Mosaic chromosomal alterations in blood across ancestries using whole-genome sequencing.

Megabase-scale mosaic chromosomal alterations (mCAs) in blood are prognostic markers for a host of human diseases. Here, to gain a better understanding of mCA rates in genetically diverse populations, we analyzed whole-genome sequencing data from 67,390 individuals from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program. We observed higher sensitivity with whole-genome sequencing data, compared with array-based data, in uncovering mCAs at low mutant cell fractions and found that individuals of European ancestry have the highest rates of autosomal mCAs and the lowest rates of chromosome X mCAs, compared with individuals of African or Hispanic ancestry. Although further studies in diverse populations will be needed to replicate our findings, we report three loci associated with loss of chromosome X, associations between autosomal mCAs and rare variants in DCPS, ADM17, PPP1R16B and TET2 and ancestry-specific variants in ATM and MPL with mCAs in cis.

Balancing growth amidst salt stress - lifestyle perspectives from the extremophyte model Schrenkiella parvula.

Schrenkiella parvula, a leading extremophyte model in Brassicaceae, can grow and complete its lifecycle under multiple environmental stresses, including high salinity. Yet, the key physiological and structural traits underlying its stress-adapted lifestyle are unknown along with trade-offs when surviving salt stress at the expense of growth and reproduction. We aimed to identify the influential adaptive trait responses that lead to stress-resilient and uncompromised growth across developmental stages when treated with salt at levels known to inhibit growth in Arabidopsis and most crops. Its resilient growth was promoted by traits that synergistically allowed primary root growth in seedlings, the expansion of xylem vessels across the root-shoot continuum, and a high capacity to maintain tissue water levels by developing thicker succulent leaves while enabling photosynthesis during salt stress. A successful transition from vegetative to reproductive phase was initiated by salt-induced early flowering, resulting in viable seeds. Self-fertilization in salt-induced early flowering was dependent upon filament elongation in flowers otherwise aborted in the absence of salt during comparable plant ages. The maintenance of leaf water status promoting growth, and early flowering to ensure reproductive success in a changing environment, were among the most influential traits that contributed to the extremophytic lifestyle of S. parvula.

Single- and Cross-Commodity Delay Discounting of Cannabis.

OBJECTIVE: Despite extensive literature that has identified high rates of delay discounting as a behavioral correlate of substance misuse, associations of cannabis use measures and delay discounting are less consistent. Furthermore, there is very limited research examining cannabis use using cross-commodity delay discounting tasks, where the immediate and delayed outcomes are different commodities. METHOD: Using conventional single-commodity delay discounting tasks for money and cannabis outcomes as well as cross-commodity delay discounting tasks (i.e., cannabis now vs. money later, money now vs. cannabis later), we examined associations of delay discounting rates with cannabis use frequency, cannabis use disorder symptom count, cannabis-related problems, and craving among young adult cannabis users (N = 115; M age = 20.7, SD = 2.6; M cannabis use days per month = 15.5, SD = 10.0). RESULTS: Although associations between cannabis use measures and rates of delay discounting in single-commodity conditions were modest, significant associations were observed with delay discounting rates in cross-commodity conditions. Of note, regression and model comparison analyses generally showed positive associations of cannabis measures with immediate cannabis versus delayed money delay discounting rates, and negative associations of cannabis measures with immediate money versus delayed cannabis delay discounting rates. CONCLUSIONS: The results suggest that problematic cannabis use may not be strictly associated with the inability to wait for delayed outcomes, as suggested by previous research implementing single-commodity delay discounting tasks, but also with a willingness to wait for delayed access to cannabis.

Valuation of future alcohol in cross-commodity delay discounting is associated with alcohol misuse/consequences.

OBJECTIVE: Delay discounting (DD) refers to the reduction in reward value as a function of its delay, and individuals who misuse alcohol typically exhibit high rates of DD, which may reflect a general preference for immediate outcomes. This interpretation is based on studies utilizing single-commodity DD tasks where the same commodity is available immediately and following a delay. Cross-commodity DD tasks require individuals to choose between different commodities at varying delays and may provide the potential to further illuminate intertemporal preference associated with alcohol misuse. The present study examined associations between single-commodity and cross-commodity DD rates with alcohol use metrics among young adults. METHOD: DD by young adults (N = 70, aged 19-24, 71% male, 80% White) who engage in hazardous drinking was examined using a fully parametric combination of immediate and delayed alcohol and money outcomes. We hypothesized that past 30-day alcohol use and alcohol-related negative consequences would be associated with preference for alcohol outcomes independent of whether alcohol was immediate or delayed. RESULTS: Results support the hypothesis, as past 30-day consumption and AUDIT scores were positively associated with rate of DD in the immediate alcohol versus delayed money task and negatively associated with rate of DD in the immediate money versus delayed alcohol task. Moreover, we found the immediate money versus delayed alcohol task provided unique explanatory power for individual alcohol use. CONCLUSIONS: The observed associations indicate that willingness to invest in future access to alcohol may be associated with elevated alcohol use and related consequences. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Expression of membrane Hsp90 is a molecular signature of T cell activation.

