Ibrutinib disrupts blood-tumor barrier integrity and prolongs survival in rodent glioma model.

In malignant glioma, cytotoxic drugs are often inhibited from accessing the tumor site due to the blood-tumor barrier (BTB). Ibrutinib, FDA-approved lymphoma agent, inhibits Bruton tyrosine kinase (BTK) and has previously been shown to independently impair aortic endothelial adhesion and increase rodent glioma model survival in combination with cytotoxic therapy. Yet additional research is required to understand ibrutinib's effect on BTB function. In this study, we detail baseline BTK expression in glioma cells and its surrounding vasculature, then measure endothelial junctional expression/function changes with varied ibrutinib doses in vitro. Rat glioma cells and rodent glioma models were treated with ibrutinib alone (1-10 µM and 25 mg/kg) and in combination with doxil (10-100 µM and 3 mg/kg) to assess additive effects on viability, drug concentrations, tumor volume, endothelial junctional expression and survival. We found that ibrutinib, in a dose-dependent manner, decreased brain endothelial cell-cell adhesion over 24 h, without affecting endothelial cell viability (p < 0.005). Expression of tight junction gene and protein expression was decreased maximally 4 h after administration, along with inhibition of efflux transporter, ABCB1, activity. We demonstrated an additive effect of ibrutinib with doxil on rat glioma cells, as seen by a significant reduction in cell viability (p < 0.001) and increased CNS doxil concentration in the brain (56 ng/mL doxil alone vs. 74.6 ng/mL combination, p < 0.05). Finally, Ibrutinib, combined with doxil, prolonged median survival in rodent glioma models (27 vs. 16 days, p < 0.0001) with brain imaging showing a - 53% versus - 75% volume change with doxil alone versus combination therapy (p < 0.05). These findings indicate ibrutinib's ability to increase brain endothelial permeability via junctional disruption and efflux inhibition, to increase BTB drug entry and prolong rodent glioma model survival. Our results motivate the need to identify other BTB modifiers, all with the intent of improving survival and reducing systemic toxicities.

Does having children matter? Associations between transitions in work-family role combinations and depressive symptoms among married women in Korea.

Although having a variety of roles is generally beneficial for mental health, little is known about the relationships between work-family role combinations and depressive symptoms among married women in Korea, where child rearing is strongly considered a mother's responsibility. This study examines how the four types of work-family role combinations may be associated with depressive symptoms among married Korean women younger than 50 years old. Data were collected from 2012 through 2020 in five surveys by the Korean Longitudinal Survey of Women & Families. In total, 4811 married women (14,851 person-period observations) were analyzed using regression models with fixed effects. This enabled estimation of the within-person effects of transitions in work-family role combinations on depressive symptoms. Work-family role combinations were categorized as follows based on whether respondents had a job or at least one child: having both worker and mother roles, having a worker role only, having neither a worker nor a mother role, and having a mother role only. The findings indicate that married women who had only a mother role had more severe depressive symptoms than the other three groups. However, after controlling for whether respondents had a preschool-aged child, only those with both worker and mother roles had significantly lower levels of depressive symptoms compared with those with a mother role only. This study suggests that transitioning to being a working mother from a full-time mother may benefit the mental health of married Korean women. Furthermore, whether married women have a child critically impacts their mental health more than the number of roles. Raising a preschool-aged child seems to potentially be especially stressful for married Korean women. Working outside the home can protect the mental health of married Korean mothers who are affected by the social pressure to immerse themselves in child-rearing.

Dataset for the analysis of gendered research productivity affected by early COVID-19 pandemic.

