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Human and murine Treg cells are functionally characterized by a decrease in both proliferation and IL-2 secretion in response to T-cell receptor (TCR) stimulation and by their ability to suppress activation of conventional T-cells . Treg cells mediate their suppressive effects only when stimulated via their TCRs , although their suppressive effector function is antigen nonspecific . Treg cells are clearly enriched within peripheral CD4 + T-cells that also express the α subunit of the IL-2 receptor (CD25), which is currently the best marker for identifying these cells . However, CD25 is also expressed on activated effector T-cells, and not all CD4 + Treg cells express CD25 . In adults, Treg cells are exclusively found in the CD45RO + memory subset, and a sizable portion of these cells express the activation marker HLA-DR and the recently identified molecule glucocorticoid-induced tumor necrosis factor receptor (GITR, also known as TNFRSF18) . Upon activation, Treg cells express the inhibitory receptor CTLA-4 at a higher level and for a longer period of time than conventional T-cells . Interestingly, Treg cells have also been shown to express high levels of certain chemokine receptors such as CCR4 and CCR8 . | 15252446_p1 | 15252446 | Introduction | 4.854651 | biomedical | Study | [
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The forkhead transcription factor FOXP3 was recently shown to be specifically expressed in mouse Treg cells and is required for their development . A mutation in the FOXP3 gene carried by the scurfy mouse strain or a knockout of this gene causes a CD4 + T-cell-mediated lymphoproliferative disease characterized by cachexia and multiorgan lymphocytic infiltrates . The human genetic disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (also called X-linked autoimmunity-allergic disregulation syndrome) is caused by mutations in the human homolog of FoxP3 and is characterized by hyperactivation of T-cells with autoimmune endocrinopathy, early-onset type 1 diabetes and thyroiditis, and in some cases manifestations of severe atopy . In addition, expression of FOXP3 in conventional T-cells either in transgenic mice or by retroviral transduction is sufficient to confer a Treg cell phenotype . However, the role of FoxP3 in the development of human Treg cells has not been examined. | 15252446_p2 | 15252446 | Introduction | 4.443898 | biomedical | Study | [
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The role of Treg cells in controlling T-cell activation during immune responses to pathogens such as chronic viral infections is currently a subject of great interest. Recently it was shown that Treg cells can regulate virus-specific or memory CD8 + T-cell responses, thus diminishing the magnitude of the immune response . Because Treg cells express CD4 , they are also potential targets of HIV in vivo. HIV entry into target cells also requires cellular expression of the chemokine receptors CCR5 or CXCR4 in conjunction with CD4 . However, the ability of HIV to establish a persistent infection is also critically dependent on activation signals that regulate HIV replication within target T-cells. Quiescent T-cells are resistant to infection unless TCR or cytokine activation signals are provided . Indeed, chronic states of T-cell hyperactivation, viral persistence, and T-cell depletion are all hallmarks of HIV infection . Consequently, this state of chronic immune activation combined with the direct destruction of CD4 + T-cells by HIV leads to a profound immunodeficiency characterized by progressive deterioration of immune function . If Treg cells are lost because of HIV infection, this could potentially result in hyperactivation of conventional T-cells due to lack of immunoregulation. In contrast, if Treg cells are activated to expand during certain stages of the infection, this could have a suppressive effect on protective immune responses against the virus. Thus, in both scenarios dysregulation of Treg subset during HIV infection could have a profound impact on anti-HIV immune responses and pathogenesis of the infection. | 15252446_p3 | 15252446 | Introduction | 4.763743 | biomedical | Study | [
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We tested the susceptibility of both naturally occurring and in vitro genetically reprogrammed Treg cells to HIV infection. We found that Treg cells isolated from healthy donors express CCR5 and are highly susceptible to HIV infection. Ectopic expression of FoxP3 in conventional human T-cells genetically reprogrammed them into a Treg phenotype and enhanced their susceptibility to HIV infection. Remarkably, we also found a profound defect of FoxP3 + CD4 + CD25 hi T-cells in HIV-infected patients with low CD4 + and a high percentage of activated T-cells. | 15252446_p4 | 15252446 | Introduction | 4.153354 | biomedical | Study | [
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Our findings have important implications in understanding the role of Treg cells and the chronic activated state of T-cells during HIV infection. Furthermore, reprogramming of T-cells in vitro into Treg cells establishes a novel system to understand the mechanism of T-cell suppression and enhanced susceptibility of this subset to HIV infection. | 15252446_p5 | 15252446 | Introduction | 4.070911 | biomedical | Study | [
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To analyze susceptibility of Treg cells to HIV infection, we first developed a method to isolate these cells from peripheral blood. A sizable portion of human CD4 + T-cells (between 10%–20%) express CD25 . However, approximately 1%–2% of CD4 + T-cells within the memory subset (CD45RO + ) express high levels of CD25 (CD25 hi ) . Previous studies suggested that human Treg cells resided within the CD45RO + CD25 hi subset . We first performed a phenotypic analysis of CD45RO + CD25 hi (referred to as Treg), CD45RO + CD25 low/neg (memory T) and CD45RO − CD25 neg (naïve T) cells. Treg cells expressed higher levels of GITR and HLA-DR , consistent with previous reports . Treg cells also expressed high levels of CCR5 and CCR4 compared to memory and naïve T-cells, while expression of CXCR4 and CCR7 was lower and CXCR3 expression was similar as compared to memory T-cells . | 15252446_p6 | 15252446 | Isolation and Characterization of Human Treg Cells | 4.13866 | biomedical | Study | [
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A low proliferative response and reduced IL-2 secretion are characteristics of Treg cells . To analyze their capacity to proliferate and secrete IL-2 upon TCR triggering, Treg and memory T-cells were sorted into highly purified populations by flow cytometry. Purified cells were then labeled with carboxy-fluorescein diacetate succinimidyl ester (CFSE) to monitor cell division in a quantitative manner and stimulated through the TCR using plate-bound anti-CD3 and soluble anti-CD28 antibodies. The secretion of IL-2 by TCR-stimulated Treg cells was about 10-fold lower as compared to memory T-cells . Treg cells also secreted lower levels of IL-4, IL-5, and IFNγ as compared to memory T-cells . The CFSE-labeled cells were analyzed 6 d after stimulation. Treg cells exhibited little proliferation, whereas most of the memory T-cells had divided four to five times . In order to demonstrate that purified Treg cells also displayed suppressive activity, both naïve and CD25 low/neg memory CD4 + T-cells were labeled with CFSE and stimulated under suboptimal T-cell activation conditions in the presence of unlabeled purified autologous Treg, naïve, or memory T-cells. Coculture with Treg cells significantly slowed the proliferation of TCR-stimulated resting naïve and memory CD4 + T-cells as compared to the coculture with either unlabeled naïve or memory T-cells . Taken together, these results confirm that human Treg cells are part of the CD4 + CD25 hi subset of T-cells. | 15252446_p7 | 15252446 | Isolation and Characterization of Human Treg Cells | 4.362982 | biomedical | Study | [
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The ability to obtain a pure population of functional human Treg cells provides an excellent model to study their role in HIV pathogenesis. To determine whether Treg cells were susceptible to HIV infection, purified Treg cells were first activated through the TCR and were infected with either replication-competent HIV, which uses CCR5 as a coreceptor (R5.HIV), or replication-defective viruses pseudotyped with vesicular stomatitis virus glycoprotein (VSV-G.HIV) that encode green fluorescent protein (GFP) as a marker of infection . Treg and memory T-cells challenged with VSV-G.HIV resulted in an equivalent infection rate, while in some experiments R5.HIV resulted in about a 2-fold higher infection rate of the Treg cells as compared to the memory T-cells . To determine the level of HIV replication in the Treg cells as compared to activated memory T-cells, both subsets were infected with R5.HIV for 2 d and washed to remove input virus. Supernatants were collected from the infected cultures daily and p24 levels were quantified by enzyme-linked immunosorbent assay (ELISA). HIV replicated in Treg cells as efficiently as in memory T-cells . To assess whether the virus produced by Treg cells was infectious, supernatants from infected cells were added to Hut78/CCR5 cells, which are highly susceptible to HIV infection, and the titer of infectious virus was determined by GFP expression. Treg cells produced levels of infectious virus similar to those of the memory T subset (data not shown). The viability of infected cultures was also determined at days 3 and 7 to determine if HIV infection killed Treg cells. Indeed, infection with replication-competent HIV was highly cytotoxic to both Treg and memory T-cells . We conclude that Treg cells are highly susceptible to HIV infection and are killed by viral replication. | 15252446_p8 | 15252446 | Treg Cells Are Highly Susceptible to HIV Infection | 4.420367 | biomedical | Study | [
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Treg cells constitute less than 1%–2% of total human T-cells . Although we could purify several hundred thousand Treg cells from 300 ml of blood as described below, isolation of sufficient numbers of Treg cells is clearly an obstacle to studying their function and susceptibility to HIV infection. Recently, a transcription factor called FOXP3 was shown to program murine T-cells into a Treg subset . Therefore we hypothesized that ectopic expression of FoxP3 in naïve T-cells could facilitate the generation of large numbers of human Treg cells. Accordingly, we subcloned FoxP3 cDNA into a HIV-derived vector (HDV) that encodes murine CD24 (mCD24) as a marker . CD4 + T-cells were purified from both neonatal cord blood (CB) and adult blood (AB), activated through the TCR and transduced with FoxP3-expressing HDV (HDV.FoxP3) or control HDV as described previously . Expression of FoxP3 mRNA in transduced cells was confirmed by real-time PCR analysis and was found to be about 50- to 100-fold higher in FoxP3 transduced primary CD4 + T-cells as compared to control HDV-transduced cells (data not shown). | 15252446_p9 | 15252446 | Genetic Reprogramming of Conventional Human T-cells into Treg Cells by Ectopic Expression of FoxP3 | 4.140014 | biomedical | Study | [