Heat shock protein 90 (Hsp90) maintains cellular proteostasis during stress and has been under investigation as a therapeutic target in cancer for over two decades. We and others have identified a membrane expressed form of Hsp90 (mHsp90) that previously appeared to be restricted to rapidly proliferating cells exhibiting a metastatic phenotype. Here, we used HS-131, a fluor-tethered mHsp90 inhibitor, to quantify the effect of T cell activation on the expression of mHsp90 in human and mouse T cells. In cell-based assays, stimulation of human T cells induced a 20-fold increase in mHsp90 expression at the plasma membrane, suggesting trafficking of mHsp90 is regulated by TCR and inflammatory mediated signaling. Following injection of HS-131 in mouse models of human rheumatoid arthritis and inflammatory bowel disease, we detected localization of the probe at sites of active disease, consistent with immune cell invasion. Moreover, despite rapid hepatobiliary clearance, HS-131 demonstrated efficacy in reducing the mean clinical score in the CIA arthritis model. Our results suggest mHsp90 expression on T cells is a molecular marker of T cell activation and potentially a therapeutic target for chronic diseases such as rheumatoid arthritis.

Exploratory examination of the effects of d-amphetamine on active-state functional connectivity: Influence of impulsivity and sensation-seeking status.

Recent advances in diagnostic research identified that individuals with higher impulsivity and sensation-seeking scores tend to report more positive subjective responses to stimulant drugs such as amphetamine. The current exploratory study hypothesized that differences in underlying mesocorticolimbic circuitry may mediate the relationship between personality and responses to stimulants due to its previously established implication in reward processes as well as the overlap between its dopaminergic projections and the pharmacodynamics of many stimulants. Forty participants (20 female) were recruited with relatively high- and low-impulsivity and sensation-seeking scores as defined by the Zuckerman-Kuhlman Personality Questionnaire (Form IIIR; Zuckerman, Kuhlman, Joireman, Teta, & Kraft, 1993) for a double-blind, placebo-controlled, intranasal amphetamine administration study conducted within an MRI scanner. Active state seed-to-voxel connectivity analyses assessed the effects of amphetamine, personality, subjective responses to amphetamine, and their interactions with mesocorticolimbic seeds on data collected during monetary incentive delay and go/no-go task performance. Results indicated that amphetamine administration largely disrupted brain activity as evidenced by connectivity values shifting toward no correlation among brain stem, striatal, and frontal cortex regions. Additionally, associations of impulsivity and connectivity between ventral tegmental and medial orbitofrontal as well as lateral orbitofrontal and putamen regions were inverted from negative to positive during the placebo and amphetamine conditions, respectively. Personality was unrelated to subjective responses to amphetamine. Results are interpreted as providing evidence of underlying differences in mesocorticolimbic circuitry being a potential target for requisite diagnostic and treatment strategies implicated with stimulant use disorders, but further research is needed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Quantifying value-based determinants of drug and non-drug decision dynamics.

RATIONALE: A growing body of research suggests that substance use disorder (SUD) may be characterized as disorders of decision making. However, drug choice studies assessing drug-associated decision making often lack more complex and dynamic conditions that better approximate contexts outside the laboratory and may lead to incomplete conclusions regarding the nature of drug-associated value. OBJECTIVES: The current study assessed isomorphic (choice between identical food options) and allomorphic (choice between remifentanil [REMI] and food) choice across dynamically changing reward probabilities, magnitudes, and differentially reward-predictive stimuli in male rats to better understand determinants of drug value. Choice data were analyzed at aggregate and choice-by-choice levels using quantitative matching and reinforcement learning (RL) models, respectively. RESULTS: Reductions in reward probability or magnitude independently reduced preferences for food and REMI commodities. Inclusion of reward-predictive cues significantly increased preference for food and REMI rewards. Model comparisons revealed that reward-predictive stimuli significantly altered the economic substitutability of food and REMI rewards at both levels of analysis. Furthermore, model comparisons supported the reformulation of reward value updating in RL models from independent terms to a shared, relative term, more akin to matching models. CONCLUSIONS: The results indicate that value-based quantitative choice models can accurately capture choice determinants within complex decision-making contexts and corroborate drug choice as a multidimensional valuation process. Collectively, the present study indicates commonalities in decision-making for drug and non-drug rewards, validates the use of economic-based SUD therapies (e.g., contingency management), and implicates the neurobehavioral processes underlying drug-associated decision-making as a potential avenue for future SUD treatment.

