PiRNAs Rise to Rescue Koalas.

PIWI-interacting small RNAs (piRNAs) establish sequence-specific adaptive restriction of resident genomic parasites to guard genome integrity. In this issue of Cell, Yu, Koppetsch, et al. describe an innate piRNA-response that specifically fragments the viral RNA genome in the germline of recently invaded koalas. This first line of defense might ensure survival until adaptive immunity develops.

Revealing the complexity of retroviral repression.

Retroviral restriction is a complex phenomenon that, despite remarkable recent progress, is far from being well understood. In this Preview, we introduce an insightful study by Yang et al. that represents the first attempt to identify the global determinants of retroviral repression in pluripotent mammalian cells.

The Arms Race Between KRAB-Zinc Finger Proteins and Endogenous Retroelements and Its Impact on Mammals.

Nearly half of the human genome consists of endogenous retroelements (EREs) and their genetic remnants, a small fraction of which carry the potential to propagate in the host genome, posing a threat to genome integrity and cell/organismal survival. The largest family of transcription factors in tetrapods, the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs), binds to specific EREs and represses their transcription. Since their first appearance over 400 million years ago, KRAB-ZFPs have undergone dramatic expansion and diversification in mammals, correlating with the invasions of new EREs. In this article we review our current understanding of the structure, function, and evolution of KRAB-ZFPs and discuss growing evidence that the arms race between KRAB-ZFPs and the EREs they target is a major driving force for the evolution of new traits in mammals, often accompanied by domestication of EREs themselves.

Transposable elements shape the evolution of mammalian development.

Transposable elements (TEs) promote genetic innovation but also threaten genome stability. Despite multiple layers of host defence, TEs actively shape mammalian-specific developmental processes, particularly during pre-implantation and extra-embryonic development and at the maternal-fetal interface. Here, we review how TEs influence mammalian genomes both directly by providing the raw material for genetic change and indirectly via co-evolving TE-binding Krüppel-associated box zinc finger proteins (KRAB-ZFPs). Throughout mammalian evolution, individual activities of ancient TEs were co-opted to enable invasive placentation that characterizes live-born mammals. By contrast, the widespread activity of evolutionarily young TEs may reflect an ongoing co-evolution that continues to impact mammalian development.

Regulation of endogenous retrovirus-derived regulatory elements by GATA2/3 and MSX2 in human trophoblast stem cells.

The placenta is an organ with extraordinary phenotypic diversity in eutherian mammals. Recent evidence suggests that numerous human placental enhancers are evolved from lineage-specific insertions of endogenous retroviruses (ERVs), yet the transcription factors (TFs) underlying their regulation remain largely elusive. Here, by first focusing on MER41, a primate-specific ERV family previously linked to placenta and innate immunity, we uncover the binding motifs of multiple crucial trophoblast TFs (GATA2/3, MSX2, GRHL2) in addition to innate immunity TFs STAT1 and IRF1. Integration of ChIP-seq data confirms the binding of GATA2/3, MSX2, and their related factors on the majority of MER41-derived enhancers in human trophoblast stem cells (TSCs). MER41-derived enhancers that are constitutively active in human TSCs are distinct from those activated upon interferon stimulation, which is determined by the binding of relevant TFs and their subfamily compositions. We further demonstrate that GATA2/3 and MSX2 have prevalent binding to numerous other ERV families - indicating their broad impact on ERV-derived enhancers. Functionally, the derepression of many syncytiotrophoblast genes after MSX2 knockdown is likely to be mediated by regulatory elements derived from ERVs - suggesting ERVs are also important for mediating transcriptional repression. Overall, this study characterizes the regulation of ERV-derived regulatory elements by GATA2/3, MSX2, and their cofactors in human TSCs, and provides mechanistic insights into the importance of ERVs in human trophoblast regulatory network.

KDM1A maintains genome-wide homeostasis of transcriptional enhancers.