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FoxP3-transduced and control cells were expanded for 14 d in IL-2-containing medium. Cells were then stained for mCD24 and also for CD25, GITR, and CCR4 markers that are expressed at higher levels on naturally occurring Treg cells . Naïve T-cells ectopically expressing FoxP3 displayed higher levels of CD25, GITR , and CCR4 as compared to control transduced T-cells. FoxP3-transduced memory T-cells displayed much less upregulation of these markers (data not shown). However, while the majority of these transduced T-cells also expressed CCR5, its expression levels on FoxP3-transduced and control T-cells were similar . To determine whether FoxP3-transduced T-cells display functional properties such as hyporesponsiveness to TCR triggering, similar to freshly isolated Treg cells, transduced cells were purified by sorting mCD24 + cells as described previously . Equal numbers of purified cells were then stimulated using plate-bound anti-CD3 and soluble anti-CD28 antibodies, and cytokine secretion was monitored. Secretion of IL-2 from both CB and AB naïve T-cells was reduced between 8- and 10-fold in FoxP3-expressing cells as compared to control cultures . Secretion of IL-4, IL-5, and IFNγ was also reduced in FoxP3-expressing naïve T-cells . In contrast, FoxP3-transduced memory T-cells secreted similar levels of IL-2 as compared to cells transduced with HDV alone . To assess the proliferative capacity of FoxP3-expressing cells, transduced cells were labeled with CFSE and stimulated through the TCR. After 4 d of activation, very few FoxP3-transduced naïve T-cells had divided as compared to control lines . Although, FoxP3-expressing memory T-cells also divided fewer times as compared to HDV-transduced cells, the effect of FoxP3 was greatly diminished in this subset . | 15252446_p10 | 15252446 | Genetic Reprogramming of Conventional Human T-cells into Treg Cells by Ectopic Expression of FoxP3 | 4.319694 | biomedical | Study | [
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The key characteristic of Treg cells is suppression of conventional T-cells activated through the TCR . Thus, purified resting CD4 + T-cells were labeled with CFSE and cocultured with unlabeled naïve or memory T-cells that were transduced either with HDV.FoxP3 or HDV and then stimulated through the TCR as described for freshly isolated Treg cells . FoxP3-expressing naïve T-cells, both from CB or AB, completely suppressed proliferation of target resting CD4 + T-cells . A significant but lower level of suppression was apparent with memory T-cells transduced with FoxP3 . We conclude that ectopic expression of FoxP3 in naïve human T-cells recapitulates key phenotypic and functional features of naturally occurring Treg cells. | 15252446_p11 | 15252446 | Genetic Reprogramming of Conventional Human T-cells into Treg Cells by Ectopic Expression of FoxP3 | 4.209115 | biomedical | Study | [
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We next determined the susceptibility of FoxP3-expressing cells to HIV infection. FoxP3-transduced cells were purified by flow cytometry sorting based on mCD24 expression and activated through their TCR or cultured in IL-2-containing medium. Subsequently, activated cells were challenged with either VSV-G.HIV or R5.HIV. Remarkably, FoxP3-expressing cells were infected at a level about 2- to 3-fold higher than control cells at different concentrations of the virus, in both activated and nonactivated conditions . FoxP3-expressing cells stimulated at suboptimal levels of anti-CD3 antibody also displayed a very similar enhancement of infection compared to HDV-transduced cells (data not shown). | 15252446_p12 | 15252446 | T-cells Ectopically Expressing FoxP3 Are More Susceptible to HIV Infection | 4.094919 | biomedical | Study | [
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We next analyzed the level of HIV replication and cell death in FoxP3-expressing cells as compared to HDV-transduced T-cells. Activated FoxP3-expressing and control cells were infected with R5.HIV, and culture supernatants were collected daily from day 3 postinfection. FoxP3-expressing cells showed increased HIV-infection and replication . Infectivity of virus produced by FoxP3-expressing cells, as assessed on Hut78/CCR5 cells, as well as cell death in these cultures, was also proportionately higher (data not shown). These findings demonstrate that the expression of FoxP3 renders CD4 + primary T-cells more susceptible to HIV infection. | 15252446_p13 | 15252446 | T-cells Ectopically Expressing FoxP3 Are More Susceptible to HIV Infection | 4.107956 | biomedical | Study | [
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Our findings that Treg cells are highly susceptible to HIV infection prompted us to determine if this subset was disturbed within HIV-infected individuals. However, a major difficulty in such analysis is that many of the cell surface markers that define Treg cells are also expressed on activated T-cells (CD25, HLA-DR, GITR). Because a portion of HIV-positive individuals contain high levels of activated T-cells, simple cell surface analysis would not be sufficiently reliable to quantify Treg cells in these donors. Therefore, we utilized FoxP3 expression as the most reliable marker that defines Treg cells. To accomplish this, we sorted CD4 + CD25 hi , naïve, and memory T-cells from 11 HIV-negative, healthy donors (median age, 31; 64% male) and 24 HIV-infected individuals (median age, 38; 85% male; 88% receiving antiretroviral therapy). Total RNA was then isolated from each subset and FoxP3 mRNA expression was quantified using real-time PCR analysis. In order to normalize for experimental variability, FoxP3 expression of the CD4 + CD25 hi cells was normalized to GAPDH levels from the same samples and compared to the naïve T-cell subset isolated from the same donor. We found that within HIV-negative subjects there was on average a 49-fold higher level of expression of FoxP3 in CD4 + CD25 hi cells as compared to naïve T-cells . The lowest FoxP3-expressor in the healthy subject group had 16-fold higher FoxP3 expression as compared to naïve T-cells from the same donor . There was a similar increase in FoxP3 expression as compared to memory T-cells (data not shown). In HIV-positive subjects FoxP3 expression was only increased a mean of 25-fold in CD4 + CD25 hi cells. In contrast to healthy donors, we also observed that in about half of the HIV-positive subjects, CD4 + CD25 hi cells expressed very low to undetectable levels of FoxP3 . FoxP3 expression in memory T-cells was similar in HIV-positive and HIV-negative subjects . | 15252446_p14 | 15252446 | HIV-Infected Patients Have Greatly Decreased Levels of FoxP3-Expressing CD4 + CD25 hi T-cells | 4.232398 | biomedical | Study | [
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Progressive HIV disease is associated with decreased CD4 + T-cell percentages and increased levels of activated T-cells. We hypothesized that this hyperactivation may be due to a loss of Treg cells. Therefore, to further evaluate relationships between FoxP3 expression and these parameters in HIV-infected individuals, samples were divided into low FoxP3 expressors (less than 10-fold higher expression in CD4 + CD25 hi T-cells compared to naïve T-cells, designated FoxP3-low) versus high FoxP3 expressors (greater than 10-fold higher expression compared to naïve T-cells, designated FoxP3-high). HIV-positive subjects with a FoxP3-low profile had significantly lower CD4 + T-cell percentages, while FoxP3-high HIV-positive subjects had CD4 + T-cell percentages comparable to HIV-seronegative subjects . Similarly, HIV-positive FoxP3-low subjects had significantly greater activated CD4 + T-cells (CD4 + HLA-DR + ) than either HIV-positive subjects with FoxP3-high profiles or HIV-seronegative subjects . Interestingly, the CD4 + CD25 hi T-cells are also significantly increased in FoxP3-low expressors as compared to HIV-negative or HIV-positive FoxP3-high expressors . These differences are most likely due to recently activated T-cells that also express high levels of CD25, as shown by higher HLA-DR expression on T-cells from the same subset of subjects . Among HIV-positive subjects there was no significant association between FoxP3 expression and plasma HIV-1 RNA concentration, age, race, sex, or whether the subject was receiving antiretroviral therapy ( P > 0.05 for each comparison). These findings demonstrate that a decrease in Treg cells is associated with HIV disease progression and suggest that loss of Treg cells may contribute to increased T-cell hyperactivation. | 15252446_p15 | 15252446 | HIV-Infected Patients Have Greatly Decreased Levels of FoxP3-Expressing CD4 + CD25 hi T-cells | 4.350967 | biomedical | Study | [
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In this study we demonstrated that human Treg cells are highly susceptible to HIV infection and that ectopic expression of FoxP3 genetically reprograms conventional naïve T-cells, phenotypically and functionally, into Treg cells. Remarkably, overexpression of FoxP3 also greatly enhances the susceptibility of activated T-cells to HIV infection. Although Treg cells constitute a small subset of the total T-cells in humans (less than 1%–2%) and thus may not be a significant target population for HIV, they appear to have very potent suppressive activity against activation of T-cells . Here we demonstrate that FoxP3-expressing CD4 + CD25 hi T-cells are greatly decreased in a portion of HIV-infected individuals with low CD4 and high activated T-cells, suggesting a loss of Treg cells. We therefore propose that infection and disruption of Treg cells during HIV infection could have a major influence on T-cell homeostasis and immune regulation. | 15252446_p16 | 15252446 | Discussion | 4.289789 | biomedical | Study | [
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Similar to previous reports, our findings demonstrate that human Treg cells appear to be enriched within the CD25 hi subset of CD4 + T-cells. However, it is not clear if Treg cells are the only population represented in the CD25 hi subset since they share this phenotype with recently activated T-cells. Indeed, a portion of purified CD25 hi cells proliferated and their suppressive function was less efficient as compared to FoxP3-expressing cells . Because the purification of Treg cells is rather arbitrary (brightest 1%–2% of antibody-stained CD25 + memory T-cells), it is conceivable that there is sizable contamination of non-Treg cells in these sorted preparations. In addition, the differences seen in the infection susceptibility of Tregs as compared to FoxP3-expressing cells may also be partly due to presence of non-Treg activated T-cells within the purified cells. Identification of the Treg subset in disease conditions with chronic T-cell activation, such as HIV, is even more problematic because a large proportion of CD4 + CD25 hi cells possibly represent recently activated T-cells. Availability of large numbers of genetically reprogrammed Treg cells should facilitate the identification of novel markers that can reliably detect human Treg cells. | 15252446_p17 | 15252446 | Discussion | 4.306777 | biomedical | Study | [
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Our results clearly demonstrate that, similar to the mouse system, ectopic expression of FoxP3 is sufficient to recapitulate all of the characteristics of Treg cells, including lower cytokine secretion, higher expression of CD25 and GITR, and their suppressive functions. This system has allowed us to generate large numbers of Treg cells, which will be invaluable in characterizing their suppressive function as well as mechanisms of enhanced HIV susceptibility. The ability to genetically manipulate primary T-cells to reprogram them into the Treg phenotype also could have profound implications for preventing graft-versus-host disease, a serious clinical condition that can be manifested following hematopoietic cell transplantation . | 15252446_p18 | 15252446 | Discussion | 4.168839 | biomedical | Study | [
