BS cells transmit only ~23% and ~53% of the neural information transmitted by their ON counterparts. Together with previously-reported natural spiking activities in ON RGCs, the higher neural information may make ON responses more recognizable, eliciting the biased percepts of bright phosphenes.

This paper (a) analyses the audience of sports broadcasting from a programme repertoire perspective and (b) clarifies the market structure of sports broadcasting in the television industry by estim...

The energetic demands of a cell are believed to increase during mitosis, but the rates of ATP synthesis and consumption during mitosis have not been quantified. Here, we monitor mitochondrial membrane potential of single lymphocytic leukemia cells and demonstrate that mitochondria hyperpolarize from the G2/M transition until the metaphase-anaphase transition. This hyperpolarization was dependent on cyclin-dependent kinase 1 (CDK1) activity. By using an electrical circuit model of mitochondria, we quantify mitochondrial ATP synthesis rates in mitosis from the single-cell time-dynamics of mitochondrial membrane potential. We find that mitochondrial ATP synthesis decreases by approximately 50% during early mitosis and increases back to G2 levels during cytokinesis. Consistently, ATP levels and ATP synthesis are lower in mitosis than in G2 in synchronized cell populations. Overall, our results provide insights into mitotic bioenergetics and suggest that cell division is not a highly energy demanding process., ATP drives most cellular processes, although ATP production and consumption levels during mitosis remain unreported. Here, the authors combine metabolic measurements and modeling to quantify ATP levels and synthesis dynamics, revealing that ATP synthesis and consumption are lowered during mitosis.

Salivary duct carcinoma (SDC) is one of the most aggressive subtypes of salivary gland cancers. Conventional chemotherapy and/or radiation have shown only limited clinical efficacy in the treatment of recurrent or metastatic SDC. Currently, clinically approved targeted-therapeutics are not generally applicable except in very limited cases, and there exists a strong need for the development of treatment against this unique tumor type. To further interrogate genomic features of SDC, we have conducted multi-omic profiling of the SDC to describe the genomic alterations prevalent in this disease. Whole-genome sequencing, whole exome-sequencing and transcriptome sequencing were performed on a discovery cohort of 10 SDC samples. Targeted genomic profiling was performed in additional 32 SDC samples to support the findings obtained from the original discovery cohort. The cancer cohort was characterized by an average mutation burden of 85 somatic exonic mutations per tumor sample. The cohort harbored a mutational signature of BRCA and APOBEC/AID. Several genes, including TP53, RB1, SMAD4, HRAS, APC, PIK3CA and GNAQ were recurrently somatically altered in SDC. A novel fusion gene, generated by genomic rearrangement, MYB-NHSL1, was also noted. Our findings represent a significant layer in the systematic understanding of potentially clinically useful genomic and molecular targets for a subset of recurrent/metastatic SDC.

Significance Cell size is believed to influence cell growth through limited transport efficiency in larger cells. However, this has not been experimentally investigated due to a lack of noninvasive, high-precision growth quantification methods suitable for measuring large cells. Here, we have engineered large versions of microfluidic mass sensors called suspended microchannel resonators in order to study the growth of single mammalian cells that range 100-fold in mass. Our measurements, which decouple growth effects caused by cell cycle and cell size, revealed that absolute cell size does not impose strict transport or other limitations that would inhibit growth and that cell cycle has a large influence on growth., Cell size is believed to influence cell growth and metabolism. Consistently, several studies have revealed that large cells have lower mass accumulation rates per unit mass (i.e., growth efficiency) than intermediate-sized cells in the same population. Size-dependent growth is commonly attributed to transport limitations, such as increased diffusion timescales and decreased surface-to-volume ratio. However, separating cell size- and cell cycle-dependent growth is challenging. To address this, we monitored growth efficiency of pseudodiploid mouse lymphocytic leukemia cells during normal proliferation and polyploidization. This was enabled by the development of large-channel suspended microchannel resonators that allow us to monitor buoyant mass of single cells ranging from 40 pg (small pseudodiploid cell) to over 4,000 pg, with a resolution ranging from ∼1% to ∼0.05%. We find that cell growth efficiency increases, plateaus, and then decreases as cell cycle proceeds. This growth behavior repeats with every endomitotic cycle as cells grow into polyploidy. Overall, growth efficiency changes 33% throughout the cell cycle. In contrast, increasing cell mass by over 100-fold during polyploidization did not change growth efficiency, indicating exponential growth. Consistently, growth efficiency remained constant when cell cycle was arrested in G2. Thus, cell cycle is a primary determinant of growth efficiency. As growth remains exponential over large size scales, our work finds no evidence for transport limitations that would decrease growth efficiency.