In many countries, COVID-19 has made it harder for women to study because they are expected to do more housework and care for children. This article encompasses different data sources that can be used to figure out how the early pandemic of COVID-19 affected the number of studies done by females, in comparison with males. This data is add-on metadata that can be used with raw Microsoft Academic Graph (MAG) from 2016 to 2020 of the Feb 6, 2021 dump. We retrieved open-source metadata from various sources, including LinkedIn, the Johns Hopkins Coronavirus Resource Center, and Google's COVID-19 Community Mobility Reports, and linked bibliographic information to characteristics of the author's environments. It consists of published journals and online preprints, including each author's gender and involvement in the publication, their position through time, the h-index of their institutes, and gender equality in the professional labor market at the country level. For each record of papers, the data also includes the information of the papers, e.g., title and field of study. By gathering this evidence, our data can support the fact diversity in science is more than just the number of active members of different groups. It should also examine minority participation in science. Our data may help scholars understand diversity in science and advance it. The article ``The effect of the COVID-19 pandemic on gendered research productivity and its correlates'' uses this data as the principal source (Kwon, Yun & Kang, 2021).

The Epigenetic Reader, Bromodomain Containing 2, Mediates Cholangiocyte Senescence via Interaction With ETS Proto-Oncogene 1.

BACKGROUND & AIMS: We reported that cholangiocyte senescence, regulated by the transcription factor ETS proto-oncogene 1 (ETS1), is a pathogenic feature of primary sclerosing cholangitis (PSC). Furthermore, histone 3 lysine 27 is acetylated at senescence-associated loci. The epigenetic readers, bromodomain and extra-terminal domain (BET) proteins, bind acetylated histones, recruit transcription factors, and drive gene expression. Thus, we tested the hypothesis that BET proteins interact with ETS1 to drive gene expression and cholangiocyte senescence. METHODS: We performed immunofluorescence for BET proteins (BRD2 and 4) in liver tissue from liver tissue from PSC patients and a mouse PSC model. Using normal human cholangiocytes (NHCs), NHCs experimentally induced to senescence (NHCsen), and PSC patient-derived cholangiocytes (PSCDCs), we assessed senescence, fibroinflammatory secretome, and apoptosis after BET inhibition or RNA interference depletion. We assessed BET interaction with ETS1 in NHCsen and tissues from PSC patient, and the effects of BET inhibitors on liver fibrosis, senescence, and inflammatory gene expression in mouse models. RESULTS: Tissue from patients with PSC and a mouse PSC model exhibited increased cholangiocyte BRD2 and 4 protein (∼5×) compared with controls without disease. NHCsen exhibited increased BRD2 and 4 (∼2×), whereas PSCDCs exhibited increased BRD2 protein (∼2×) relative to NHC. BET inhibition in NHCsen and PSCDCs reduced senescence markers and inhibited the fibroinflammatory secretome. ETS1 interacted with BRD2 in NHCsen, and BRD2 depletion diminished NHCsen p21 expression. BET inhibitors reduced senescence, fibroinflammatory gene expression, and fibrosis in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine-fed and Mdr2-/- mouse models. CONCLUSION: Our data suggest that BRD2 is an essential mediator of the senescent cholangiocyte phenotype and is a potential therapeutic target for patients with PSC.

The effect of the COVID-19 pandemic on gendered research productivity and its correlates.

Female researchers may have experienced more difficulties than their male counterparts since the COVID-19 outbreak because of gendered housework and childcare. To test it, we constructed a unique dataset that connects 15,280,382 scholarly publications and their 11,828,866 authors retrieved from Microsoft Academic Graph data between 2016 and 2020 to various national characteristics from LinkedIn, Johns Hopkins Coronavirus Resource Center, and Covid-19 Community Mobility Reports from Google. Using the dataset, this study estimated how much the proportion of female authors in academic journals on a global scale changed in 2020 (net of recent yearly trends). We observed a decrease in research productivity for female researchers in 2020, mostly as first authors, followed by last author position. We also identified various factors that amplified the gender gap by dividing the authors' backgrounds into individual, organizational and national characteristics. Female researchers were more vulnerable when they were in their mid-career, affiliated to the least influential organizations, and more importantly from less gender-equal countries with higher mortality and restricted mobility as a result of COVID-19. Our findings suggest that female researchers were not necessarily excluded from but were marginalized in research since the COVID-19 outbreak and we discuss its policy implications.