Cross species multi-omics reveals cell wall sequestration and elevated global transcript abundance as mechanisms of boron tolerance in plants.

Boron toxicity is a world-wide problem for crops, yet we have a limited understanding of the genetic responses and adaptive mechanisms to this stress in plants. We employed a cross-species comparison between boron stress-sensitive Arabidopsis thaliana and its boron stress-tolerant extremophyte relative Schrenkiella parvula, and a multi-omics approach integrating genomics, transcriptomics, metabolomics and ionomics to assess plant responses and adaptations to boron stress. Schrenkiella parvula maintains lower concentrations of total boron and free boric acid than Arabidopsis when grown with excess boron. Schrenkiella parvula excludes excess boron more efficiently than Arabidopsis, which we propose is partly driven by SpBOR5, a boron transporter that we functionally characterize in this study. Both species use cell walls as a partial sink for excess boron. When accumulated in the cytoplasm, excess boron appears to interrupt RNA metabolism. The extremophyte S. parvula facilitates critical cellular processes while maintaining the pool of ribose-containing compounds that can bind with boric acid. The S. parvula transcriptome is pre-adapted to boron toxicity. It exhibits substantial overlaps with the Arabidopsis boron-stress responsive transcriptome. Cell wall sequestration and increases in global transcript levels under excess boron conditions emerge as key mechanisms for sustaining plant growth under boron toxicity.

H3K4 trimethylation dynamics impact diverse developmental and environmental responses in plants.

MAIN CONCLUSION: The H3K4me3 histone mark in plants functions in the regulation of gene expression and transcriptional memory, and influences numerous developmental processes and stress responses. Plants execute developmental programs and respond to changing environmental conditions via adjustments in gene expression, which are modulated in part by chromatin structure dynamics. Histone modifications alter chromatin in precise ways on a global scale, having the potential to influence the expression of numerous genes. Trimethylation of lysine 4 on histone H3 (H3K4me3) is a prominent histone modification that is dogmatically associated with gene activity, but more recently has also been linked to gene repression. As in other eukaryotes, the distribution of H3K4me3 in plant genomes suggests it plays a central role in gene expression regulation, however the underlying mechanisms are not fully understood. Transcript levels of many genes related to flowering, root, and shoot development are affected by dynamic H3K4me3 levels, as are those for a number of stress-responsive and stress memory-related genes. This review examines the current understanding of how H3K4me3 functions in modulating plant responses to developmental and environmental cues.

Are You Sure: Preference and Ambivalence in Delay Discounting.

Delay discounting (DD) research has become ubiquitous due to its robust associations with clinical outcomes. Typical DD tasks involve multiple trials in which participants indicate preference between smaller, sooner and larger, later rewards. Scoring of these binary choice tasks has not considered trial-level ambivalence as a possible decision-making construct. The present study explored the extent to which trial-level ambivalence varied within-individual using an established assessment of DD (the Monetary Choice Questionnaire). Results indicate that degree of ambivalence peaks around the trials associated with the DD rate. Moreover, ambivalence is associated with a diminished impact of reward delay differences on choice, where greater delay differences decrease the odds of choosing the larger, later rewards. Taken together, we believe ambivalence to be a relevant construct for research on intertemporal decision making, and it may be particularly useful in the study of manipulations on individual rates of DD.

Russell and the Handshake: Greeting in Spiritual Care.

One of the most common practices in spiritual care involves welcoming or greeting others. Despite this, there is little literature exploring this practice in terms of how it is experienced by those we greet, how it impacts people and relationships, and how it should occur. By reflecting on several stories of handshakes and greeting, this paper seeks to call to attention the experience, impact, and "how-to" of greeting in spiritual care.

Low-Phosphate Chromatin Dynamics Predict a Cell Wall Remodeling Network in Rice Shoots.

Phosphorus (P) is an essential plant macronutrient vital to fundamental metabolic processes. Plant-available P is low in most soils, making it a frequent limiter of growth. Declining P reserves for fertilizer production exacerbates this agricultural challenge. Plants modulate complex responses to fluctuating P levels via global transcriptional regulatory networks. Although chromatin structure plays a substantial role in controlling gene expression, the chromatin dynamics involved in regulating P homeostasis have not been determined. Here we define distinct chromatin states across the rice (Oryza sativa) genome by integrating multiple chromatin marks, including the H2A.Z histone variant, H3K4me3 modification, and nucleosome positioning. In response to P starvation, 40% of all protein-coding genes exhibit a transition from one chromatin state to another at their transcription start site. Several of these transitions are enriched in subsets of genes differentially expressed under P deficiency. The most prominent subset supports the presence of a coordinated signaling network that targets cell wall structure and is regulated in part via a decrease of H3K4me3 at transcription start sites. The P starvation-induced chromatin dynamics and correlated genes identified here will aid in enhancing P use efficiency in crop plants, benefitting global agriculture.