Transcriptional enhancers enable exquisite spatiotemporal control of gene expression in metazoans. Enrichment of monomethylation of histone H3 lysine 4 (H3K4me1) is a major chromatin signature of transcriptional enhancers. Lysine (K)-specific demethylase 1A (KDM1A, also known as LSD1), an H3K4me2/me1 demethylase, inactivates stem-cell enhancers during the differentiation of mouse embryonic stem cells (mESCs). However, its role in undifferentiated mESCs remains obscure. Here, we show that KDM1A actively maintains the optimal enhancer status in both undifferentiated and lineage-committed cells. KDM1A occupies a majority of enhancers in undifferentiated mESCs. KDM1A levels at enhancers exhibit clear positive correlations with its substrate H3K4me2, H3K27ac, and transcription at enhancers. In Kdm1a-deficient mESCs, a large fraction of these enhancers gains additional H3K4 methylation, which is accompanied by increases in H3K27 acetylation and increased expression of both enhancer RNAs (eRNAs) and target genes. In postmitotic neurons, loss of KDM1A leads to premature activation of neuronal activity-dependent enhancers and genes. Taken together, these results suggest that KDM1A is a versatile regulator of enhancers and acts as a rheostat to maintain optimal enhancer activity by counterbalancing H3K4 methylation at enhancers.

Parsing state mindfulness effects on neurobehavioral markers of cognitive control: A within-subject comparison of focused attention and open monitoring.

Over the past two decades, scientific interest in understanding the relationship between mindfulness and cognition has accelerated. However, despite considerable investigative efforts, pervasive methodological inconsistencies within the literature preclude a thorough understanding of whether or how mindfulness influences core cognitive functions. The purpose of the current study is to provide an initial "proof-of-concept" demonstration of a new research strategy and methodological approach designed to address previous limitations. Specifically, we implemented a novel fully within-subject state induction protocol to elucidate the neurobehavioral influence of discrete mindfulness states-focused attention (FA) and open monitoring (OM), compared against an active control-on well-established behavioral and ERP indices of executive attention and error monitoring assessed during the Eriksen flanker task. Bayesian mixed modeling was used to test preregistered hypotheses pertaining to FA and OM effects on flanker interference, the stimulus-locked P3, and the response-locked ERN and Pe. Results yielded strong but unexpected evidence that OM selectively produced a more cautious and intentional response style, characterized by higher accuracy, slower RTs, and reduced P3 amplitude. Follow-up exploratory analyses revealed that trait mindfulness moderated the influence of OM, such that individuals with greater trait mindfulness responded more cautiously and exhibited higher trial accuracy and smaller P3s. Neither FA nor OM modulated the ERN or Pe. Taken together, our findings support the promise of our approach, demonstrating that theoretically distinct mindfulness states are functionally dissociable among mindfulness-naive participants and that interactive variability associated with different operational facets of mindfulness (i.e., state vs. trait) can be modeled directly.

Long Terminal Repeats: From Parasitic Elements to Building Blocks of the Transcriptional Regulatory Repertoire.

The life cycle of endogenous retroviruses (ERVs), also called long terminal repeat (LTR) retrotransposons, begins with transcription by RNA polymerase II followed by reverse transcription and re-integration into the host genome. While most ERVs are relics of ancient integration events, "young" proviruses competent for retrotransposition-found in many mammals, but not humans-represent an ongoing threat to host fitness. As a consequence, several restriction pathways have evolved to suppress their activity at both transcriptional and post-transcriptional stages of the viral life cycle. Nevertheless, accumulating evidence has revealed that LTR sequences derived from distantly related ERVs have been exapted as regulatory sequences for many host genes in a wide range of cell types throughout mammalian evolution. Here, we focus on emerging themes from recent studies cataloging the diversity of ERV LTRs acting as important transcriptional regulatory elements in mammals and explore the molecular features that likely account for LTR exaptation in developmental and tissue-specific gene regulation.

Lower Extremity Vascular Injury in the Pediatric Trauma Patient: Management and Outcomes at an Adult Level I Trauma Center.

BACKGROUND: Traumatic vascular injuries of the lower extremity in the pediatric population are uncommon but can result in significant morbidity. The objective of this study is to demonstrate our experience with these injuries by describing patterns of traumatic vascular injury, the initial management, and data regarding early outcomes. METHODS: In total, 506 patients presented with lower extremity vascular injury between January 1, 2009 and January 1, 2021 to Grady Memorial Hospital, an urban, adult Level I trauma center in Atlanta, Georgia. Thirty-two of the 506 patients were aged less than 18 years and were evaluated for a total of 47 lower extremity vascular injuries. To fully elucidate the injury patterns and clinical course in this population, we examined patient demographics, mechanism of injury, type of vessel injured, surgical repair performed, and early outcomes and complications. RESULTS: The median (interquartile range) age was 16 (2) years (range, 3-17 years), and the majority were male (n = 29, 90.6%). Of the vascular injuries identified, 28 were arterial and 19 were venous. Of these injuries, 14 patients had combined arterial-venous injuries. The majority of injuries were the result of a penetrating injury (n = 28, 87.5%), and of these, all but 2 were attributed to gunshot wounds. Twenty-seven vascular interventions were performed by nonpediatric surgeons: 11 by trauma surgeons, 13 by vascular surgeons, 2 by orthopedic surgeons, and 1 by an interventional radiologist. Two patients required amputation: 1 during the index admission and 1 delayed at 3 months. Overall survival was 96.9%. CONCLUSIONS: Vascular injuries as the result of trauma at any age often require early intervention, and we believe that these injuries in the pediatric population can be safely managed in adult trauma centers with a multidisciplinary team composed of trauma, vascular, and orthopedic surgeons with the potential to decrease associated morbidity and mortality from these injuries.