How the Popularity of Bullies Influences the Self-Esteem of Their Classmates: A Study of First-Year Middle School Students in South Korea.

This study investigated whether and how classroom-level bullies' friendship networks, which reflect the popularity of bullies, were associated with the self-esteem of middle school students in the classroom. We analyzed survey data from 2,444 students in 101 classrooms from 22 middle schools in Korea. Respondents reported their friends' and bullies' names from their classroom. For each student, we generated the number of close friends that a respondent reported (outdegree) and the number of classmates who nominated him or her as a close friend (indegree). Bullies' popularity was measured by the sum of all the bullies' indegrees in a classroom. The findings showed that students in a classroom of bullies with larger popularity had a lower level of self-esteem. Moreover, bullies' popularity was harmful to nonvictims' self-esteem as well as victims' self-esteem. This study suggests that even indirect exposure to bullying in a classroom can decrease the self-esteem of nonvictims by leading to negative emotions such as anger, anxiety, fear, and/or guilty feelings.

SIRT7-mediated modulation of glutaminase 1 regulates TGF-ß-induced pulmonary fibrosis.

In the current work we show that the profibrotic actions of TGF-ß are mediated, at least in part, through a metabolic maladaptation in glutamine metabolism and how the inhibition of glutaminase 1 (GLS1) reverses pulmonary fibrosis. GLS1 was found to be highly expressed in fibrotic vs normal lung fibroblasts and the expression of profibrotic targets, cell migration, and soft agar colony formation stimulated by TGF-ß required GLS1 activity. Moreover, knockdown of SMAD2 or SMAD3 as well as inhibition of PI3K, mTORC2, and PDGFR abrogated the induction of GLS1 by TGF-ß. We further demonstrated that the NAD-dependent protein deacetylase, SIRT7, and the FOXO4 transcription factor acted as endogenous brakes for GLS1 expression, which are inhibited by TGF-ß. Lastly, administration of the GLS1 inhibitor CB-839 attenuated bleomycin-induced pulmonary fibrosis. Our study points to an exciting and unexplored connection between epigenetic and transcriptional processes that regulate glutamine metabolism and fibrotic development in a TGF-ß-dependent manner.

IPF pathogenesis is dependent upon TGFß induction of IGF-1.

Pathogenic fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), have some of the worst prognoses and affect millions of people worldwide. With unclear etiology and minimally effective therapies, two-thirds of IPF patients die within 2-5 years from this progressive interstitial lung disease. Transforming Growth Factor Beta (TGFß) and insulin-like growth factor-1 (IGF-1) are known to promote fibrosis; however, myofibroblast specific upregulation of IGF-1 in the initiation and progression of TGFß-induced fibrogenesis and IPF have remained unexplored. To address this, the current study (1) documents the upregulation of IGF-1 via TGFß in myofibroblasts and fibrotic lung tissue, as well as its correlation with decreased pulmonary function in advanced IPF; (2) identifies IGF-1's C1 promoter as mediating the increase in IGF-1 transcription by TGFß in pulmonary fibroblasts; (3) determines that SMAD2 and mTOR signaling are required for TGFß-dependent Igf-1 expression in myofibroblasts; (4) demonstrates IGF-1R activation is essential to support TGFß-driven profibrotic myofibroblast functions and excessive wound healing; and (5) establishes the effectiveness of slowing the progression of murine lung fibrosis with the IGF-1R inhibitor OSI-906. These findings expand our knowledge of IGF-1's role as a novel fibrotic-switch, bringing us one step closer to understanding the complex biological mechanisms responsible for fibrotic diseases and developing effective therapies.