Research Questions: The purpose of study was to investigate spectating behavior impacts on the sports fans' life satisfaction. Research Methods: We used multiple regression analysis with survey dat...

Purpose The purpose of this study is to examine and propose the appropriate operation structure for the sports betting business in Korea(Sports Toto) by analyzing foreign cases. Methods To accomplish the purpose of this study, literature and case studies were conducted on preceding studies, the World Lottery Association compendium, and Internet data. Results The results were as follows. Firstly, in terms of competition, it was deducted that maintaining the monopoly method was appropriate among the monopoly, partial competition, and free competition methods. Secondly, as for the business operator, it was deducted reasonable to adopt the non-profit operation method between the non-profit operation and the for-profit operation methods. Also, it was identified as necessary to review the adequacy of the three-level redundant business management structure, which is rarely found abroad. Conclusions This study examined all the sports betting business operation structure of foreign countries presented so far, and deducted a new classification of operation structure considering the competition. The results of this study will be useful for policymakers to review the appropriateness of the Sports Toto’s operation structure more systematically and rationally.

Background The present study investigated the joint impact of adolescent sport experience and dopamine‐related genes (i.e., DRD2 and COMT genes) on sport participation in adulthood. Methods Using the National Longitudinal Study of Adolescent Health (Add Health) data, the hierarchical multivariable logistic regression models for predicting sport participation in wave 3 (around 20 years of age) and wave 4 (around 30 years of age) were conducted separately by gender (male and female) and gene (DRD2 and COMT genes). Results Adolescent sport experience significantly interacted with the number of DRD2 A1 alleles and COMT Met alleles in affecting wave 3 sport participation among male adults. The interaction between adolescent sport experience and DRD2 gene significantly affected wave 4 sport participation in opposite direction to that affected wave 3 sport participation among male participants. Among female participants, there were no significant interaction effects between dopamine‐related genes and adolescent sport experience on sport participation in both wave 3 and 4. Conclusions Since adult sport participation is most likely to be influenced by the joint impact of environmental and genetic factors, it is important to consider gene‐by‐environment interactions when designing policies or programs to promote adult sport participation., The significant effects of the number of DRD2 A1 alleles on wave 3 sport participation became insignificant if male participants actively participated in sports in adolescence, indicating that adolescent sport experience may overpower the effect of DRD2 genes on sport participation in adults aged around 20 years.

Description, Small cell size preserves the function of hematopoietic stem cells (HSCs); HSC enlargement during aging causes their dysfunction., Stem cells are remarkably small. Whether small size is important for stem cell function is unknown. We find that hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferation and was accompanied by altered metabolism. Preventing HSC enlargement or reducing large HSCs in size averts the loss of stem cell potential under conditions causing stem cell exhaustion. Last, we show that murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function in vivo and propose that stem cell enlargement contributes to their functional decline during aging.

Intracellular density impacts the physical nature of the cytoplasm and can globally affect cellular processes, yet density regulation remains poorly understood. Here, using a new quantitative phase imaging method, we determined that dry-mass density in fission yeast is maintained in a narrow distribution and exhibits homeostatic behavior. However, density varied during the cell cycle, decreasing during G2, increasing in mitosis and cytokinesis, and dropping rapidly at cell birth. These density variations were explained by a constant rate of biomass synthesis, coupled to slowdown of volume growth during cell division and rapid expansion post-cytokinesis. Arrest at specific cell-cycle stages exacerbated density changes. Spatially heterogeneous patterns of density suggested links between density regulation, tip growth, and intracellular osmotic pressure. Our results demonstrate that systematic density variations during the cell cycle are predominantly due to modulation of volume expansion, and reveal functional consequences of density gradients and cell-cycle arrests.