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It is interesting to note that naïve T-cells are more prone to reprogramming into a Treg phenotype than memory T-cells are. This loss in flexibility of reprogramming with a master transcription factor is reminiscent of Th1- and Th2-type T-cell reprogramming with ectopic expression of lineage-specific transcription factors T-bet and GATA-3, respectively . The loss of flexibility in genetic modification of effector/memory T-cells could reflect heritable epigenetic changes at effector gene loci that might otherwise be responsive to FoxP3-mediated transcription. A recent study supports this hypothesis by demonstrating that lineage-committed human memory cells failed to modify their histone acetylation patterns of cytokine genes, unlike naïve T-cells, to differentiate into Th1- or Th2-type cells . | 15252446_p19 | 15252446 | Discussion | 4.34879 | biomedical | Study | [
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The cause of progressive depletion of CD4 + cells and the reason for high T-cell activation or turnover during HIV infection remains controversial . It is thought that HIV-mediated destruction of CD4 + T-cells results in decline of this subset and that to maintain homeostasis the immune system attempts to replenish this subset, resulting in a massive turnover of T-cells . This excessive turnover rate eventually compromises proper function of homeostatic responses. Alternatively, T-cell depletion could result from disrupted thymic and peripheral homeostatic mechanisms by virus-induced generalized T-cell activation and gradual wasting of T-cell supplies, eventually leading to T-cell depletion . | 15252446_p20 | 15252446 | Discussion | 4.289549 | biomedical | Study | [
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Indeed, several mechanisms control unwanted activation of T-cells, including thymic deletion of autoreactive T-cells and induction of anergy in the periphery. In addition to these passive mechanisms, recent evidence clearly demonstrates that Treg cells exert an active suppression of T-cell activation. We postulate that the high susceptibility of Treg cells to HIV in vivo, as demonstrated by our in vitro studies, could result in gradual elimination of this subset. This Treg cell decline during HIV infection would in turn reduce active suppression of conventional T-cells and, hence, contribute to hyperactivation of T-cells. Our analyses of peripheral blood T-cells from HIV-infected subjects support this hypothesis that loss of Treg cells during HIV infection contributes to HIV disease progression. Indeed, we found that in a subset of HIV-infected subjects, the CD4 + CD25 hi T-cell subset had greatly reduced FoxP3 expression, suggesting that these cells represent recently activated T-cells rather then Treg cells. The presence of a higher percent of activated T-cells in this FoxP3-low profile supports this conjecture. The HIV-infected subjects with lower levels of FoxP3 + T-cells also contained a lower percentage of CD4 + T-cells. It is conceivable that the loss of Treg cells may be a correlative factor for disease progression; however, more detailed prospective studies will be required to address this important implication of our findings. | 15252446_p21 | 15252446 | Discussion | 4.353885 | biomedical | Study | [
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Our findings show a 2- to 3-fold enhancement of HIV infection in FoxP3-expressing T-cells. While freshly purified Treg and memory T-cells are similar in their susceptibility to HIV infection, activated effector T-cells become gradually more resistant to infection (unpublished results). Indeed, preactivated T-cells require reactivation to render them susceptible to infection after about 1–2 weeks in culture (unpublished results). We do not yet know the mechanisms by which FoxP3 renders activated T-cells more susceptible to infection; however, two possibilities can be considered: (1) FoxP3 may be overcoming innate resistance factor(s) that accumulate in activated T-cells that block HIV infection, or (2) FoxP3 expression may be inducing critical host factors that are required for efficient completion of the HIV life cycle in primary T-cells. It is important to note that since FoxP3 expression enhances VSV-G.HIV single-round infections, it likely affects an early, postentry step in viral replication. Determining the mechanisms by which FoxP3 enhances HIV infection could reveal host factors involved in this process. | 15252446_p22 | 15252446 | Discussion | 4.369875 | biomedical | Study | [
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In summary, our results indicate that both naturally occurring and genetically reprogrammed Treg cells are susceptible to HIV infection and that ectopic FoxP3 expression greatly increases the susceptibility of T-cells to HIV infection. Our finding that FoxP3-expressing CD4 + CD25 + T-cells are greatly reduced in HIV patients with low CD4 + T-cell percentages and increased T-cell activation suggests that loss of Treg cells may contribute to HIV disease progression. Further prospective studies will be required to unravel the role of this important subset in HIV infection. The ability to genetically reprogram conventional human T-cells to generate Treg cells will also lead the way to identifying unique markers expressed on this population in order to further investigate their status in HIV-infected individuals. Moreover, understanding how FoxP3 enhances HIV infection and programs T-cells into the Treg subset could help in the identification of novel host factors that mediate HIV infection in primary T-cells and decoding the molecular mechanisms by which Treg cells mediate their suppressive function. | 15252446_p23 | 15252446 | Discussion | 4.247972 | biomedical | Study | [
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Healthy subjects ( n = 11) were adults who were HIV-negative and with no history of chronic viral infections such as Hepatitis B or C. Blood samples from adults with HIV infection ( n = 24) were obtained during routine primary care visits at the Comprehensive Care Center, Vanderbilt University Medical School, Nashville, Tennessee, United States. There were no selection criteria based on race or sex. All subjects provided written consent, and the study was approved by the Vanderbilt Institutional Review Board. Continuous variables were compared by a Mann–Whitney U test, and categorical variables by an χ 2 test. All significance levels were based on two-tailed tests. Statistical analyses were performed using SPSS, version 12.0 (SPSS, Chicago, Illinois, United States). | 15252446_p24 | 15252446 | Study subjects and statistical analysis | 3.731548 | biomedical | Study | [
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Peripheral blood mononuclear cells (PBMCs) were separated from buffy coats of healthy and HIV-positive donors through Ficoll–Hypaque separation (Pharmacia-LKB Technology, Uppsala, Sweden). Resting CD4 + T-cells were purified as previously described . This purification protocol typically resulted in 99.5% purity of positively selected cells, as determined by postpurification fluorescence-activated cell sorting (FACS) analysis. To isolate Treg cells, PBMCs, or purified CD4 + cells, were stained with CD45RO, CD25, CD4, and HLA-DR antibodies (BD Biosciences Pharmingen, San Diego, California, United States), and CD4 + CD45RO + CD25 hi and CD4 + CD45RO − CD25 low/neg cells were sorted using flow cytometry (FACS Aria; BD Biosciences Pharmingen). For some experiments, adult CD4 + T-cells were sorted into CD45RO + (memory) and CD45RO − (naïve) T-cells with anti-CD45RO conjugated magnetic beads (Miltenyi Biotec, Bergisch Gladbach, Germany) using AutoMACS (Miltenyi Biotec). Purified resting T-cells were activated by cross-linking with plate-bound anti-CD3 antibody (OKT-3; American Type Culture Collection, Manassas, Virginia, United States) and soluble anti-CD28 antibody (1 μg/ml, BD Biosciences Pharmingen). The plates were first coated with goat antimouse IgG (10 μg/ml, CalTag Laboratories, Burlingame, California, United States) followed by either 3 μg/ml anti-CD3 for optimal TCR stimulation or 100 ng/ml anti-CD3 for suboptimal stimulation. The culture medium used in all experiments was RPMI (Life Technologies, Carlsbad, California, United States) and was prepared as previously described . All cytokines were purchased from R & D Systems (Minneapolis, Minnesota, United States). Monocyte-derived dendritic cells were generated as previously described . Superantigen, staphylococcal enterotoxin B (Sigma, St. Louis, Missouri, United States) was used to stimulate resting T-cells in the presence of dendritic cells . | 15252446_p25 | 15252446 | Cell isolation and culture | 4.207082 | biomedical | Study | [
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] | [
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0.0004882107605226338,
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] | en | 0.999998 |
VSV-G.HIV particles were generated as previously described . R5-HIV was prepared similarly by transfecting 293T-cells with HIV that encodes R5-tropic (BAL) envelope and enhanced GFP (Clontech, Palo Alto, California, United States) in place of the nef gene as previously described . Typically viral titers ranged from 1–5 × 10 6 ifu/ml for replication-competent viruses and 10–30 × 10 6 for VSV-G.HIV. T-cells were infected at varying multiplicities of infection (MOI), and infection was quantified by GFP expression using flow cytometry. In some experiments, cells inoculated with virus were centrifuged for 1 h at 2,000 rpm to enhance infectivity, as described by O'Doherty et al. . Viral replication in T-cell cultures was determined by measuring p24 levels within supernatants by an ELISA , and infectious virus production by infected T-cells was determined by culturing Hut78 cells expressing CCR5 (Hut78/CCR5) in infected T-cell supernatants. | 15252446_p26 | 15252446 | Virus production and infections | 4.152365 | biomedical | Study | [
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] | [
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] | en | 0.999998 |
Cell division was measured by labeling the T-cells with CFSE (Molecular Probes, Eugene, Oregon, United States). Purified cells were first washed and resuspended in PBS. While vortexing the cells, CFSE was added at a final concentration of 5 μM. The mixture was vortexed for an additional 15 s and incubated at 37 °C for 3 min. Labeling was quenched by addition of 50% fetal calf serum in PBS. Cells were washed one more time with 50% serum PBS, followed by two washes with RPMI-supplemented medium. All CFSE labeling and culturing were performed under dark conditions. | 15252446_p27 | 15252446 | CFSE labeling | 4.08405 | biomedical | Study | [
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T-cells were stained with the relevant antibody on ice for 30 min in PBS buffer containing 2% fetal calf serum and 0.1% sodium azide. Cells were then washed twice, fixed with 1% paraformaldehyde, and analyzed with a FACSCalibur four-color cytometer. Live cells were gated based on forward- and side-scatter properties, and analysis was performed using FlowJo software (Tree Star, Ashland, Oregon, United States). The following antihuman antibodies were used for staining: CD3, CD4, CD45RO, CD45RA, CD25, GITR, HLA-DR, CCR5, CCR4, CCR7, CXCR4, CXCR3, and antimouse CD24, all obtained from PharMingen (San Diego, California, United States). Cytokines (IL-2, IL-4, IL-5, and IFNγ) in the supernatants were assayed using a commercially available cytometric bead array (CBA) (BD Biosciences Pharmingen) and analyzed using CBA 6-bead analysis software (BD Biosciences Pharmingen). | 15252446_p28 | 15252446 | FACS analysis and cytokine assay | 4.117457 | biomedical | Study | [
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RNA was isolated from activated human T-cells using an RNeasy kit (Qiagen, Valencia, California, United States). To synthesize cDNA 100 ng RNA was used (Superscript II Reverse Transcriptase; Invitrogen, Carlsbad, California, United States). FoxP3 was PCR amplified from T-cell cDNA with the following primers: FoxP3 forward, 5′-AGATATCCCAGCCATGCCCAACCCCAGGCCTGGCAAG-3′; FoxP3 reverse, 5′-TCAGGGGCCAGGTGTAGGGTTGGAACACCT-3′. The forward primer included an EcoRV restriction site to facilitate cloning. The FoxP3 PCR product was subcloned into a TOPO shuttle vector (pcDNA3.1/CT-GFP-TOPO; Invitrogen). Following an EcoRV digest, FoxP3 was ligated into an HDV-encoding mCD24 down stream of an internal ribosome entry site . The FoxP3 coding sequence was confirmed by DNA sequencing. | 15252446_p29 | 15252446 | Cloning of human FoxP3 | 4.145585 | biomedical | Study | [