Transforming growth factor beta induces fibroblasts to express and release the immunomodulatory protein PD-L1 into extracellular vesicles.

Transforming growth factor-beta (TGFß) is an enigmatic protein with various roles in healthy tissue homeostasis/development as well as the development or progression of cancer, wound healing, fibrotic disorders, and immune modulation, to name a few. As TGFß is causal to various fibroproliferative disorders featuring localized or systemic tissue/organ fibrosis as well as the activated stroma observed in various malignancies, characterizing the pathways and players mediating its action is fundamental. In the current study, we found that TGFß induces the expression of the immunoinhibitory molecule Programed death-ligand 1 (PD-L1) in human and murine fibroblasts in a Smad2/3- and YAP/TAZ-dependent manner. Furthermore, PD-L1 knockdown decreased the TGFß-dependent induction of extracellular matrix proteins, including collagen Iα1 (colIα1) and alpha-smooth muscle actin (α-SMA), and cell migration/wound healing. In addition to an endogenous role for PD-L1 in profibrotic TGFß signaling, TGFß stimulated-human lung fibroblast-derived PD-L1 into extracellular vesicles (EVs) capable of inhibiting T cell proliferation in response to T cell receptor stimulation and mediating fibroblast cell migration. These findings provide new insights and potential targets for a variety of fibrotic and malignant diseases.

Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-ß.

Metabolic dysregulation in fibroblasts is implicated in the profibrotic actions of transforming growth factor-ß (TGF-ß). Here, we present evidence that hexokinase 2 (HK2) is important for mediating the fibroproliferative activity of TGF-ß both in vitro and in vivo. Both Smad-dependent and Smad-independent TGF-ß signaling induced HK2 accumulation in murine and human lung fibroblasts through induction of the transcription factor c-Myc. Knockdown of HK2 or pharmacological inhibition of HK2 activity with Lonidamine decreased TGF-ß-stimulated fibrogenic processes, including profibrotic gene expression, cell migration, colony formation, and activation of the transcription factors YAP and TAZ, with no apparent effect on cellular viability. Fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) exhibited an increased abundance of HK2. In a mouse model of bleomycin-induced lung fibrosis, Lonidamine reduced the expression of genes encoding profibrotic markers (collagenΙα1, EDA-fibronectin, α smooth muscle actin, and connective tissue growth factor) and stabilized or improved lung function as assessed by measurement of peripheral blood oxygenation. These findings provide evidence of how metabolic dysregulation through HK2 can be integrated within the context of profibrotic TGF-ß signaling.

B7-1 drives TGF-ß stimulated pancreatic carcinoma cell migration and expression of EMT target genes.

B7-1 proteins are routinely expressed on the surface of antigen presenting cells (APC) and within the innate immune system. They function to establish a biologically optimal and dynamic balance between immune activation and inhibition or self-tolerance. Interactions between B7-1 and its receptors, which include CD28, CTLA4 and PD-L1, contribute to both stimulatory as well as inhibitory or homeostatic regulation. In the current study, we investigated whether the tumor-promoting actions of transforming growth factor beta (TGF-ß) disrupted this equilibrium in pancreatic cancer to promote malignant progression and an enhanced means to evade immune detection. The data show that B7-1 is (i) upregulated following treatment of pancreatic carcinoma cells with TGF-ß; (ii) induced by TGF-ß via both Smad2/3-dependent and independent pathways; (iii) required for pancreatic tumor cell in vitro migration/invasion; and (iv) necessary for TGF-ß regulated epithelial-mesenchymal transition (EMT) through induction of Snail family members. Results from the proposed studies provide valuable insights into mechanisms whereby TGF-ß regulates both the innate immune response and intrinsic properties of pancreatic tumor growth.

Subdural Fluid Collection After the Clipping of Unruptured Intracranial Aneurysms: Its Clinical Course and Significance.

