Episodic retrieval allows people to access memories from the past to guide current thoughts and decisions. In many real‐world situations, retrieval occurs under conditions of acute stress, either ...elicited by the retrieval task or driven by other, unrelated concerns. Memory under such conditions may be hindered, as acute stress initiates a cascade of neuromodulatory changes that can impair episodic retrieval. Here, we review emerging evidence showing that dissociable stress systems interact over time, influencing neural function. In addition to the adverse effects of stress on hippocampal‐dependent retrieval, we consider how stress biases attention and prefrontal cortical function, which could further affect controlled retrieval processes. Finally, we consider recent data indicating that stress at retrieval increases activity in a network of brain regions that enable reflexive, rapid responding to upcoming threats, while transiently taking offline regions supporting flexible, goal‐directed thinking. Given the ubiquity of episodic memory retrieval in everyday life, it is critical to understand the theoretical and applied implications of acute stress. The present review highlights the progress that has been made, along with important open questions.
The ability to anticipate and flexibly plan for the future is critical for achieving goal-directed outcomes. Extant data suggest that neural and cognitive stress mechanisms may disrupt memory ...retrieval and restrict prospective planning, with deleterious impacts on behavior. Here, we examined whether and how acute psychological stress influences goal-directed navigational planning and efficient, flexible behavior. Our methods combined fMRI, neuroendocrinology, and machine learning with a virtual navigation planning task. Human participants were trained to navigate familiar paths in virtual environments and then (concurrent with fMRI) performed a planning and navigation task that could be most efficiently solved by taking novel shortcut paths. Strikingly, relative to non-stressed control participants, participants who performed the planning task under experimentally induced acute psychological stress demonstrated (1) disrupted neural activity critical for mnemonic retrieval and mental simulation and (2) reduced traversal of shortcuts and greater reliance on familiar paths. These neural and behavioral changes under psychological stress were tied to evidence for disrupted neural replay of memory for future locations in the spatial environment, providing mechanistic insight into why and how stress can alter planning and foster inefficient behavior.
•Human participants engaged in a VR prospective navigational planning task•Psychological stress was manipulated post-learning during novel route planning•Cortical memory replay signals dynamically tracked prospective route planning•Stress disrupted memory and control circuitry and route neural replay and behavior
Brown et al. find neural replay of environment memories during route planning, which tracks subsequent navigation behavior. Critically, stress disrupts memory and cognitive control during route planning, restricting neural simulation of future routes and biasing people away from planning efficient shortcuts in favor of familiar routes.
Natural killer (NK) cells are a critical component of the innate immune system. However, their ontogenic origin has remained unclear. Here, we report that NK cell potential first arises from ...Hoxaneg/low Kit+CD41+CD16/32+ hematopoietic-stem-cell (HSC)-independent erythro-myeloid progenitors (EMPs) present in the murine yolk sac. EMP-derived NK cells and primary fetal NK cells, unlike their adult counterparts, exhibit robust degranulation in response to stimulation. Parallel studies using human pluripotent stem cells (hPSCs) revealed that HOXAneg/low CD34+ progenitors give rise to NK cells that, similar to murine EMP-derived NK cells, harbor a potent cytotoxic degranulation bias. In contrast, hPSC-derived HOXA+ CD34+ progenitors, as well as human cord blood CD34+ cells, give rise to NK cells that exhibit an attenuated degranulation response but robustly produce inflammatory cytokines. Collectively, our studies identify an extra-embryonic origin of potently cytotoxic NK cells, suggesting that ontogenic origin is a relevant factor in designing hPSC-derived adoptive immunotherapies.
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•NK cell potential arises from erythro-myeloid progenitors (EMPs) in the yolk sac•EMP-derived NK cells, similar to fetal NK cells, have a potent degranulation response•hPSC differentiation yields 2 distinct CD34+ populations, each with NK cell potential•hPSC-derived EMP-like NK cells are more potently cytotoxic than adult CD16+ NK cells
NK cell potential is thought to arise from lymphoid progenitors; however, in parallel studies of murine embryos and human pluripotent stem cells, Dege et al. demonstrate that NK cells with a potent cytotoxic degranulation response arise from erythro-myeloid progenitors.