On the psychometric evaluation of cognitive control tasks: An Investigation with the Dual Mechanisms of Cognitive Control (DMCC) battery.

The domain of cognitive control has been a major focus of experimental, neuroscience, and individual differences research. Currently, however, no theory of cognitive control successfully unifies both experimental and individual differences findings. Some perspectives deny that there even exists a unified psychometric cognitive control construct to be measured at all. These shortcomings of the current literature may reflect the fact that current cognitive control paradigms are optimized for the detection of within-subject experimental effects rather than individual differences. In the current study, we examine the psychometric properties of the Dual Mechanisms of Cognitive Control (DMCC) task battery, which was designed in accordance with a theoretical framework that postulates common sources of within-subject and individual differences variation. We evaluated both internal consistency and test-retest reliability, and for the latter, utilized both classical test theory measures (i.e., split-half methods, intraclass correlation) and newer hierarchical Bayesian estimation of generative models. Although traditional psychometric measures suggested poor reliability, the hierarchical Bayesian models indicated a different pattern, with good to excellent test-retest reliability in almost all tasks and conditions examined. Moreover, within-task, between-condition correlations were generally increased when using the Bayesian model-derived estimates, and these higher correlations appeared to be directly linked to the higher reliability of the measures. In contrast, between-task correlations remained low regardless of theoretical manipulations or estimation approach. Together, these findings highlight the advantages of Bayesian estimation methods, while also pointing to the important role of reliability in the search for a unified theory of cognitive control.

Linear relationship between absorbed radiation dose and pulse rate during fluoroscopy.

PURPOSE: To identify the relationship between fluoroscopy pulse rate and absorbed radiation dose. We compared absorbed radiation dose with common proxy measurements such as fluoroscopy time and C-arm reported dose. METHODS: Using a simulated patient model, 60 s fluoroscopy exposures were performed using pulse rates of 30, 8, 4, 2, and 1 pulse(s) per second. Each experiment was performed with both standard and low-dose settings using a GE OEC 9800 plus C-arm. Landauer nanoDot™ OSL dosimeters were used to measure the absorbed radiation dose. RESULTS: Fluoroscopy pulse rate and absorbed radiation dose demonstrated a linear correlation for both standard (R2 = 0.995, p < 0.001) and low-dose (R2 = 0.998, p < 0.001) settings. For any given pulse rate, using the low-dose setting reduced absorbed radiation dose by 58 ± 2.8%. Fluoroscopy time demonstrated a linear relationship with absorbed radiation dose for both standard (R2 = 0.996, p < 0.001) and low-dose (R2 = 0.991, p < 0.001) settings, but did not change with use of the low-dose setting. C-arm reported radiation dose correlated linearly with absorbed dose (R2 = 0.999) but consistently under-estimated measured values by an average of 49 ± 3.5%. Using a combination of 1 pulse-per-second and low-dose fluoroscopy, absorbed dose was reduced by 97.7 ± 0.1% compared to standard dose and 30 pulse-per-second settings. CONCLUSION: Absorbed radiation dose decreases linearly with fluoroscopy pulse rate during equivalent exposure times. Adjusting fluoroscopy pulse rate and utilizing low-dose settings significantly reduces overall absorbed radiation exposure by up to 98%.

Image-Guided Spine Interventions for Pain: Ongoing Controversies.