OBJECTIVE: We evaluated the clinical course and significance of postoperative subdural fluid collection (SFC) and identified the patients who were at risk of developing postoperative chronic subdural hematoma (CSDH) after the clipping of unruptured intracranial aneurysms (UIAs). METHODS: Between January 2012 and June 2014, we retrospectively reviewed 298 patients with UIAs treated by microsurgical clipping. Among them, 257 patients were enrolled in the present study. Subdural lesions (SDLs) were defined as SFC at 1-month follow-up computed tomography (CT) and a CSDH at any time within 1 month after the clipping of UIAs. We examined the volume changes, Hounsfield unit (HU) values, and the end results of SFC in serial CT scans. RESULTS: The incidence of postoperative CSDH that needed burr hole surgery was 2.5%. Changes in SFC volume that occurred within 1 week of surgery were a risk factor for the occurrence of SDL at the 1-month follow-up CT (odds ratio 34.039; P < 0.001). The corrected average HU value of SCF (cut-off value: 11.9, with a sensitivity of 83.3% and specificity of 73.7%) on postoperative day 7 was an independent risk factor for development of a CSDH at the 1-month follow-up CT (odds ratio 19.261; P = 0.003). CONCLUSIONS: SDLs seen during 1-month follow-up may be associated with the occurrence of increased SFC volume within a week after the clipping of UIAs. The corrected average HU value of the SFC on postoperative day 7 was the only risk factor for the development of CSDHs at 1-month follow-up CT.

Fatty acid synthase is required for profibrotic TGF-ß signaling.

Evidence is provided that the fibroproliferative actions of TGF-ß are dependent on a metabolic adaptation that sustains pathologic growth. Specifically, profibrotic TGF-ß signaling is shown to require fatty acid synthase (FASN), an essential anabolic enzyme responsible for the de novo synthesis of fatty acids. With the use of pharmacologic and genetic approaches, we show that TGF-ß-stimulated FASN expression is independent of Smad2/3 and is mediated via mammalian target of rapamycin complex 1. In the absence of FASN activity or protein, TGF-ß-driven fibrogenic processes are reduced with no apparent toxicity. Furthermore, as increased FASN expression was also observed to correlate with the degree of lung fibrosis in bleomycin-treated mice, inhibition of FASN was examined in a murine-treatment model of pulmonary fibrosis. Remarkably, inhibition of FASN not only decreased expression of profibrotic targets, but lung function was also stabilized/improved, as assessed by peripheral blood oxygenation.-Jung, M.-Y., Kang, J.-H., Hernandez, D. M., Yin, X., Andrianifahanana, M., Wang, Y., Gonzalez-Guerrico, A., Limper, A. H., Lupu, R., Leof, E. B. Fatty acid synthase is required for profibrotic TGF-ß signaling.

Basolateral delivery of the type I transforming growth factor beta receptor is mediated by a dominant-acting cytoplasmic motif.

Delivery of biomolecules to the correct subcellular locales is critical for proper physiological function. To that end, we have previously determined that type I and II transforming growth factor beta (TGF-ß) receptors (TßRI and TßRII, respectively) localize to the basolateral domain in polarized epithelia. While TßRII targeting was shown to be regulated by sequences between amino acids 529 and 538, the analogous region(s) within TßRI is unknown. To address that question, sequential cytoplasmic TßRI truncations and point mutations identified a targeting motif between residues 158 and 163 (VxxEED) required for basolateral TßRI expression. Further studies documented that receptor internalization, down-regulation, direct recycling, or Smad signaling were unaffected by motif mutations that caused TßRI mislocalization. However, inclusion of amino acids 148-217 containing the targeting motif was able to direct basolateral expression of the apically sorted nerve growth factor receptor (NGFR, p75; extracellular and transmembrane regions) in a dominant manner. Finally, coexpression of apically targeted type I and type II TGF-ß receptors mediated Smad3 signaling from the apical membrane of polarized epithelial cells. These findings demonstrate that the absence of apical TGF-ß signaling in normal epithelia is primarily a reflection of domain-specific receptor expression and not an inability to couple with the signaling machinery.

