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Reciprocal interactions between breast cancer cells and the tumor microenvironment (TME) are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAF) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the TME and to restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non–cell-autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the TME and to enhance therapeutic efficacy.Significance:Sphingosine kinase 2 (SphK2) facilitates the activation of stromal fibroblasts to tumor-promoting cancer-associated fibroblasts by suppressing host p53 activity, revealing SphK2 as a potential target to reprogram the TME.

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Reciprocal interactions between breast cancer cells and the tumor microenvironment (TME) are important for cancer progression and metastasis. We report here that the deletion or inhibition of sphingosine kinase 2 (SphK2), which produces sphingosine-1-phosphate (S1P), markedly suppresses syngeneic breast tumor growth and lung metastasis in mice by creating a hostile microenvironment for tumor growth and invasion. SphK2 deficiency decreased S1P and concomitantly increased ceramides, including C16-ceramide, in stromal fibroblasts. Ceramide accumulation suppressed activation of cancer-associated fibroblasts (CAF) by upregulating stromal p53, which restrained production of tumor-promoting factors to reprogram the TME and to restrict breast cancer establishment. Ablation of p53 in SphK2-deficient fibroblasts reversed these effects, enabled CAF activation and promoted tumor growth and invasion. These data uncovered a novel role of SphK2 in regulating non–cell-autonomous functions of p53 in stromal fibroblasts and their transition to tumor-promoting CAFs, paving the way for the development of a strategy to target the TME and to enhance therapeutic efficacy.Significance:Sphingosine kinase 2 (SphK2) facilitates the activation of stromal fibroblasts to tumor-promoting cancer-associated fibroblasts by suppressing host p53 activity, revealing SphK2 as a potential target to reprogram the TME.

Membrane contact sites (MCS), close membrane apposition between organelles, are platforms for interorganellar transfer of lipids including cholesterol, regulation of lipid homeostasis, and co-ordination of endocytic trafficking. Sphingosine kinases (SphKs), two isoenzymes that phosphorylate sphingosine to the bioactive sphingosine-1-phosphate (S1P), have been implicated in endocytic trafficking. However, the physiological functions of SphKs in regulation of membrane dynamics, lipid trafficking and MCS are not known. Here, we report that deletion of SphKs decreased S1P with concomitant increases in its precursors sphingosine and ceramide, and markedly reduced endoplasmic reticulum (ER) contacts with late endocytic organelles. Expression of enzymatically active SphK1, but not catalytically inactive, rescued the deficit of these MCS. Although free cholesterol accumulated in late endocytic organelles in SphK null cells, surprisingly however, cholesterol transport to the ER was not reduced. Importantly, deletion of SphKs promoted recruitment of the ER-resident cholesterol transfer protein Aster-B (also called GRAMD1B) to the plasma membrane (PM), consistent with higher accessible cholesterol and ceramide at the PM, to facilitate cholesterol transfer from the PM to the ER. In addition, ceramide enhanced in vitro binding of the Aster-B GRAM domain to phosphatidylserine and cholesterol liposomes. Our study revealed a previously unknown role for SphKs and sphingolipid metabolites in governing diverse MCS between the ER network and late endocytic organelles versus the PM to control the movement of cholesterol between distinct cell membranes.

Non-alcoholic steatohepatitis (NASH) results from the accumulation of excessive liver lipids leading to hepatocellular injury, inflammation, and fibrosis that greatly increase the risk for hepatocellular carcinoma (HCC). Despite the well-characterized clinical and histological pathology for NASH-driven HCC in humans, its etiology remains unclear and there is a deficiency in pre-clinical models that recapitulate the progression of the human disease. Therefore, we developed a new mouse model amenable to genetic manipulations and gene targeting that mimics the gradual NASH to HCC progression observed in humans. C57BL/6NJ mice were fed a Western high-fat diet and sugar water (HFD/SW) and monitored for effects on metabolism, liver histology, tumor development, and liver transcriptome for up to 54 weeks. Chronic HFD/SW feeding led to significantly increased weight gain, serum and liver lipid levels, liver injury, and glucose intolerance. Hepatic pathology progressed and mice developed hepatocellular ballooning, inflammation, and worse fibrosis was apparent at 16 weeks, greatly increased through 32 weeks, and remained elevated at 54 weeks. Importantly, hepatocellular cancer spontaneously developed in 75% of mice on HFD/SW, half of which were HCC, whereas none of the mice on the chow diet developed HCC. Chronic HFD/SW induced molecular markers of de novo lipogenesis, endoplasmic reticulum stress, inflammation, and accumulation of p62, all of which also participate in the human pathology. Moreover, transcriptome analysis revealed activation of HCC-related genes and signatures associated with poor prognosis of human HCC. Overall, we have identified a new preclinical model that recapitulates known hallmarks of NASH-driven HCC that can be utilized for future molecular mechanistic studies of this disease.