An expanding array of image-guided spine interventions have the potential to provide immediate and effective pain relief. Innovations in spine intervention have proceeded rapidly, with clinical adoption of new techniques at times occurring before the development of bodies of evidence to establish efficacy. Although new spine interventions have been evaluated by clinical trials, acceptance of results has been hindered by controversies regarding trial methodology. This article explores controversial aspects of four categories of image-guided interventions for painful conditions: spine interventions for postdural puncture headache resulting from prior lumbar procedures, epidural steroid injections for cervical and lumbar radiculopathy, interventions for facet and sacroiliac joint pain, and vertebral augmentations for compression fractures. For each intervention, we summarize the available literature, with an emphasis on persistent controversies, and discuss how current areas of disagreement and challenge may shape future research and innovation. Despite the ongoing areas of debate regarding various aspects of these procedures, effective treatments continue to emerge and show promise for aiding relief of a range of debilitating conditions.

Metacognitive training for psychosis (MCT): past, present, and future.

This article provides an overview and retrospective on metacognitive training for psychosis (MCT), which first appeared approximately 2 decades ago. We recount how our empirical understanding of psychosis at that time led to the first preliminary version of the program. We describe setbacks and challenges that led to major changes, including revisions to existing modules (e.g., more focus on metacognitive variables, particularly on decision confidence as one of the primary targets of treatment) and the creation of new modules addressing mood, as well as attempts to improve sustainability of effects via homework exercises and a smartphone app ( www.uke.de/mct_app ). We have also enhanced dissemination efforts by creating new culturally sensitive language versions and facilitating low-threshold training through e-learning courses ( www.uke.de/e-mct ). Finally, we discuss several meta-analyses on the efficacy of MCT that have been published over the last decade. While reviews were initially inconsistent, possibly reflecting the insufficient statistical power and lower design quality of the first MCT studies, more recent meta-analyses have confirmed the efficacy of MCT on positive symptoms, insight, and cognitive biases, which has led to the inclusion of MCT in some national treatment guidelines for schizophrenia.

Experiences of UK and Irish family carers of people with profound and multiple intellectual disabilities during the COVID-19 pandemic.

BACKGROUND: People with profound and multiple intellectual disabilities (PMID) have high and intensive support needs that ordinarily place significant strain on family carers. This was further heightened by the removal of many external supports during the COVID-19 pandemic. We sought to explore the experiences of family carers of people with PMID during the COVID-19 pandemic and understand what the longer-term impact might be on their lives. METHODS: Focus group interviews (n = 32) were conducted with family carers (n = 126) from the four countries of the UK and the Republic of Ireland. Participants were asked questions relating to their experiences of the COVID-19 pandemic, coping strategies, and challenges faced. All focus groups were conducted using the online platform, Zoom. These were audio recorded, transcribed verbatim and analysed employing inductive thematic analysis. FINDINGS: Three main themes were generated from the data including (1.0) COVID-19 as a double-edged sword (2.0), The struggle for support (3.0), Constant nature of caring. These included 11 subthemes. (1.1) 'COVID-19 as a catalyst for change', (1.2) 'Challenges during COVID-19: dealing with change', (1.3) 'Challenges during COVID-19: fear of COVID-19', (1.4); 'The online environment: the new normal' (2.1) 'Invisibility of male carers', (2.2) 'Carers supporting carers', (2.3) 'The only service you get is lip service: non-existent services', (2.4); 'Knowing your rights' (3.1) 'Emotional response to the caring role: Feeling devalued', (3.2) 'Emotional response to the caring role: Desperation of caring', (3.3) 'Multiple demands of the caring role.' CONCLUSIONS: The COVID-19 pandemic presented immense challenges to family carers of people with PMID but also provided some opportunities. Families had already struggled to receive many of the supports and services to which they were entitled to only to have these removed at the onset of the pandemic. The experiences of male carers have been largely absent from the literature with this research showing they want to be included in decision making and require tailored support services. Service providers should see the end of the COVID-19 pandemic as providing opportunity to re-examine current provision and design services with family carers. As the direct threat from COVID-19 diminishes and the experiences of those who lived through this period come to the fore, there is a need to re-examine current models and provision of support to family carers to better meet their needs.

KRAB zinc finger protein diversification drives mammalian interindividual methylation variability.