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated ...with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
The combined approach of incubating environmental samples with stable isotope-labeled substrates followed by single-cell analyses through high-resolution secondary ion mass spectrometry (NanoSIMS) or ...Raman microspectroscopy provides insights into the in situ function of microorganisms. This approach has found limited application in soils presumably due to the dispersal of microbial cells in a large background of particles. We developed a pipeline for the efficient preparation of cell extracts from soils for subsequent single-cell methods by combining cell detachment with separation of cells and soil particles followed by cell concentration. The procedure was evaluated by examining its influence on cell recoveries and microbial community composition across two soils. This approach generated a cell fraction with considerably reduced soil particle load and of sufficient small size to allow single-cell analysis by NanoSIMS, as shown when detecting active N2-fixing and cellulose-responsive microorganisms via 15N2 and 13C-UL-cellulose incubations, respectively. The same procedure was also applicable for Raman microspectroscopic analyses of soil microorganisms, assessed via microcosm incubations with a 13C-labeled carbon source and deuterium oxide (D2O, a general activity marker). The described sample preparation procedure enables single-cell analysis of soil microorganisms using NanoSIMS and Raman microspectroscopy, but should also facilitate single-cell sorting and sequencing.
A procedure is presented that allows one to investigate the activity of soil microorganisms at the single-cell level by combining stable isotope-labeled substrate incubations with NanoSIMS or Raman microspectroscopy.
Plant roots release recent photosynthates into the rhizosphere, accelerating decomposition of organic matter by saprotrophic soil microbes ("rhizosphere priming effect") which consequently increases ...nutrient availability for plants. However, about 90% of all higher plant species are mycorrhizal, transferring a significant fraction of their photosynthates directly to their fungal partners. Whether mycorrhizal fungi pass on plant-derived carbon (C) to bacteria in root-distant soil areas, i.e., incite a "hyphosphere priming effect," is not known. Experimental evidence for C transfer from mycorrhizal hyphae to soil bacteria is limited, especially for ectomycorrhizal systems. As ectomycorrhizal fungi possess enzymatic capabilities to degrade organic matter themselves, it remains unclear whether they cooperate with soil bacteria by providing photosynthates, or compete for available nutrients. To investigate a possible C transfer from ectomycorrhizal hyphae to soil bacteria, and its response to changing nutrient availability, we planted young beech trees (
) into "split-root" boxes, dividing their root systems into two disconnected soil compartments. Each of these compartments was separated from a litter compartment by a mesh penetrable for fungal hyphae, but not for roots. Plants were exposed to a
C-CO
-labeled atmosphere, while
N-labeled ammonium and amino acids were added to one side of the split-root system. We found a rapid transfer of recent photosynthates via ectomycorrhizal hyphae to bacteria in root-distant soil areas. Fungal and bacterial phospholipid fatty acid (PLFA) biomarkers were significantly enriched in hyphae-exclusive compartments 24 h after
C-CO
-labeling. Isotope imaging with nanometer-scale secondary ion mass spectrometry (NanoSIMS) allowed for the first time
visualization of plant-derived C and N taken up by an extraradical fungal hypha, and in microbial cells thriving on hyphal surfaces. When N was added to the litter compartments, bacterial biomass, and the amount of incorporated
C strongly declined. Interestingly, this effect was also observed in adjacent soil compartments where added N was only available for bacteria through hyphal transport, indicating that ectomycorrhizal fungi were acting on soil bacteria. Together, our results demonstrate that (i) ectomycorrhizal hyphae rapidly transfer plant-derived C to bacterial communities in root-distant areas, and (ii) this transfer promptly responds to changing soil nutrient conditions.