The “replication crisis” may well be the single most important challenge facing empirical psychological research today. It appears that highly trained scientists, often without understanding the potentially dire long-term implications, have been mishandling standard statistical procedures in the service of attaining statistical “significance.” Exacerbating the problem, most academic journals do not publish research that has not produced a “significant” result. This toxic combination has resulted in journals apparently publishing many Type I errors and declining to publish many true failures to reject H0. In response, there has been an urgent call from some psychologists that studies be registered in advance so that their rationales, hypotheses, variables, sample sizes, and statistical analyses are recorded in advance, leaving less room for post hoc manipulation. In this chapter, I argue that this “open science” approach, though laudable, will prove insufficient because the null hypothesis significance test (NHST) is a poor criterion for scientific truth, even when it is handled correctly. The root of the problem is that, whatever statistical problems psychology may have, the discipline never developed the theoretical maturity required. For decades it has been satisfied testing weak theories that predict, at best, only the direction of the effect, rather than the size of effect. Indeed, uncritical acceptance of NHST by the discipline may have served to stunt psychology’s theoretical growth by giving researchers a way of building a successful career without having to develop models that make precise predictions. Improving our statistical “hygiene” would be a good thing, to be sure, but it is unlikely to resolve psychology’s growing credibility problem until our theoretical practices mature considerably.

Now in its 25th year, the journal has become an important institution within the discipline since an article of the editor's (on Aristotle's theory of mind) was the first to appear on its pages in back in 1998. It is the editor's aim to build the journal in ways that serve the community of historians of psychology even better than it has over the past quarter of a century. First, the editor intended to follow and expand even further the previous editor's impressive efforts to have the journal reflect the diversity of its disciplinary community. Second, the editor also hopes to encourage innovative practitioners of the historiographic craft-especially digital researchers-to look to the journal as a friendly outlet. Third, in sympathy with APA's adoption of the Transparency and Openness Promotion (TOP) guidelines, the editor will work with authors to ensure that the sources of their historical claims are as clear as possible. Finally, please allow the editor to personally invite you, the reader, to assist me in supporting and enriching this journal. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

SummarySpermatogenesis is a highly regulated process that produces sperm to transmit genetic information to the next generation. Although extensively studied in mice, our current understanding of primate spermatogenesis is limited to populations defined by state-specific markers defined from rodent data. As between-species differences have been reported in the process duration and cellular differentiation hierarchy, it remains unclear how molecular markers and cell states are conserved or have diverged from mice to man. To address this challenge, we employ single-cell RNA-sequencing to identify transcriptional signatures of major germ and somatic cell-types of the testes in human, macaque and mice. This approach reveals differences in expression throughout spermatogenesis, including the stem/progenitor pool of spermatogonia, classical markers of differentiation, potential regulators of meiosis, the kinetics of RNA turnover during spermatid differentiation, and germ cell-soma communication. These datasets provide a rich foundation for future targeted mechanistic studies of primate germ cell development and in vitro gametogenesis.