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RNA was extracted, as described above, from cells transduced with HDV or HDV.FoxP3 or sorted Treg, naïve, and memory T-cells from HIV-positive and HIV-negative subjects. RNA (100 ng) was used to synthesize cDNA (as described above). Taqman Assays-on-Demand Gene Expression Primers (Applied Biosystems, Foster City, California, United States) were used in real-time PCR analyses: GAPDH primer mix assay ID Hs99999905_m1; FoxP3 primer mix assay ID Hs00203958_m1. | 15252446_p30 | 15252446 | Real-time PCR protocol | 4.079038 | biomedical | Study | [
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Real-time PCR was performed using the ABI 7700 apparatus (PE Applied Biosystems, Weiterstadt, Germany). The reaction mixtures (20-μl total volume) contained 2 μl of serially diluted cDNA, 10 μl of Taqman Universal PCR Master Mix (PE Applied Biosystems), and 1 μl of either FoxP3 or GAPDH primer mix. The reactions were amplified as follows: 50 °C for 2 min and 95 °C for 10 min, followed by 40 cycles of 95 °C for 1 min and 65 °C for 1 min. Expression of FoxP3 was normalized to GAPDH expression in each sample. | 15252446_p31 | 15252446 | Real-time PCR protocol | 4.083349 | biomedical | Study | [
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The GenBank ( http://www.ncbi.nlm.nih.gov/ ) accession number for the gene FoxP3 discussed in this paper is AF277993. | 15252446_p32 | 15252446 | Accession Number | 1.542126 | biomedical | Other | [
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Fostering motivation is essential to effective teaching. More motivated students persist longer in the face of setbacks, learn and retain more, and are more likely to pursue additional learning ( 1 – 3 ). Self-determination theory (SDT), one of the most prominent psychological models of motivation, posits that intrinsic motivation is founded on three core elements: connectedness, mastery, and autonomy ( 4 , 5 ). Ample evidence demonstrates that policies informed by SDT can improve student motivation ( 6 ). Many classroom interventions target connectedness, emphasizing inclusive teaching, group work, and fostering a sense of belonging ( 7 – 9 ). Others focus on mastery, emphasizing the importance of scaffolding and calibrating difficulty to build confidence ( 10 – 12 ). However, despite a large literature on the importance of autonomy to motivation and achievement, many policies recommended by university teaching and learning centers—such as mandatory attendance, mandatory drafts, syllabus quizzes, and so on—serve to undermine feelings of autonomy. | 39018403_p0 | 39018403 | INTRODUCTION | 1.53274 | other | Other | [
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As used in psychology, “autonomy” (sometimes called “agency”) refers to the perception of an internal locus of control—the sense that one’s actions flow from one’s desires, and not merely from external demands. Autonomy has been shown to have a host of positive motivational, well-being ( 4 ), and educational benefits [( 13 ); for reviews, see ( 2 , 14 , 15 )]. Black and Deci ( 16 ) found that students of autonomy-supporting teachers enjoy class more, perform better, and experience less anxiety [for similar results, see ( 17 )]. Both laboratory ( 18 ) and field studies ( 19 ) have shown that autonomy-supportive learning tasks substantially increase students’ interest in and mastery of course materials. These effects of autonomy have been demonstrated across cultures ( 20 , 21 ) and across disciplines ranging from STEM (science, technology, engineering, and math) ( 22 ) to foreign languages ( 23 ). | 39018403_p1 | 39018403 | INTRODUCTION | 2.538413 | other | Review | [
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University teaching and learning centers are responsible for disseminating best practices to instructors, so how well do their resources reflect the importance of student autonomy? Our analysis of the websites of 13 prominent centers revealed a striking disparity in the resources available for promoting autonomy compared to those focused on mastery and belongingness ( Table 1 ). Terms related to mastery appeared around 20 times more frequently than those linked to autonomy, while belongingness-related terms surfaced around 40 times more often. Some websites completely lacked discussion on student choice, while others argued against meaningful student autonomy, claiming that students’ underdeveloped metacognitive skills might undermine their own learning [e.g., ( 24 )]. | 39018403_p2 | 39018403 | INTRODUCTION | 1.056111 | other | Study | [
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Given the substantial evidence demonstrating the benefits of autonomy in educational settings, we argue that a better approach is to develop autonomy-promoting interventions that simultaneously encourage students to make wise decisions. Research on choice architecture has shown that it is often possible to devise policies that promote good decision making without the need for autonomy-undermining constraints [( 25 ); for a recent meta-analysis, see ( 26 )]. We argue that this approach can be profitably applied in higher education. Here, we describe and test easy-to-implement policies for promoting student autonomy in two key areas: attendance and assessment. | 39018403_p3 | 39018403 | INTRODUCTION | 1.06845 | other | Other | [
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Students who attend class reliably learn more than students who do not. One landmark meta-analysis that encompassed data from over 21,000 students found that attendance is a stronger predictor of college GPA (grade point average) than any other known factor, including measures of preparedness (e.g., SAT scores), work ethic (e.g., study habits), and effective study skills ( 27 ). Yet, many students skip class when given the freedom to do so. | 39018403_p4 | 39018403 | Study 1: Attendance policies | 1.071831 | other | Other | [
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Attendance rates are affected by many factors ( 28 ). However, mandatory attendance policies have been shown to increase attendance and improve learning outcomes [( 27 – 30 ), but see ( 31 ) for a possible counterexample]. At the high school level and younger, many states have truancy laws that legally compel students to attend class [although evidence for their effectiveness for at-risk youth is mixed at best ( 32 )]. For these reasons, mandatory attendance policies are popular in higher education. | 39018403_p5 | 39018403 | Study 1: Attendance policies | 1.052163 | other | Other | [
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But students do not like mandatory attendance. We asked 101 students to rate various attendance policies using 11-point Likert scales. Analysis of the survey data showed no significant dependencies between different policy ratings, so we treat each rating as an independent sample. Students reported learning more in classes with mandatory as opposed to optional attendance policies: d = 0.45, 95% confidence interval (CI) 0.070 to 0.82, t (111) = 2.4, P = 0.020. However, they enjoyed such classes far less: d = −0.96, 95% CI −1.4 to −0.57, t (111) = −5.1, P < 0.001. Students gave more favorable overall evaluations to classes with optional attendance, d = 0.61, 95% CI 0.23 to 0.98, t (111) = 3.2, P = 0.002, and were far more motivated to take such classes in the future: d = 1.2, 95% CI 0.79 to 1.6, t (111) = 6.4, P < 0.001. | 39018403_p6 | 39018403 | Study 1: Attendance policies | 1.882667 | other | Study | [
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These results point to a conundrum: How can educators promote the learning benefits associated with reliable attendance without undermining student motivation? | 39018403_p7 | 39018403 | Study 1: Attendance policies | 1.174283 | other | Other | [
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We propose “optional-mandatory” attendance as a solution. This policy allows students to choose at the beginning of the semester whether to make attendance a component of their grade, harnessing the power of pre-commitment when their motivation is likely to be highest. By deciding for themselves whether attendance will count, students who commit to mandatory attendance may reap the learning benefits of reliably showing up to class without suffering the motivational costs of controlling mandates [for identified/integrated regulation, see ( 33 , 34 )]. In our survey, students expected optional-mandatory to promote learning as effectively as mandatory attendance, d = 0.081, 95% CI −0.30 to 0.46, t (103) = 0.41, P = 0.680, while simultaneously giving optional-mandatory similar overall evaluations to purely optional attendance, d = 0.078, 95% CI −0.29 to 0.45, t (110) = 0.41, P = 0.681. Students additionally expected to be more motivated by optional-mandatory policies, d = 0.45, 95% CI 0.069 to 0.82, t (110) = 2.4, P = 0.020. | 39018403_p8 | 39018403 | Study 1: Attendance policies | 1.609985 | other | Study | [
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One might intuitively think that most students would prefer to maintain the flexibility of purely optional attendance and thus, when given the choice, would opt out of making their attendance mandatory. Yet, across five different classes ranging from 60 to 200 students, we have found that 73 to 95% of students choose mandatory attendance. By the end of these classes, at most 10% of students reported being unhappy with their decision to make their attendance mandatory. These high rates can be attributed to two features of the choice architecture ( 25 ). Students can be encouraged to opt in to mandatory attendance with thoughtful incentives, and people sometimes voluntarily limit their choices to promote desirable future behavior ( 35 ). Thus, students might choose mandatory attendance as a pre-commitment device. | 39018403_p9 | 39018403 | Study 1: Attendance policies | 1.282409 | other | Other | [
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To test optional-mandatory attendance, we ran a randomized controlled field study in an introductory-level, Gen-Ed philosophy course ( n = 104). Four teaching assistants (TAs) each taught two 50-minute weekly discussion sections. Each TA was randomly assigned to teach one section under a mandatory attendance policy and one under an optional-mandatory policy. TAs explained the relevant policy in the first meeting of each section and did not announce that attendance policies varied across sections. Students in the mandatory groups could miss up to three meetings without penalty. Missing no more than three meetings granted a 3% bonus to the final grade, while missing more than three resulted in a 3% penalty. Students in the optional-mandatory groups could choose whether attendance affected their grade. If they opted in, the policy was identical to the mandatory one; if they opted out, their attendance was not tracked and had no impact on their grade. Ninety percent of students chose to make their attendance mandatory. | 39018403_p10 | 39018403 | Study 1: Attendance policies | 1.829366 | other | Study | [