Single-celled protists use elaborate cytoskeletal structures, including arrays of microtubules at the cell periphery, to maintain polarity and rigidity. The obligate intracellular parasite Toxoplasma gondii has unusually stable cortical microtubules beneath the alveoli, a network of flattened membrane vesicles that subtends the plasmalemma. However, anchoring of microtubules along alveolar membranes is not understood. Here, we show that GAPM1a, an integral membrane protein of the alveoli, plays a role in maintaining microtubule stability. Degradation of GAPM1a causes cortical microtubule disorganisation and subsequent depolymerisation. These changes in the cytoskeleton lead to parasites becoming shorter and rounder, which is accompanied by a decrease in cellular volume. Extended GAPM1a depletion leads to severe defects in division, reminiscent of the effect of disrupting other alveolar proteins. We suggest that GAPM proteins link the cortical microtubules to the alveoli and are required to maintain the shape and rigidity of apicomplexan zoites., Cortical microtubules of Toxoplasma gondii are exceptionally stable, but it isn’t known how they are anchored along membranes. Here, Harding et al. show that GAPM proteins localize to the inner membrane complex and are essential for maintaining the structural stability of parasites.

Stem cells are remarkably small in size. Whether small size is important for stem cell function is unknown. We find that murine hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferative potential. Preventing HSC enlargement by inhibiting macromolecule biosynthesis or reducing large HSCs size by shortening G1 averts the loss of stem cell potential under conditions causing stem cell exhaustion. Finally, we show that a fraction of murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function in vivo and propose that stem cell enlargement contributes to their functional decline during aging.One Sentence SummarySize increase drives stem cell aging.

Intracellular density is a critical parameter that impacts the physical nature of the cytoplasm and has the potential to globally affect cellular processes. How density is regulated during cell growth is poorly understood. Here, using a new quantitative phase imaging method, we show that dry-mass density varies during the cell cycle in the fission yeast Schizosaccharomyces pombe. Density decreased during G2 phase, increased in mitosis and cytokinesis, and rapidly dropped at cell birth. These density variations can be explained mostly by a constant rate of biomass synthesis throughout the cell cycle, coupled to slowdown of volume growth during mitosis and cytokinesis and rapid expansion post-cytokinesis. Arrest at specific cell-cycle stages led to continued increases or decreases in density. Spatially heterogeneous patterns of density suggested a link between tip growth and density regulation. Density differences between daughter cells in cells delayed in cytokinesis resulted in bending of the septum away from the high-density daughter, suggesting that intracellular density correlates with turgor pressure. Our results demonstrate that the systematic variations in density during the cell cycle are determined predominantly by modulation of volume expansion, and reveal functional consequences of intracellular density gradients.

The oncogene YAP has been shown previously to promote tumor growth and metastasis. However, how YAP influences the behavior of tumor cells traveling within the circulatory system has not been as well explored. Given that rate-limiting steps of metastasis are known to occur while tumor cells enter, travel through, or exit circulation, we sought to study how YAP influences tumor cell behavior within the circulatory system. Intravital imaging in live zebrafish embryos revealed that YAP influenced the distribution of tumor cells within the animal following intravenous injection. Control cells became lodged in the first capillary bed encountered in the tail, whereas cells overexpressing constitutively active YAP were able to travel through this capillary plexus, reenter systemic circulation, and seed in the brain. YAP controlled transit through these capillaries by promoting active migration within the vasculature. These results were corroborated in a mouse model following intravenous injection, where active YAP increased the number of circulating tumor cells over time. Our results suggest a possible mechanism whereby tumor cells can spread to organs beyond the first capillary bed downstream from the primary tumor. These results also show that a specific gene can affect the distribution of tumor cells within an animal, thereby influencing the global pattern of metastasis in that animal. Significance: These findings demonstrate that YAP endows tumor cells with the ability to move through capillaries, allowing them to return to and persist in circulation, thereby increasing their metastatic spread. See related commentary by Davidson, p. 3797