Most transposable elements (TEs) in the mouse genome are heavily modified by DNA methylation and repressive histone modifications. However, a subset of TEs exhibit variable methylation levels in genetically identical individuals, and this is associated with epigenetically conferred phenotypic differences, environmental adaptability, and transgenerational epigenetic inheritance. The evolutionary origins and molecular mechanisms underlying interindividual epigenetic variability remain unknown. Using a repertoire of murine variably methylated intracisternal A-particle (VM-IAP) epialleles as a model, we demonstrate that variable DNA methylation states at TEs are highly susceptible to genetic background effects. Taking a classical genetics approach coupled with genome-wide analysis, we harness these effects and identify a cluster of KRAB zinc finger protein (KZFP) genes that modifies VM-IAPs in trans in a sequence-specific manner. Deletion of the cluster results in decreased DNA methylation levels and altered histone modifications at the targeted VM-IAPs. In some cases, these effects are accompanied by dysregulation of neighboring genes. We find that VM-IAPs cluster together phylogenetically and that this is linked to differential KZFP binding, suggestive of an ongoing evolutionary arms race between TEs and this large family of epigenetic regulators. These findings indicate that KZFP divergence and concomitant evolution of DNA binding capabilities are mechanistically linked to methylation variability in mammals, with implications for phenotypic variation and putative paradigms of mammalian epigenetic inheritance.

The KRAB zinc finger protein ZFP809 is required to initiate epigenetic silencing of endogenous retroviruses.

Retroviruses have been invading mammalian germlines for millions of years, accumulating in the form of endogenous retroviruses (ERVs) that account for nearly one-tenth of the mouse and human genomes. ERVs are epigenetically silenced during development, yet the cellular factors recognizing ERVs in a sequence-specific manner remain elusive. Here we demonstrate that ZFP809, a member of the Krüppel-associated box zinc finger protein (KRAB-ZFP) family, initiates the silencing of ERVs in a sequence-specific manner via recruitment of heterochromatin-inducing complexes. ZFP809 knockout mice display highly elevated levels of ZFP809-targeted ERVs in somatic tissues. ERV reactivation is accompanied by an epigenetic shift from repressive to active histone modifications but only slight destabilization of DNA methylation. Importantly, using conditional alleles and rescue experiments, we demonstrate that ZFP809 is required to initiate ERV silencing during embryonic development but becomes largely dispensable in somatic tissues. Finally, we show that the DNA-binding specificity of ZFP809 is evolutionarily conserved in the Muroidea superfamily of rodents and predates the endogenization of retroviruses presently targeted by ZFP809 in Mus musculus. In sum, these data provide compelling evidence that ZFP809 evolved to recognize foreign DNA and establish histone modification-based epigenetic silencing of ERVs.

The multi-angle extended three-dimensional activities (META) stimulus set: A tool for studying event cognition.

To study complex human activity and how it is perceived and remembered, it is valuable to have large-scale, well-characterized stimuli that are representative of such activity. We present the Multi-angle Extended Three-dimensional Activities (META) stimulus set, a structured and highly instrumented set of extended event sequences performed in naturalistic settings. Performances were captured with two color cameras and a Kinect v2 camera with color and depth sensors, allowing the extraction of three-dimensional skeletal joint positions. We tracked the positions and identities of objects for all chapters using a mixture of manual coding and an automated tracking pipeline, and hand-annotated the timings of high-level actions. We also performed an online experiment to collect normative event boundaries for all chapters at a coarse and fine grain of segmentation, which allowed us to quantify event durations and agreement across participants. We share these materials publicly to advance new discoveries in the study of complex naturalistic activity.

Poverty dynamics and the determining factors among East African smallholder farmers.

CONTEXT: Rapid economic development in East Africa is matched by extremely dynamic smallholder livelihoods. Objective: To quantify the changes in poverty of smallholder farmers, to evaluate the potential of farm and off-farm activities to alleviate poverty, and to evaluate the potential barriers to poverty alleviation. METHODS: The analyses were based on a panel survey of 600 households undertaken in 2012 and re-visited approximately four years later in four sites in East Africa. The sites represented contrasting smallholder farming systems, linked to urban centres undergoing rapid economic and social change (Nairobi, Kampala, Kisumu, and Dar-es-Salaam). The surveys assessed farm management, farm productivity, livelihoods, and various measures of household welfare. RESULTS AND CONCLUSIONS: Almost two thirds of households rose above or fell below meaningful poverty thresholds - more than previously measured in this context - but overall poverty rates remained constant. Enhanced farm value production and off-farm income proved to be important mechanisms to rise out of poverty for households that were already resource-endowed. However, households in the poorest stratum in both panels appeared to be stuck in a poverty trap. They owned significantly fewer productive assets in the first panel compared to other groups (land and livestock), and these baseline assets were found to be positively correlated with farm income in the second panel survey. Equally these households were also found to be among the least educated, while education was found to be an important enabling factor for the generation of high value off-farm income. SIGNIFICANCE: Rural development that aims to stimulate increases in farm produce value as a means to alleviate poverty are only viable for already resource-endowed households, as they have the capacity to enhance farm value production. Conversely, the alleviation of extreme poverty should focus on different means, perhaps cash transfers, or the development of more sophisticated social safety nets. Furthermore, while off-farm income presents another important mechanism for poverty alleviation in rural areas, these opportunities are restricted to those households that have had access to education. As more households turn to off-farm activities to supplement or replace their livelihoods, farming approaches will also change affecting the management of natural resources. These dynamics ought to be better understood to better manage land-use transitions.