The articles authored by Flis and van Eck (2018) and by Burman (2018) serve as fine examples of the ways in which digital historical methods can illuminate aspects of psychology's past that would probably not be possible otherwise. This success, however, presents no reason to think that digital history is some kind of threat to conventional historiography or that former aims to replace the latter. The two can work complementarily-so closely, in fact, that it sometimes becomes difficult to know which of the two one is practicing at any given moment. Multiple skill sets need not define the historian as being a particular "kind": They just enable any historian to do his or her work more completely than before. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Brain "inflammaging," a low-grade and chronic inflammation, is a major hallmark for aging-related neurodegenerative diseases. Here, by profiling H3K27ac and gene expression patterns in human and mouse brains, we found that age-related up-regulated (Age-Up) and down-regulated (Age-Down) genes have distinct H3K27ac patterns. Although both groups show promoter H3K27ac, the Age-Up genes, enriched for inflammation-related functions, are additionally marked by broad H3K27ac distribution over their gene bodies, which is progressively reduced during aging. Age-related gene expression changes can be predicted by gene-body H3K27ac level. Contrary to the presumed transcription activation function of promoter H3K27ac, we found that broad gene-body hyper H3K27ac suppresses overexpression of inflammaging genes. Altogether, our findings revealed opposite regulations by H3K27ac of Age-Up and Age-Down genes and a mode of broad gene-body H3K27ac in repressing transcription.

Over the course of psychology’s first several decades, the language used to convey the subject matter gradually shifted from being free and literary to being strictly constrained and disciplined by increasingly focused theoretical demands. The project described here, “Disciplining Psychology,” aimed to depict this transformation by generating images of the faces of three highly influential psychologists—William James, Sigmund Freud, and B. F. Skinner. Each image is composed of the words used in one of each individual’s most important books. The tightening of the disciplinary vocabulary is revealed in the differences among the three arrays of words themselves, but I have also striven to reflect it in the aesthetic aspects of each image. The method used here could easily be extended to a wider array of authors, texts, and psychological topics.

Psychology has a long tradition of creating lists of the most eminent members of the discipline. Such lists are typically created under the assumption that there is a general answer to the question of eminence, covering all psychologists everywhere. We wondered, however, to what degree perceived eminence depends on the individual's particular demographic situation. Specifically, are different historical figures “eminent” to people of different genders, ages, and geographical locations? We tested this by asking a wide swath of people – mostly psychologists – who they think has had the most impact on the discipline of psychology, historically. We used an online game in which “players” were shown a series of pairs of significant figures from psychology's past and asked to select which had had the greater impact. We then converted these selections into a ranked list using the Elo rating system. Although our overall rankings had considerable similarity with traditional efforts, we also found that rankings differed markedly among different demographic groups, undermining the assumption of a general measure of eminence that is valid for all.

The American Psychological Association (APA) began 125 years ago as a small club of a few dozen members in the parlor of its founder, G. Stanley Hall. In the decades since, it has faced many difficulties and even a few existential crises. Originally a scientific society, it spent the decades between the world wars figuring out how to accommodate the growing community of applied psychologists while still retaining and enhancing its scientific reputation. After World War II, with an expanded mandate, it developed formal training models for clinical psychologists and became an important player in legal cases pertaining to civil rights and other social justice issues. With practitioners taking an ever-greater role in the governance of the organization in the late 1970s, and the financial viability of the association in doubt in the 1980s, many psychological scientists felt the need to create a separate organization for themselves. The 1990s and early 2000s brought more challenges: declining divisional memberships; a legal dispute over fees with practitioners; and a serious upheaval over the APA Board of Directors' cooperation with governmental defense and intelligence agencies during the "war on terror." These clashes appear to have precipitated a decline in the association's membership for the first time in its history. The APA has faced many storms over its century-and-a-quarter, but has, thus far, always ultimately found a way forward for itself, for its members, and for the wider discipline of psychology. (PsycINFO Database Record

What is the relationship between being highly prolific in the realm of publication and being remembered as a great psychologist of the past? In this study, the PsycINFO database was used to identify the historical figures who wrote the most journal articles during the half-century from 1890 to 1939. Although a number of the 10 most prolific authors are widely remembered for their influence on the discipline today—E. L. Thorndike, Karl Pearson, E. B. Titchener, Henri Piéron—the majority are mostly forgotten. The data were also separated into the 5 distinct decades. Once again, a mixture of eminent and obscure individuals made appearances. Most striking, perhaps, was the great increase in articles published over the course of the half-century—approximately doubling each decade—and the enormous turnover in who was most prolific, decade over decade. In total, 100 distinct individuals appeared across just 5 lists of about 25 names each.