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We analyzed 794 observations using a logistic mixed-effects model. Our dependent variable was class attendance (attended versus absent). We included fixed effects for attendance policy, meeting number, and TA, along with interactions between these variables. To account for the repeated-measures design, we included a random intercept, which improved the model’s fit substantially: marginal R 2 = 0.08, conditional R 2 = 0.31, Likelihood Ratio Test (LRT) χ 2 (12) = 105, P < 0.001. Around 25% of the variance in attendance was attributable to differences between students (see the Supplementary Materials for more details and for alternative model specifications). | 39018403_p11 | 39018403 | Attendance outcomes | 3.634196 | biomedical | Study | [
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Compared to students in the mandatory groups, optional-mandatory students were more likely to attend weekly sections [odds ratio (OR) = 1.7, 95% CI 0.96 to 2.9], but this effect did not meet the conventional standard of statistical significance: P = 0.072. However, while all students were relatively motivated at the start of the semester—nearly 75% attended the first meeting of their section—we found a significant interaction between policy and meeting number (i.e., week): OR = 1.14, 95% CI 1.0 to 1.3, P = 0.025. Simple effects tests revealed that attendance in the mandatory groups declined over the course of the semester: χ 2 = 13, OR = 0.86, 95% CI 0.79 to 0.93, z = −3.6, P < 0.001. However, it was stable in the optional-mandatory groups: χ 2 = 0.37, OR = 0.98, 95% CI 0.91 to 1.1, z = −0.61, P = 0.541 . The pattern emerged across all sections, and we observed no interaction between policy and TA (all P s ≥ 0.397). These results were robust across alternative model specifications (see “Alternative Models” in the Supplementary Materials). | 39018403_p12 | 39018403 | Attendance outcomes | 3.591464 | other | Study | [
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Despite the high student uptake of mandatory attendance, the minority of students who choose optional attendance could be cause for some concern. Will these students fall through the cracks? To preserve students’ perceptions of autonomy, we did not require those who opted for fully optional attendance to register their presence in class when they chose to attend. For this reason, we cannot say how these students behaved. However, while we acknowledge that it is possible they opted out of attending class altogether, it is worth noting that choosing optional attendance is not the same as not attending; it merely implies maintaining flexibility regarding attendance. Even for students who opt out, optional-mandatory may discourage truancy because it fosters intrinsic motivation. Additionally, it is worth remembering that mandatory attendance policies do not ensure perfect attendance. Students still miss class; they just take penalties for doing so. | 39018403_p13 | 39018403 | Attendance outcomes | 1.056042 | other | Other | [
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Regular assessment followed by timely feedback is a crucial ingredient of effective teaching ( 36 , 37 ). However, students often seek to minimize the effort required to complete assignments ( 38 , 39 ). Teachers can push students to spend more time and effort on their assignments by weighting them more heavily, but such strategies can backfire by causing stress that may hurt both academic performance and well-being [e.g., ( 40 )]. The challenge, then, is to induce students to work hard without the use of controlling incentives. | 39018403_p14 | 39018403 | Study 2: Assessment options | 1.225451 | other | Other | [
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One approach is to give students greater control over how they are assessed. Forcing students to complete assignments can lead to reactance due to a loss of autonomy ( 41 , 42 ). This can result in students devoting less time and effort to the assignments, procrastinating, or foregoing the assignment entirely. Giving students a choice of assessment options might allow for a greater sense of autonomy, which as we have seen can powerfully bolster motivation. | 39018403_p15 | 39018403 | Study 2: Assessment options | 1.311907 | other | Other | [
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0.0006674461183138192
] | en | 0.999996 |
To test this hypothesis, we ran a study on students in an introductory philosophy course taught over two fall semesters by the same professor at the same institution ( n = 114). We assigned students to treatment groups by cohort: | 39018403_p16 | 39018403 | Study 2: Assessment options | 1.69612 | other | Study | [
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] | [
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] | en | 0.999997 |
1) In the first cohort (“mandatory”), all students were required to complete a series of 20 challenging argument analysis problem sets ( m difficulty = 3.8/5, 95% CI 3.7 to 3.8, where “5” = “Extremely difficult”). Problem sets were designed to train high-level reasoning skills using a technique known as “argument visualization” ( 43 ). | 39018403_p17 | 39018403 | Study 2: Assessment options | 2.623475 | other | Study | [
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] | [
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] | en | 0.999997 |
2) In the second cohort (“free-to-switch”), students chose between problem set–based assessment and a second option—essay-based assessment—which required relatively little work. Students who chose this second option were assessed based on weekly reading questions and short (five-page) midterm and final essays. Students were made aware of the relative difficulty of the two options and were allowed to switch into the low-effort, essay-based assessment stream at any point before the midterm essay deadline. | 39018403_p18 | 39018403 | Study 2: Assessment options | 1.233339 | other | Other | [
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0.0006379375699907541,
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] | [
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0.9432894587516785,
0.0014371138531714678,
0.0011120140552520752
] | en | 0.999998 |
Because our study assigned students to treatment groups in cohorts, we cannot rule out the possibility of unmeasured confounds. However, it is reassuring to note that there were no meaningful differences in students’ seniority, home college, home department, or major (all P s ≥ 0.392, γ = −0.030 to −0.040; see the Supplementary Materials for detailed comparisons). | 39018403_p19 | 39018403 | Study 2: Assessment options | 2.124017 | other | Study | [
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] | [
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0.00011299901234451681
] | en | 0.999996 |
Ninety percent of students in the free-to-switch cohort initially set out to pursue problem set–based assessment, and only 5% of those students later switched into the essay-based stream. If the students who chose the low-effort assessment option were weaker than average, including their data could increase the relative performance of the free-to-switch cohort. We therefore excluded submissions from students ranked below the 15th percentile in the mandatory cohort. Although this represents a conservative assumption that only the lowest-performing students opted out, it did not affect our results. To ensure our comparison was based solely on students completing assignments with identical instructions, we excluded assignments that changed between cohorts. After these exclusions, 1036 submissions remained for analysis. In this study, we explored two dependent variables. First, students’ self-reported time on each problem set and second, the quality of their work as assessed by TAs blind to the hypothesis under study. | 39018403_p20 | 39018403 | Study 2: Assessment options | 1.724364 | other | Study | [
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] | [
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] | en | 0.999997 |
Whenever students submitted problem sets, they reported how long they spent on the homework assignment using a six-point scale. We constructed an ordinal logistic mixed model with fixed effects for assessment policy (mandatory versus free-to-switch), problem set number (1 to 12), their interaction, and a random intercept to account for the repeated-measures design. The inclusion of the random intercept significantly improved the model fit: marginal R 2 = 0.080, conditional R 2 = 0.44, LRT χ 2 (4) = 342, P < 0.001. Approximately 39% of the total variance in time spent on assignments could be attributed to differences between students. | 39018403_p21 | 39018403 | Problem set effort | 3.07652 | other | Study | [
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0.0010840174509212375,
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] | [
0.9955129027366638,
0.0037843934260308743,
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0.0001512835151515901
] | en | 0.999997 |
Across both cohorts, each additional assignment reduced the odds of reporting a higher time investment by around 7%: OR = 0.93, 95% CI 0.90 to 0.97, z = −3.8, P < 0.001. We found no interaction between assignment number and cohort, indicating that the trend of spending less time on homework assignments as the semester progressed was consistent across the groups: χ 2 (1) = 0.0060, P = 0.937. Crucially, a significant effect of cohort emerged: χ 2 (1) = 15, P < 0.001. Relative to students in the mandatory cohort, students in the free-to-switch cohort had 3.6 times the odds of reporting a higher category of time invested on homework assignments: 95% CI 1.9 to 6.9, z = 3.1, P = 0.002 . As in Study 1, our qualitative conclusions are robust to alternative model specifications. | 39018403_p22 | 39018403 | Problem set effort | 3.537765 | other | Study | [
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0.0013518653577193618,
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] | [
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0.0012141707120463252,
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0.00008311792771564797
] | en | 0.999998 |
Problem sets were graded on a three-point scale (0, 1, 2). The standard for earning one point was submitting a “meaningful attempt” before the deadline. After excluding the seven lowest-performing students in the mandatory cohort (as explained above), all submissions received either a “1” or “2.” In the free-to-switch cohort, only 0.16% of submissions received a “0.” For ease of interpretation, we excluded these submissions and tested a logistic mixed-effects model. This decision did not change the qualitative pattern of results (see the Supplementary Materials for alternative models and model specifications). | 39018403_p23 | 39018403 | Problem set performance | 1.776415 | other | Study | [
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] | [
0.967285692691803,
0.03166015073657036,
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0.0004023793153464794
] | en | 0.999997 |
We fitted a logistic mixed-effects model using a logit link function and a binomial distribution. The model included fixed effects for assessment policy (mandatory versus free-to-switch), homework assignment number (1 to 12), and their interaction, and a random intercept to account for the repeated-measures design. The inclusion of the random intercept significantly improved the model fit: marginal R 2 = 0.10, conditional R 2 = 0.24, LRT χ 2 (4) = 87, P < 0.001. | 39018403_p24 | 39018403 | Problem set performance | 4.106183 | biomedical | Study | [
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0.0005472004413604736,
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] | [
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] | en | 0.999997 |