Cell-penetrating peptides selectively targeting SMAD3 inhibit profibrotic TGF-ß signaling.

TGF-ß is considered a master switch in the pathogenesis of organ fibrosis. The primary mediators of this activity are the SMAD proteins, particularly SMAD3. In the current study, we have developed a cell-penetrating peptide (CPP) conjugate of the HIV TAT protein that is fused to an aminoterminal sequence of sorting nexin 9 (SNX9), which was previously shown to bind phosphorylated SMAD3 (pSMAD3). We determined that specifically preventing the nuclear import of pSMAD3 using the TAT-SNX9 peptide inhibited profibrotic TGF-ß activity in murine cells and human lung fibroblasts as well as in vivo with no demonstrable toxicity. TGF-ß signaling mediated by pSMAD2, bone morphogenetic protein 4 (BMP4), EGF, or PDGF was unaffected by the TAT-SNX9 peptide. Furthermore, while the TAT-SNX9 peptide prevented TGF-ß's profibrotic activity in vitro as well as in 2 murine treatment models of pulmonary fibrosis, a 3-amino acid point mutant that was unable to bind pSMAD3 proved ineffective. These findings indicate that specifically targeting pSMAD3 can ameliorate both the direct and indirect fibroproliferative actions of TGF-ß.

Homophily in an Anonymous Online Community: Sociodemographic Versus Personality Traits.

In what traits do people interact with others who are similar to them in completely anonymous online communication? Can those traits contribute to greater exchange of opinion and information across the sociodemographic boundaries that often limit interaction between social strata? To answer this question concerning online homophily, we combined survey data on 7,287 users (aged 18 and above) of a Korean online dating advice platform with their behavioral data from June 2015 to August 2015 and explored whether advice exchange occurred between users with similar sociodemographic and personality traits. On this platform, two types of interactions occurred as follows: (1) responses to a randomly distributed problem submitted by an advice seeker and (2) the seeker's indication of approval of any of the responses given. The study found that (1) a receiver was more likely to respond to problems submitted by seekers of a comparable age and that (2) seekers were more likely to approve of a response if the seeker and receiver had similar educational backgrounds. By contrast, homophily based on personality traits was not observed even though some personality traits significantly affected the likelihood of both response and approval. Our findings suggest that online communication may breed sociodemographic homophily, whether based on age or education, more than expected or intended while not easily fostering alternative forms of homophily, such as personality homophily, which can potentially cut across borders dividing sociodemographic groups.

Profibrotic up-regulation of glucose transporter 1 by TGF-ß involves activation of MEK and mammalian target of rapamycin complex 2 pathways.

TGF-ß plays a central role in the pathogenesis of fibroproliferative disorders. Defining the exact underlying molecular basis is therefore critical for the development of viable therapeutic strategies. Here, we show that expression of the facilitative glucose transporter 1 (GLUT1) is induced by TGF-ß in fibroblast lines and primary cells and is required for the profibrotic effects of TGF-ß. In addition, enhanced GLUT1 expression is observed in fibrotic areas of lungs of both patients with idiopathic pulmonary fibrosis and mice that are subjected to a fibrosis-inducing bleomycin treatment. By using pharmacologic and genetic approaches, we demonstrate that up-regulation of GLUT1 occurs via the canonical Smad2/3 pathway and requires autocrine activation of the receptor tyrosine kinases, platelet-derived and epidermal growth factor receptors. Engagement of the common downstream effector PI3K subsequently triggers activation of the MEK and mammalian target of rapamycin complex 2, which cooperate in regulating GLUT1 expression. Of note, inhibition of GLUT1 activity and/or expression is shown to impair TGF-ß-driven fibrogenic processes, including cell proliferation and production of profibrotic mediators. These findings provide new perspectives on the interrelation of metabolism and profibrotic TGF-ß signaling and present opportunities for potential therapeutic intervention.-Andrianifahanana, M., Hernandez, D. M., Yin, X., Kang, J.-H., Jung, M.-Y., Wang, Y., Yi, E. S., Roden, A. C., Limper, A. H., Leof, E. B. Profibrotic up-regulation of glucose transporter 1 by TGF-ß involves activation of MEK and mammalian target of rapamycin complex 2 pathways.