Dietary interventions dramatically affect metabolic disease and lifespan in various aging models. Here, we profiled liver microRNA (miRNA), coding, and long non-coding RNA (lncRNA) expression by high-throughput deep sequencing in mice across multiple energy intake and expenditure interventions. Strikingly, three dietary intervention network design patterns were uncovered: (1) lifespan-extending interventions largely repressed the expression of miRNAs, lncRNAs, and transposable elements; (2) protein-coding mRNAs with expression positively correlated with long lifespan are highly targeted by miRNAs; and (3) miRNA-targeting interactions mainly target chromatin-related functions. We experimentally validated miR-34a, miR-107, and miR-212-3p targeting of the chromatin remodeler Chd1 and further demonstrate that Chd1 knockdown mimics high-fat diet and aging-induced gene expression changes and activation of transposons. Our findings demonstrate lifespan-extending diets repress miRNA-chromatin remodeler interactions and safeguard against deregulated transcription induced by aging and lifespan shortening diets, events linked by microRNA, chromatin, and ncRNA crosstalk.

Look at any introductory psychology book that covers psychoanalysis, and you are likely to find an image of an iceberg floating in the sea. The image serves as an illustrative metaphor for Freud's theory of the mind: Only a fragment of our ideas and feelings are conscious or "visible" to us, while the vast bulk of our mental content is unconscious or "invisible" to everyday introspection. A simple Internet search of the terms "Freud iceberg" will bring forth hundreds of examples. The problem is that Freud never mentioned the iceberg in his published writings. It is a metaphor that has become ubiquitous in (English-language) writings about Freudian theory, but that does not find its source in his work. So the question is, where did it come from? Much attention has been directed to a passage in Ernest Jones's biography of Freud. Many have taken this to mean that the Freudian iceberg metaphor derives directly from Fechner. Jones encouraged this interpretation, quoting Freud on being "open to the ideas of G. T. Fechner and following that thinker upon many important points." The iceberg metaphor of mind has another source with a solid connection to Freud: Granville Stanley Hall. Hall was one of the founders of American psychology. The mystery of the Freudian iceberg is not completely resolved, but we have made considerable progress. The mystery that remains is why Hall believed the metaphor's origin to lay somewhere in Fechner's writings. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Recent research has used networks of scholarly journal articles to investigate the intellectual structure of the discipline of psychology from the later 1880s to the early 1920s. Here, instead, we examined the networks of philosophical journals that were closely aligned with psychology-The Monist, Philosophical Review, and The Journal of Philosophy, Psychology, and Scientific Methods-between 1890 and 1913. We discovered that, although the first 2 of these journals published a great deal of psychologically relevant material up to 1903, material of that sort seemed to evaporate after the launch of the third journal in 1904. It was not so much that material migrated from the old journals to the new one. It was rather that the new journal was able to attract new trends in American philosophical psychology, while interest in traditional approaches seemed to dry up. The result was that psychology moved into a new and expansive era, while America philosophy was left somewhat destabilized as it attempted to reconfigure its disciplinary identity. (PsycINFO Database Record

There are many different ways to assess the significance of historical figures. Often we look at the influence of their writings, or at the important offices they held with disciplinary institutions such as universities, journals, and scholarly societies. In this study, however, we took a novel approach: we took the complete memberships, ca. 1900, of four organizations-the American Psychological Association, the Western Philosophical Association, the American Philosophical Association, and the Southern Society for Philosophy and Psychology-and visualized them as a network. We then identified individuals who "bridged" between two or more of these groups and considered what might be termed their "centrality" to the psychological-philosophical community of their time. First, we examined these figures qualitatively, briefly describing their lives and careers. Then we approached the problem mathematically, considering several alternative technical realizations of "centrality" and then explaining our reasons for choosing eigenvector centrality as the best for our purposes. We found a great deal of overlap among the results of the qualitative and quantitative approaches, but also some telling differences. J. Mark Baldwin, Edward Buchner, Christine Ladd Franklin, and Frank Thilly consistently emerged as highly central figures. Some more marginal figures such as Max Meyer, and Frederick J. E. Woodbridge, Edward A. Pace, Edward H. Griffin played interesting roles as well.