Abstract
Despite decades of science investigating the neural underpinnings of episodic memory retrieval, a critical question remains: how does stress influence remembering and the neural mechanisms ...of recollection in humans? Here, we used functional magnetic resonance imaging and multivariate pattern analyses to examine the effects of acute stress during retrieval. We report that stress reduced the probability of recollecting the details of past experience, and that this impairment was driven, in part, by a disruption of the relationship between hippocampal activation, cortical reinstatement, and memory performance. Moreover, even memories expressed with high confidence were less accurate under stress, and this stress-induced decline in accuracy was explained by reduced posterior hippocampal engagement despite similar levels of category-level cortical reinstatement. Finally, stress degraded the relationship between the engagement of frontoparietal control networks and retrieval decision uncertainty. Collectively, these findings demonstrate the widespread consequences of acute stress on the neural systems of remembering.
Patients with advanced pancreatic adenocarcinoma have a poor prognosis and limited second-line treatment options. Evidence suggests a role for the Janus kinase (JAK)/signal transducer and activator ...of transcription pathway in the pathogenesis and clinical course of pancreatic cancer.
In this double-blind, phase II study, patients with metastatic pancreatic cancer who had experienced treatment failure with gemcitabine were randomly assigned 1:1 to the JAK1/JAK2 inhibitor ruxolitinib (15 mg twice daily) plus capecitabine (1,000 mg/m(2) twice daily) or placebo plus capecitabine. The primary end point was overall survival (OS); secondary end points included progression-free survival, clinical benefit response, objective response rate, and safety. Prespecified subgroup analyses evaluated treatment heterogeneity and efficacy in patients with evidence of inflammation.
In the intent-to-treat population (ruxolitinib, n = 64; placebo, n = 63), the hazard ratio was 0.79 (95% CI, 0.53 to 1.18; P = .25) for OS and was 0.75 (95% CI, 0.52 to 1.10; P = .14) for progression-free survival. In a prespecified subgroup analysis of patients with inflammation, defined by serum C-reactive protein levels greater than the study population median (ie, 13 mg/L), OS was significantly greater with ruxolitinib than with placebo (hazard ratio, 0.47; 95% CI, 0.26 to 0.85; P = .011). Prolonged survival in this subgroup was supported by post hoc analyses of OS that categorized patients by the modified Glasgow Prognostic Score, a systemic inflammation-based prognostic system. Grade 3 or greater adverse events were observed with similar frequency in the ruxolitinib (74.6%) and placebo (81.7%) groups. Grade 3 or greater anemia was more frequent with ruxolitinib (15.3%; placebo, 1.7%).
Ruxolitinib plus capecitabine was generally well tolerated and may improve survival in patients with metastatic pancreatic cancer and evidence of systemic inflammation.
Despite many studies showing that landscape corridors increase dispersal and species richness for disparate taxa, concerns persist that corridors can have unintended negative effects. In particular, ...some of the same mechanisms that underlie positive effects of corridors on species of conservation interest may also increase the spread and impact of antagonistic species (e.g., predators and pathogens), foster negative effects of edges, increase invasion by exotic species, increase the spread of unwanted disturbances such as fire, or increase population synchrony and thus reduce persistence. We conducted a literature review and meta‐analysis to evaluate the prevalence of each of these negative effects. We found no evidence that corridors increase unwanted disturbance or non‐native species invasion; however, these have not been well‐studied concerns (1 and 6 studies, respectively). Other effects of corridors were more often studied and yielded inconsistent results; mean effect sizes were indistinguishable from zero. The effect of edges on abundances of target species was as likely to be positive as negative. Corridors were as likely to have no effect on antagonists or population synchrony as they were to increase those negative effects. We found 3 deficiencies in the literature. First, despite studies on how corridors affect predators, there are few studies of related consequences for prey population size and persistence. Second, properly designed studies of negative corridor effects are needed in natural corridors at scales larger than those achievable in experimental systems. Third, studies are needed to test more targeted hypotheses about when corridor‐mediated effects on invasive species or disturbance may be negative for species of management concern. Overall, we found no overarching support for concerns that construction and maintenance of habitat corridors may result in unintended negative consequences. Negative edge effects may be mitigated by widening corridors or softening edges between corridors and the matrix. Other negative effects are relatively small and manageable compared with the large positive effects of facilitating dispersal and increasing diversity of native species.
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