Marital status and mortality: Does family structure in childhood matter?

It is well known that marital status is significantly associated with mortality risk. Little is known, however, regarding whether and how the effects of marital status are moderated by one's own family structure in childhood. The purposes of this study are to examine whether marital status (i.e., family structure in adulthood) and living with both biological parents in childhood (i.e., family structure in childhood) are associated with mortality risk, and whether and how the effects of marital status vary depending on family structure in childhood and gender. We analyze the risk of death in five waves of the General Social Survey (GSS) from 1994 through 2002 after linking the GSS data to death certificate data from the National Death Index through 2008. The findings indicate that being widowed increases the risk of mortality, while living with both parents in childhood lowers it. Interestingly, analysis of the interaction between marital status and family structure in childhood reveals that the disadvantage of widowhood in terms of mortality is significantly stronger for those who lived with both parents in childhood than for those who did not. Subsample analysis by gender shows that the moderating effect of living with both parents is largely equal across men and women, though statistically more robust for men. These findings suggest that living with both parents during childhood may increase vulnerability to marital disruptions due to unwanted life events such as spousal loss. Childhood advantages, ironically, may form more stressful contexts of spousal loss by lowering one's adaptability or immunity to adulthood hardships, especially when the hardships in adulthood are characteristically opposite from the childhood advantages.

Sorting nexin 9 differentiates ligand-activated Smad3 from Smad2 for nuclear import and transforming growth factor ß signaling.

Transforming growth factor ß (TGFß) is a pleiotropic protein secreted from essentially all cell types and primary tissues. While TGFß's actions reflect the activity of a number of signaling networks, the primary mediator of TGFß responses are the Smad proteins. Following receptor activation, these cytoplasmic proteins form hetero-oligomeric complexes that translocate to the nucleus and affect gene transcription. Here, through biological, biochemical, and immunofluorescence approaches, sorting nexin 9 (SNX9) is identified as being required for Smad3-dependent responses. SNX9 interacts with phosphorylated (p) Smad3 independent of Smad2 or Smad4 and promotes more rapid nuclear delivery than that observed independent of ligand. Although SNX9 does not bind nucleoporins Nup153 or Nup214 or some ß importins (Imp7 or Impß), it mediates the association of pSmad3 with Imp8 and the nuclear membrane. This facilitates nuclear translocation of pSmad3 but not SNX9.

Religious Affiliation, Religious Service Attendance, and Mortality.

Very few studies have examined the effects of both religious affiliation and religiosity on mortality at the same time, and studies employing multiple dimensions of religiosity other than religious attendance are rare. Using the newly created General Social Survey-National Death Index data, our report contributes to the religion and mortality literature by examining religious affiliation and religiosity at the same time. Compared to Mainline Protestants, Catholics, Jews, and other religious groups have lower risk of death, but Black Protestants, Evangelical Protestants, and even those with no religious affiliation are not different from Mainline Protestants. While our study is consistent with previous findings that religious attendance leads to a reduction in mortality, we did not find other religious measures, such as strength of religious affiliation, frequency of praying, belief in an afterlife, and belief in God to be associated with mortality. We also find interaction effects between religious affiliation and attendance. The lowest mortality of Jews and other religious groups is more apparent for those with lower religious attendance. Thus, our result may emphasize the need for other research to focus on the effects of religious group and religious attendance on mortality at the same time.