A Representational Similarity Analysis of Cognitive Control during Color-Word Stroop.

Progress in understanding the neural bases of cognitive control has been supported by the paradigmatic color-word Stroop task, in which a target response (color name) must be selected over a more automatic, yet potentially incongruent, distractor response (word). For this paradigm, models have postulated complementary coding schemes: dorsomedial frontal cortex (DMFC) is proposed to evaluate the demand for control via incongruency-related coding, whereas dorsolateral PFC (DLPFC) is proposed to implement control via goal and target-related coding. Yet, mapping these theorized schemes to measured neural activity within this task has been challenging. Here, we tested for these coding schemes relatively directly, by decomposing an event-related color-word Stroop task via representational similarity analysis. Three neural coding models were fit to the similarity structure of multivoxel patterns of human fMRI activity, acquired from 65 healthy, young-adult males and females. Incongruency coding was predominant in DMFC, whereas both target and incongruency coding were present with indistinguishable strength in DLPFC. In contrast, distractor information was strongly encoded within early visual cortex. Further, these coding schemes were differentially related to behavior: individuals with stronger DLPFC (and lateral posterior parietal cortex) target coding, but weaker DMFC incongruency coding, exhibited less behavioral Stroop interference. These results highlight the utility of the representational similarity analysis framework for investigating neural mechanisms of cognitive control and point to several promising directions to extend the Stroop paradigm.SIGNIFICANCE STATEMENT How the human brain enables cognitive control - the ability to override behavioral habits to pursue internal goals - has been a major focus of neuroscience research. This ability has been frequently investigated by using the Stroop color-word naming task. With the Stroop as a test-bed, many theories have proposed specific neuroanatomical dissociations, in which medial and lateral frontal brain regions underlie cognitive control by encoding distinct types of information. Yet providing a direct confirmation of these claims has been challenging. Here, we demonstrate that representational similarity analysis, which estimates and models the similarity structure of brain activity patterns, can successfully establish the hypothesized functional dissociations within the Stroop task. Representational similarity analysis may provide a useful approach for investigating cognitive control mechanisms.

Dorsal Anterior Cingulate Cortex Encodes the Integrated Incentive Motivational Value of Cognitive Task Performance.

Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well understood how these signals are "bundled" in the brain to modulate cognitive control. The dorsal ACC (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, although this hypothesis has yet to receive rigorous confirmation. In the present study, we examined the role of human dACC in motivational incentive integration. Healthy young adult men and women were scanned with fMRI while engaged in an experimental paradigm that quantifies the combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. Monetary incentives modulated trial-by-trial dACC activation, whereas block-related effects of liquid incentives on dACC activity were observed. When bundled together, incentive-related dACC modulation predicted fluctuations in both cognitive performance and self-report motivation ratings. Statistical mediation analyses suggest that dACC encoded the incentives in terms of their integrated subjective motivational value, and that this value signal was most proximally associated with task performance. Finally, we confirmed that these incentive integration effects were selectively present in dACC. Together, the results support an account in which dACC integrates motivational signals to compute the expected value of goal-directed cognitive control.SIGNIFICANCE STATEMENT How are primary and secondary incentives integrated in the brain to influence goal-directed behavior? Using an innovative experimental fMRI paradigm that combines motivational incentives that have historically been studied independently between species (e.g., monetary rewards for humans, food rewards for animals), we examine the relationship between incentive motivational value and cognitive control allocation. We find evidence that the integrated incentive motivational value of combined incentives is encoded in human dorsal ACC. Further, self-reported motivational shifts mediated the effects of incentive-modulated dorsal ACC activity on task performance, revealing convergence in how self-reported and experimentally induced motivation are encoded in the human brain. Our findings may inform future translational studies examining affective/motivational and cognitive impairments in psychopathology (e.g., anxiety, depression, addiction).