We predicted that higher motivation in the free-to-switch cohort would, over time, translate into greater proficiency as manifested in students’ grades. Confirming this prediction, a statistically robust interaction between assessment policy and assignment number emerged: OR = 1.16, 95% CI 1.06 to 1.26, z = 3.2, P = 0.002. For each additional assignment, the odds of achieving a grade of “2” increased by roughly 16% more in the free-to-switch cohort than in the mandatory cohort . Simple effects tests revealed that while students did not improve significantly when they were forced to complete problem sets (χ 2 = 0.76, P = 0.383), they did improve when they were given greater autonomy (χ 2 = 28, P < 0.001). As before, this pattern emerged across alternative model specifications. | 39018403_p25 | 39018403 | Problem set performance | 2.603575 | other | Study | [
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] | [
0.9940667152404785,
0.005199459381401539,
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] | en | 0.999997 |
This cohort study illustrates several points: | 39018403_p26 | 39018403 | Problem set performance | 1.970428 | biomedical | Study | [
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] | [
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] | en | 0.999996 |
1) Eighty-five percent of students opted for a more demanding assessment option and stuck with their choice. In two subsequent classes, 94 to 97% of students did the same ( N s = 157 and 197). Direct comparisons between these classes and the cohorts studied here are not possible due to differences in course materials. However, we have consistently replicated the widespread student adoption of a high-effort assessment option. | 39018403_p27 | 39018403 | Problem set performance | 1.210895 | other | Other | [
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0.000728726212400943,
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] | [
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0.0020631852094084024
] | en | 0.999996 |
2) Giving students meaningful control over their own learning increased the time they spent studying and improved their performance on complex, high-level reasoning tasks. | 39018403_p28 | 39018403 | Problem set performance | 1.48263 | other | Other | [
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] | [
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] | en | 0.999997 |
3) Although few students in the free-to-switch cohort chose the less demanding essay-based assessment, the mere availability of this choice appeared to boost motivation and learning. | 39018403_p29 | 39018403 | Problem set performance | 1.146179 | other | Other | [
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] | [
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] | en | 0.999997 |
This suggests that controlling mandates are not always needed to engage students in rigorous learning, and that increasing student autonomy can provide powerful motivational benefits even in the absence of a binding pre-commitment. | 39018403_p30 | 39018403 | Problem set performance | 1.164492 | other | Other | [
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] | [
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] | en | 0.999996 |
It is important to acknowledge that some students ultimately chose the less challenging option, which may have resulted in a less rigorous learning experience compared to those who opted for the more demanding alternative. However, it is not clear that those students would have engaged more meaningfully with the material even if problem sets had been mandated—it is not uncommon for students to fail to turn in required assignments and simply take the penalty to their grades. | 39018403_p31 | 39018403 | Problem set performance | 1.095766 | other | Other | [
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0.0006261724629439414,
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] | [
0.007720198016613722,
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] | en | 0.999997 |
Many resources are available for educators to improve students’ perceptions of belongingness and mastery. However, there is a dearth of research validating interventions to promote autonomy in higher education. This is despite a large literature consistently showing the importance of autonomy in driving intrinsic motivation in general ( 4 , 5 ) and in the classroom ( 15 , 44 ). Indeed, in a recent large-scale review of choice architecture interventions, fewer than 10 targeted education and none were related to promoting autonomy ( 45 ). Our evaluation of resources from over a dozen prominent university teaching and learning centers revealed almost no advice for implementing autonomy-supportive policies in undergraduate classrooms ( Table 1 ). By addressing this gap, these centers can better assist instructors in implementing evidence-based practices that foster motivation, proficiency, and well-being. This is particularly important in STEM fields where there is considerable interest in improving persistence rates [e.g., ( 46 , 47 )]. | 39018403_p32 | 39018403 | DISCUSSION | 1.319384 | other | Study | [
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] | [
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] | en | 0.999995 |
To begin addressing this lack of autonomy-supportive interventions in higher education, we developed and investigated two classroom interventions that can be implemented with minimal financial or logistical costs, and we provided empirical evidence for their effectiveness. Allowing students to commit to mandatory attendance and to choose more rigorous assignments led them to attend class more reliably, to put more effort into their assignments, and to understand the material better. While we have focused on attendance and assessment, similar choice architectures can be applied to many other course elements. For any mandatory course element, it is worth considering whether making it optional-mandatory might serve students better ( Table 2 ). | 39018403_p33 | 39018403 | DISCUSSION | 1.18695 | other | Study | [
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] | [
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] | en | 0.999997 |
Despite these promising initial results, several caveats are in order when interpreting our data. First, our data represent students from just one school. Carnegie Mellon is a selective university known for attracting students with a strong work ethic. Our studies did not measure participants’ demographic characteristics, and therefore cannot speak to how such characteristics may interact with autonomy-supportive policies. Thus, it is possible that these interventions affect different populations differently. However, academically at-risk students also experience educational benefits from autonomy-supportive learning environments ( 48 ). | 39018403_p34 | 39018403 | DISCUSSION | 1.624953 | other | Study | [
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] | [
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Carnegie Mellon is a culturally diverse institution, ranking 14th out of over 1200 colleges and universities in international popularity, with nearly one in six students coming from outside the United States ( 49 ). Nevertheless, the university is situated within a Western individualist cultural context, and our results may not generalize to other contexts. However, the benefits of autonomy-supportive interventions have been demonstrated across multiple cultures ( 50 , 51 ). | 39018403_p35 | 39018403 | DISCUSSION | 1.206471 | other | Other | [
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] | [
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] | en | 0.999995 |
All our participants were college-age students. While we expect our results to generalize to older students, it is less certain how they translate to younger demographics, such as elementary school students. However, decades of research amply demonstrate the importance of autonomy for children of all ages ( 52 ). Although the specific interventions explored here may not directly transfer to younger students, the underlying principle of fostering autonomy remains crucial ( 53 ). Moreover, there were undoubtedly neurodiverse individuals in our samples. However, we cannot isolate the policies’ effect on them. Some evidence suggests that autonomy-supportive policies are especially important for neurodiverse individuals ( 54 – 57 ). While this work is certainly encouraging, it cannot license a confident generalization of the present results to these populations. | 39018403_p36 | 39018403 | DISCUSSION | 1.993551 | other | Study | [
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] | [
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] | en | 0.999996 |
The present studies were run exclusively on popular introductory level courses in the humanities and social sciences. While we are not aware of any reason to suspect that the material covered was especially conducive to demonstrating the benefits of autonomy, it remains an empirical question whether our findings extend to more technical material. Similarly, autonomy promotion may have a different effect when applied to electives as opposed to required courses, which by their very nature restrict autonomy. The extent to which autonomy-promoting interventions interact with other features of a class—such as whether it is perceived to be valuable, whether students have intrinsic interest in the material, and the quality of teaching—also remains unclear. | 39018403_p37 | 39018403 | DISCUSSION | 1.286345 | other | Study | [
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] | en | 0.999995 |
In short, research should explore the generalizability of our results across multiple dimensions. These include the selectivity of the educational institution, the cultural context in which the institution is situated, the age and neurodiversity of the participants, and the nature of the course content and delivery modality. In future studies, we plan to investigate how these factors interact with autonomy-supportive course policies, thereby providing a more comprehensive understanding of their effectiveness and boundary conditions. | 39018403_p38 | 39018403 | DISCUSSION | 2.274996 | other | Study | [
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] | [
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] | en | 0.999997 |
Issues of generalization aside, several weaknesses in the present studies should be acknowledged. First, sample sizes were limited by the number of students enrolled in the courses where the interventions were tested. Moreover, university and institutional review board (IRB) policies limited our ability to randomly assign participants to treatment groups. For instance, in Study 1, discussion sections were randomly assigned to implement either a mandatory or optional-mandatory attendance policy. However, following standard university procedures, students were not randomly assigned to sections. This lack of random assignment might have introduced various confounds, dependencies, or failures of randomization. For example, if groups of students from a particular extracurricular activity all enrolled in the same section, it could have led to nonrandom clustering of participants. Similarly, in Study 2, different policies were adopted in different semesters, as it is not feasible to adopt different grading standards for students in the same class during the same semester. It is possible that there were unmeasured differences in the composition of the cohorts or subtle differences in how the class was taught that were unrelated to the intervention, but which influenced the results. As is often the case with field studies, the trade-off for increased naturalistic validity is a loss of some experimental control. | 39018403_p39 | 39018403 | DISCUSSION | 3.673464 | other | Study | [
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] | [
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] | en | 0.999998 |
Finally, our studies do not offer much mechanistic insight. The choice architecture we applied yielded meaningful improvements in both subjective and objective measures, but we lack evidence to make strong claims about why the interventions were so successful. | 39018403_p40 | 39018403 | DISCUSSION | 2.00656 | biomedical | Study | [