Cell size is believed to influence cell growth and metabolism. Consistently, several studies have revealed that large cells have lower mass accumulation rates per unit mass (i.e. growth efficiency) than intermediate sized cells in the same population. Size-dependent growth is commonly attributed to transport limitations, such as increased diffusion timescales and decreased surface-to-volume ratio. However, separating cell size and cell cycle dependent growth is challenging. To decouple and quantify cell size and cell cycle dependent growth effects we monitor growth efficiency of freely proliferating and cycling polyploid mouse lymphocytes with high resolution. To achieve this, we develop large-channel suspended microchannel resonators that allow us to monitor mass of single cells ranging from 40 pg (small diploid lymphocyte) to over 4000 pg, with a resolution ranging from ~1% to ~0.05%. We find that mass increases exponentially with respect to time in early cell cycle but transitions to linear dependence during late S and G2 stages. This growth behavior repeats with every endomitotic cycle as cells grow in to polyploidy. Overall, growth efficiency changes 29% due to cell cycle. In contrast, growth efficiency did not change due to cell size over a 100-fold increase in cell mass during polyploidization. Consistently, growth efficiency remained constant when cell cycle was arrested in G2. Thus, cell cycle is a primary determinant of growth efficiency and increasing cell size does not impose transport limitations that decrease growth efficiency in cultured mammalian cells.Significance statementCell size is believed to influence cell behavior through limited transport efficiency in larger cells, which could decrease the growth rate of large cells. However, this has not been experimentally investigated due to a lack of non-invasive, high-precision growth quantification methods suitable for measuring large cells. Here, we have engineered large versions of microfluidic mass sensors called suspended microchannel resonators in order to study the growth of single mammalian cells that range 100-fold in mass. This revealed that the absolute size of a cell does not impose strict transport or other limitations that would inhibit growth. In contrast to cell size, however, cell cycle has a relatively large influence on growth and our measurements allow us to decouple and quantify the growth effects caused by cell cycle and cell size.

The energetic demands of a cell are believed to increase during mitosis1–7. As cells transit from G2 into mitosis, mitochondrial electron transport chain (ETC) activity increases4,8,9, and cellular ATP levels progressively decrease until the metaphase-anaphase transition3,7,10, consistent with elevated consumption. The rates of ATP synthesis during mitosis, however, have not been quantified. Here, we monitor mitochondrial membrane potential of single lymphocytes and demonstrate that cyclin-dependent kinase 1 (CDK1) activity causes mitochondrial hyperpolarization from G2/M until the metaphase-anaphase transition. By using an electrical circuit model of mitochondria, we quantify the time-dynamics of mitochondrial membrane potential under normal and perturbed conditions to extract mitochondrial ATP synthesis rates in mitosis. We found that mitochondrial ATP synthesis decreases by approximately 50 % during early mitosis, when CDK1 is active, and increases back to G2 levels during cytokinesis. Consistently, acute inhibition of mitochondrial ATP synthesis failed to delay cell division. Our results provide a quantitative understanding of mitochondrial bioenergetics in mitosis and challenge the traditional dogma that cell division is a highly energy demanding process.

Sporting event attendance is determined by ex ante expectations about the quality of the game, but because changing television channels costs nothing, sporting event viewership is influenced by actual game progression. This implies that demand determinants for televised baseball may change as games progress. This study examined the dynamic relationship between demand for televised baseball games and the uncertainty of outcome hypothesis (UOH). In particular, we analyzed inning-varying coefficients in a television rating regression equation. According to our empirical study, there are large dynamics in TV viewership demand for sports events and the marginal effects of factors on viewership changes significantly as innings progress. The estimation results can be summarized as (1) the UOH was shown to be significant not only statistically but also economically; (2) although ex ante variables were more effective in earlier innings and ex post variables were more effective in later innings, we found that ex ante expectations of outcome uncertainty remain significantly influential in later innings; and (3) after the matchup, the ex ante game quality is the second most significant factor among the examined effects on ratings.

The aim of this paper was to investigate specific mechanisms of how sport fans’ perceived corporate social responsibility (CSR) of teams could enhance their sense of pride, team identification, and regional attachment. The mediating effect of gender was also examined. A theoretical research model was investigated via multi-group structural equation modeling (SEM) using 317 survey responses. The results indicate that pride is an important mediator of the relationship between perceived CSR and team identification, and team identification was found an important predictor of regional attachment. Additionally, the results suggest that these relationships were much stronger amongst males. In both genders, perceived CSR was an important indicator for enhancing pride.