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] | [
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] | en | 0.999997 |
It is clear that increasing autonomy per se is not sufficient to yield results like those reported here. After all, making attendance fully optional preserves student autonomy but results in lower turnout [e.g., ( 27 , 28 )]. Why, then, was optional-mandatory attendance so successful? One reason may be due to when the choices are made. In an optional-mandatory regime, students opt into mandatory attendance exactly once: at the beginning of the term, before they are overwhelmed by a heavy workload and when their identity as a scholar is most psychologically salient ( 58 ). In a purely optional regime, students are forced to make difficult trade-offs repeatedly over the course of the semester (“Do I trudge through the snow to get to class or stay home in comfort?”). The more often students face such decisions, the more likely they are to sometimes choose not to come to class. By having students pre-commit to attendance when these trade-offs are not as salient, the choice architecture provides choice in a context when students are most likely to make educationally beneficial decisions. Of course, this is speculative, and future research should explore such mechanisms in greater detail. | 39018403_p41 | 39018403 | DISCUSSION | 1.218193 | other | Other | [
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] | [
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] | en | 0.999995 |
While the effectiveness of pre-commitment strategies has been established in other contexts—e.g., health ( 59 ) and gambling addiction ( 60 )—there is little work on the subject in higher education. The results of Study 1 suggest that pre-commitment is an important tool in the choice architects’ toolbox for higher education, and future research should explore its implications more thoroughly. However, it is also important to note that our findings cannot be entirely explained by the effectiveness of pre-commitment. In Study 2, students in the free-to-switch cohort showed greater engagement and improvement than those in the mandatory cohort, despite having the option to abandon their initial choice at any time before the midterm essay deadline. This suggests that autonomy itself, even in the absence of strong pre-commitment, can be a powerful motivator. | 39018403_p42 | 39018403 | DISCUSSION | 1.404354 | other | Study | [
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] | [
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] | en | 0.999996 |
Besides educational gains, fostering student autonomy can yield broader benefits. A sense of personal autonomy is linked to both better physical ( 61 – 63 ) and mental health ( 64 , 65 ). This is crucial given the high rates of depression and anxiety observed among college students ( 66 , 67 ). Moreover, giving students meaningful control over their own learning, even if they occasionally err, serves as practical training for decision-making. Studies suggest that an error rate of about 15% is optimal for learning across many domains ( 68 ). If we aim to promote independent decision making, incorporating autonomy in the classroom can have long-lasting advantages. | 39018403_p43 | 39018403 | DISCUSSION | 1.914987 | other | Other | [
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Finally, students juggle various responsibilities beyond academics, balancing careers, caregiver duties, service activities, health care needs, and so on. Although they may be well-intentioned, faculty-imposed mandates can place an undue burden on students, particularly those who are disadvantaged and/or disabled. Autonomy-supportive policies empower students to better manage their complex lives. | 39018403_p44 | 39018403 | DISCUSSION | 1.180768 | other | Other | [
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Evidence for the importance of student autonomy has been accumulating for decades ( 4 ), so why has it had so little impact on higher education? One possibility is that faculty doubt that students will make good decisions [see ( 24 )]. When we informally polled our faculty colleagues on their expectations for the present studies, most believed that fewer than 20% of students would opt into mandatory attendance (whereas 73 to 95% actually do). They also believed that almost no students would voluntarily complete problem sets (whereas 80 to 97% actually do). Why are faculty predictions about student decisions so inaccurate? | 39018403_p45 | 39018403 | DISCUSSION | 1.071224 | other | Other | [
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] | [
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] | en | 0.999996 |
One explanation is that faculty are too quick to explain students’ behavior in terms of stable dispositions rather than environmental factors [( 69 ); but see ( 70 )]. Students do care about their academic success and consider their scholar-self as a core part of their identity ( 58 ). However, when situational constraints, such as coming to campus during a blizzard, difficulty finding a parking space, needing to study for another exam, or a personal crisis, prevent students from attending class, professors may mistakenly attribute the absence to the student’s personality (e.g., “Students just don’t care about my class like they used to”) rather than the situational constraints. | 39018403_p46 | 39018403 | DISCUSSION | 1.246396 | other | Other | [
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] | [
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] | en | 0.999995 |
Faulty intuitions about the drivers of human motivation might also make faculty reluctant to grant students greater autonomy. For example, although people believe that they are more likely to persist in challenging behaviors such as dieting and exercise when they focus on long-term benefits, research suggests that attending to immediate rewards leads to greater persistence ( 71 ). Faculty might similarly turn to autonomy-undermining extrinsic motivators if they forget that learning should be inherently fun and rewarding. Moreover, research on preferences for paternalistic policies in educational contexts reveals that a meaningful fraction of people believe it is a professor’s job to protect students from making poor decisions in and even outside of the classroom ( 72 ). Thus, paternalistic attitudes could lead faculty to believe that they must make wise decisions on students’ behalf. | 39018403_p47 | 39018403 | DISCUSSION | 1.680075 | other | Other | [
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] | en | 0.999997 |
Of course, another possibility is that faculty want to give students more autonomy but lack tools for doing so. We hope that this article will provide them with ideas while galvanizing further research on practical, autonomy-promoting classroom interventions. | 39018403_p48 | 39018403 | DISCUSSION | 1.059124 | other | Other | [
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] | [
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0.00044117579818703234
] | en | 0.999998 |
We have focused here on interventions to increase student autonomy, but it is worth mentioning that research has found that members of the teaching team also benefit from autonomy-supportive policies ( 73 ). TAs are often given little choice over what their sections will focus on, what their schedule will look like, what assignments they will grade, or when they will grade them. While faculty are typically afforded much more autonomy in how they teach, there is a growing tendency to impose top-down requirements on professors. For example, some schools standardize content across sections, have requirements about language that must be included in syllabi, and restrict what classes faculty can teach. Because autonomy is likely to be as motivating to teachers as it is to students, administrators would be wise to consider how campus policies could be changed to promote teachers’ autonomy. | 39018403_p49 | 39018403 | DISCUSSION | 1.090122 | other | Other | [
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] | [
0.011522392742335796,
0.9858750700950623,
0.0017904634587466717,
0.0008120588026940823
] | en | 0.999997 |
The role of autonomy promotion outside of specific classrooms and throughout the wider curriculum is also worth considering. Required classes, whether they be for general education or toward completing a major or degree program, by their nature restrict choice. To the extent that students perceive a curricular requirement as threatening their autonomy, they may experience psychological reactance ( 74 ), which can undermine whatever intrinsic interest they would otherwise have in the topic ( 75 ). Exposure to autonomy-restricting policies throughout schooling has been repeatedly linked to decreased love of learning [e.g., ( 76 )]. | 39018403_p50 | 39018403 | DISCUSSION | 1.14897 | other | Other | [
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] | [
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0.9661152958869934,
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0.001091238111257553
] | en | 0.999998 |
The shift to online and hybrid education presents both opportunities and risks for student autonomy. Completion and retention rates of massive open online courses (MOOCs) and other online courses remain disturbingly low—often below 15% ( 77 , 78 ). Promoting autonomy in online education might improve persistence rates. However, online students face countless distractions, some of which may prove too tempting to resist [( 79 ); however, see ( 80 ) for a promising example]. Similarly, new technologies can be used to support autonomy or to restrict it. This is an area ripe for exploration by choice architects. | 39018403_p51 | 39018403 | DISCUSSION | 1.011031 | other | Other | [
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] | [
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0.9882141351699829,
0.002871556207537651,
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] | en | 0.999997 |
Much research in psychology has demonstrated that autonomy is a core human need and a fundamental component of intrinsic motivation ( 4 , 5 ). However, despite good evidence that this applies in educational settings, there are surprisingly few studies that explore concrete interventions for increasing student autonomy in higher education. University teaching and learning centers and many other resources intended to help educators improve their craft largely neglect autonomy support. Here, we have identified two interventions and provided evidence for their effectiveness in higher education. We have also suggested other places in the classroom and curriculum where autonomy-supportive approaches might be profitably applied. We leave the choice of whether to apply them in your own classroom up to you. | 39018403_p52 | 39018403 | DISCUSSION | 1.063336 | other | Study | [
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0.0003051944659091532,
0.9944234490394592
] | [
0.5315103530883789,
0.4551173448562622,
0.010563693940639496,
0.0028086411766707897
] | en | 0.999998 |
Participants were 101 students who had taken at least one course with at least one of the authors. After providing informed consent, participants were asked about their experiences with seven different course policies, including mandatory attendance (“Your attendance is tracked, and you are penalized if you are absent”), optional attendance (“There is no record of whether or not you attend class, and attending is not obligatory”), and optional-mandatory attendance (“By default, there is no attendance record and you are not required to attend. However, you may choose to sign up for mandatory attendance; if you do, your attendance will be tracked and you will be penalized if you are absent”). Participants indicated whether they had experience with each policy, and if so, whether it had been in the context of a required or elective class. Participants then used 10-point scales to indicate how they believed the policy affected their motivation, enjoyment, learning, relationship with the teaching team, and their likelihood of taking another course with the policy. Students who indicated no experience with a policy were asked to predict how it would affect them. Survey questions are reproduced in the Supplementary Materials, and survey data can be found in this article’s Dryad repository. | 39018403_p53 | 39018403 | Student survey | 1.807031 | other | Study | [
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0.001164095476269722,
0.9087934494018555
] | [
0.9787554740905762,
0.020194116979837418,
0.0006442759186029434,
0.0004061264335177839
] | en | 0.999995 |
Participants were 104 students enrolled in a large Gen-Ed philosophy course at Carnegie Mellon University. Discussion sections were taught by TAs blind to the hypothesis under study. TAs were randomly assigned to teach one section under a mandatory attendance policy and one under an optional-mandatory policy. Sections met either at 1 p.m. or 2 p.m. on most Fridays of the semester. To reduce the probability of a conflict with another course or extracurricular biasing our results, Mandatory and Optional-Mandatory sections were counterbalanced across meeting times. One TA lost their attendance records, and we therefore base our analysis on the six sections for which we have complete data. | 39018403_p54 | 39018403 | Study 1 | 1.549005 | other | Study | [
0.06444638222455978,
0.001029481994919479,
0.9345241189002991
] | [
0.9424927830696106,
0.05617291480302811,
0.0007012406131252646,
0.0006330659962259233
] | en | 0.999996 |
In the first meeting of the semester, students in the mandatory sections were told by their TAs: “In this class, you are permitted to miss up to three recitations without permission or penalty. If you miss no more than three recitations, you will receive +3% on your final grade. If you do not keep your commitment by missing three or more recitations, your final score will be docked by −3%.” | 39018403_p55 | 39018403 | Study 1 | 1.046232 | other | Other | [
0.0027728350833058357,
0.0007281012367457151,
0.9964990615844727
] | [
0.0040756408125162125,
0.9945705533027649,
0.0006009472999721766,
0.0007529083522967994
] | en | 0.999997 |
Students in the optional-mandatory sections were told: “In this class, you choose if you would like your attendance at recitations to count toward your final grade. Students who choose to make attendance count will be assessed as follows. You are permitted to miss up to three recitation meetings without permission or penalty. If you miss no more than three meetings, you will receive +3% on your final grade. If you miss three or more recitations, your final grade will be docked by −3%. If you choose not to make your attendance count, whether you attend will not affect your grade.” | 39018403_p56 | 39018403 | Study 1 | 1.054501 | other | Other | [
0.002863359870389104,
0.0007139821536839008,
0.9964225888252258
] | [
0.004695830401033163,
0.9939752221107483,
0.000605568231549114,
0.0007233581854961812
] | en | 0.999997 |
Thus, when students in the optional-mandatory condition chose to make their attendance mandatory, they exposed themselves to the same policy as students in the mandatory condition. Students used a custom mobile app to participate in class discussions. Anonymized records from the app were used to generate attendance reports for 10 section meetings distributed across the semester. | 39018403_p57 | 39018403 | Study 1 | 1.182994 | other | Other | [
0.013979515060782433,
0.0006473531830124557,
0.9853731989860535
] | [
0.04509660601615906,
0.9528748393058777,
0.0009507570066489279,
0.0010777979623526335
] | en | 0.999997 |
Participants were 114 students in an introductory philosophy course offered in two fall semesters by the same professor at the same institution: | 39018403_p58 | 39018403 | Study 2 | 1.2511 | other | Other | [
0.04222271218895912,
0.0008038180531002581,
0.9569735527038574
] | [
0.16329897940158844,
0.8335269689559937,
0.0018858632538467646,
0.0012881280854344368
] | en | 0.999996 |
1) In the first cohort, Mandatory (M), all students were required to complete problem sets. | 39018403_p59 | 39018403 | Study 2 | 1.55909 | other | Other | [
0.23550383746623993,
0.002277534455060959,
0.7622186541557312
] | [
0.12305164337158203,
0.8739591836929321,
0.001880136551335454,
0.0011090352199971676
] | en | 0.999997 |
2) In the second cohort, Free-to-Switch (F), students were given the same choice and were also allowed to switch out of problem set–based assessment and into the essay-based stream at any time before the deadline for the first essay (midterm). | 39018403_p60 | 39018403 | Study 2 | 1.14096 | other | Other | [
0.018337151035666466,
0.0006967085064388812,
0.9809660911560059
] | [
0.038328688591718674,
0.9594183564186096,
0.0012612499995157123,
0.0009917666902765632
] | en | 0.999996 |
Across both cohorts, students submitted 1693 problem sets. To maximize comparability between cohorts, we included only homework assignments that were offered without modification across cohorts. This excluded 304 submissions from M and 246 from F. Submissions from students who dropped the course were excluded, removing 28 submissions (six students) in M and 13 (nine students) in F. Only 11 students in F, representing 15% of their cohort, chose the lower-effort essay-based assessment option. Consequently, to control for potential advantages in this cohort, we excluded the seven students in M ranked below the 15th percentile of their cohort (41 submissions). Our final dataset consisted of a total of 1036 submissions representing 98 students. | 39018403_p61 | 39018403 | Study 2 | 1.515558 | other | Study | [
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0.0006780524272471666,
0.9486691355705261
] | [
0.8276057839393616,
0.17041192948818207,
0.0009657731861807406,
0.0010165642015635967
] | en | 0.999995 |
Problem sets required students to analyze argumentative philosophical texts by creating argument visualizations—diagrams designed to lay bare the inferential structures implicit in argumentative prose ( 43 ). When students submitted a problem set for assessment, they reported how difficult they found it and how long they worked on it using a six-point scale: “Less than 1 hour,” “1 to 2 hours,” “2 to 3 hours,” “3 to 4 hours,” “4 to 5 hours,” and “More than 5 hours.” In 39% of submissions, students reported spending between 1 and 2 hours on each homework assignment, and a further 52% reported spending over 2 hours. | 39018403_p62 | 39018403 | Study 2 | 1.351203 | other | Other | [
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0.00043562817154452205,
0.9829460382461548
] | [
0.37440869212150574,
0.621064305305481,
0.0030133146792650223,
0.0015137020964175463
] | en | 0.999997 |
Because study 2 assigned students to treatment groups in cohorts, we cannot rule out the possibility of unmeasured confounds. However, it is reassuring to note that there were no meaningful differences between cohorts in students’ seniority, χ 2 (3) = 1.7, P = 0.627, γ = −0.030, home department, χ 2 (23) = 20, P = 0.639, γ = −0.040, or major, χ 2 (26) = 27, P = 0.392, γ = −0.035. We report values for both chi-squared and gamma to provide a comprehensive view of the associations; the former assesses the significance of the associations, while the latter quantifies their strength and direction in a nonparametric manner. | 39018403_p63 | 39018403 | Study 2 | 3.492759 | biomedical | Study | [
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0.0009965489152818918,
0.28834524750709534
] | [
0.9979397654533386,
0.001673729857429862,
0.0003335143846925348,
0.00005297000825521536
] | en | 0.999996 |
A third cohort was also tested; however, due to unforeseen staffing changes, many problem sets in this cohort remained ungraded or were graded by the instructor who was not blind to the hypothesis under study. Despite these limitations, the overall pattern of results aligned with our theoretical account. Descriptive statistics for the third cohort can be found in the Supplementary Materials, and all data can be found in this article’s Dryad repository. | 39018403_p64 | 39018403 | Study 2 | 1.860375 | biomedical | Study | [
0.9010534882545471,
0.0017629987560212612,
0.09718354046344757
] | [
0.9543124437332153,
0.04418583959341049,
0.0008597014821134508,
0.0006420048302970827
] | en | 0.999998 |
Premature birth (PTB), defined as the delivery of a baby before reaching 37 weeks of gestational age, is a significant global concern . Recent data indicates that approximately 13.4 million newborns were born prematurely, and this number continues to rise, emphasizing the urgency of addressing this issue . Infants born prematurely face an increased risk of developing a range of problems, including inflammatory diseases, neurodevelopmental disorders, metabolic issues, and the potential for lifelong disabilities . Comprehending the complex pathogenesis of PTB is fundamental for devising innovative treatments and effective preventive measures that will ultimately enhance the well-being of newborns. | PMC467042_p0 | PMC467042 | Introduction | 3.955353 | biomedical | Review | [
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] | [
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] | en | 0.999997 |
During pregnancy, the uterus experiences a series of physiological and biochemical alterations that can lead to the occurrence of endoplasmic reticulum stress (ERS). It has been observed that ERS within the placenta is associated with adverse pregnancy outcomes in cases of complicated pregnancies [ , , ]. ERS triggers the unfolded protein response (UPR), a cellular mechanism designed to restore equilibrium within the ER . Research indicates that ERS leads to increased uterine caspase-3 and caspase-8 levels at the onset of PTB, potentially affecting fertility . Understanding how ERS is involved in PTB may shed light on potential interventions to mitigate its impact, making it a valuable area of study. | PMC467042_p1 | PMC467042 | Introduction | 4.13857 | biomedical | Study | [
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] | [
0.976874053478241,
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] | en | 0.999996 |
LIM Homeobox 1 (LHX1) belongs to the LIM-HD transcription factor family, recognized for its pivotal role in regulating organogenesis during embryonic development [ , , ]. LHX1 is a key regulator in endometrial development and remodeling, with the ability to facilitate cell growth and the epithelial-mesenchymal transition (EMT) process in uterine corpus endometrial carcinoma . However, despite these recognized roles, the specific connection between LHX1 and PTB, particularly in the context of ERS, remains largely unexplored. The decision to investigate LHX1 is driven by its regulatory influence on crucial cellular processes in the uterus, prompting the need to unravel its potential contributions to PTB and its association with ERS. Moreover, the intriguing observation that LHX1 is subject to downregulation via GRP78, a vital regulator of ERS and a major sensor for activating the UPR , adds complexity to LHX1's potential roles. This intricate relationship positions LHX1 as a compelling focus for research, suggesting potential interplay between LHX1, ERS, and PTB. Thus, our study aims to bridge this knowledge gap by investigating into the uncharted territories of LHX1's involvement in PTB and its connection with the UPR. | PMC467042_p2 | PMC467042 | Introduction | 4.434602 | biomedical | Study | [
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] | [
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0.00023918614897411317,
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] | en | 0.999995 |
Subsets and Splits