Ethylene and Phloem Signals Are Involved in the Regulation of Responses to Fe and P Deficiencies in Roots of Strategy I Plants.

Iron (Fe) and phosphorus (P) are two essential mineral nutrients whose acquisition by plants presents important environmental and economic implications. Both elements are abundant in most soils but scarcely available to plants. To prevent Fe or P deficiency dicot plants initiate morphological and physiological responses in their roots aimed to specifically acquire these elements. The existence of common signals in Fe and P deficiency pathways suggests the signaling factors must act in conjunction with distinct nutrient-specific signals in order to confer tolerance to each deficiency. Previous works have shown the existence of cross talk between responses to Fe and P deficiency, but details of the associated signaling pathways remain unclear. Herein, the impact of foliar application of either P or Fe on P and Fe responses was studied in P- or Fe-deficient plants of Arabidopsis thaliana, including mutants exhibiting altered Fe or P homeostasis. Ferric reductase and acid phosphatase activities in roots were determined as well as the expression of genes related to P and Fe acquisition. The results obtained showed that Fe deficiency induces the expression of P acquisition genes and phosphatase activity, whereas P deficiency induces the expression of Fe acquisition genes and ferric reductase activity, although only transitorily. Importantly, these responses were reversed upon foliar application of either Fe or P on nutrient-starved plants. Taken together, the results reveal interactions between P- and Fe-related phloem signals originating in the shoots that likely interact with hormones in the roots to initiate adaptive mechanisms to tolerate deficiency of each nutrient.

Differences in rats and pigeons suboptimal choice may depend on where those stimuli are in their behavior system.

Timberlake (1993) proposed that much learning research can be better understood in the context of behavior systems theory. Learning theories generally have not considered how procedures may interact with evolutionarily prepared foraging contexts, thereby leading to anomalous conclusions. An example of such a conclusion is the apparent species difference when given a choice between a lower percentage of signaled reinforcement (20%) and higher percentage of unsignaled reinforcement (50%). Pigeons generally show a preference for the suboptimal alternative. Rats, however, often choose optimally. Orduña et al. have suggested that rats choose optimally because they show conditioned inhibition to signals for nonreinforcement, whereas pigeons do not. We suggest, however, that such fundamental species differences are unlikely. Rather, differences in the search mode elicited by the stimuli, together with some generalization between the signals for reinforcement and nonreinforcement are more likely to account for the species differences in suboptimal choice. When we used a retractable lever as the signal for reinforcement and a light stimulus as the signal for nonreinforcement, the rats showed suboptimal choice, not unlike that of pigeons. In this case, how the conditioned stimuli conform to the animals' behavior systems natural predispositions appears to affect how the animals react to those stimuli. Thus, when the search modes are matched between species and there is no generalization between the two signals, similar behavior can be found. Timberlake's contribution of behavior systems provides an evolutionary context in which species differences in sensory, response, and motivational differences can be separated from learning differences.

Midsession reversal task with pigeons: Parallel processing of alternatives explains choices.

Most models of choice assume a "tug of war" (ToW) between options present at the time of the choice, arguing that preferences are built on this process, and implying that adding options increases delay to act. In contrast, the sequential choice model (SCM) proposes that choices are driven by parallel expression of the mechanisms that control action in sequential encounters, without comparative deliberation at choice time. Only the SCM predicts choice preferences based on latencies to respond in single-option encounters. SCM further predicts that latencies to choose should either be the same or shorter than those in sequential encounters. We contrasted these models using a midsession reversal task with pigeons. Responses to one alternative (S1) were rewarded in the first half of each session and those to the other (S2) in the second half. Single-option (sequential) and two-option (choice) trials were intermingled. In choice trials subjects strongly preferred S1 early in the session, showed intermediate preferences toward the midsession, and preferred S2 late. These preferences were all predicted by changes in latency toward the presently negative alternative (S2 early and S1 late) in single-option trials. Latency toward presently positive stimuli were minimal throughout, in both single and two option trials, with no evidence of an evaluation time cost of choice. The ability to predict choice preference from latencies in sequential encounters and the absence of a choice delay support the SCM against ToW models, consistently with results from other protocols and species. (PsycINFO Database Record

Rice H2A.Z negatively regulates genes responsive to nutrient starvation but promotes expression of key housekeeping genes.

The H2A.Z histone variant plays a role in the modulation of environmental responses, but the nature of the associated mechanisms remains enigmatic. We investigated global H2A.Z deposition and transcriptomic changes in rice (Oryza sativa) upon exposure to phosphate (Pi) deficiency and in response to RNAi knockdown of OsARP6, which encodes a key component of the H2A.Z exchange complex. Both Pi deficiency and OsARP6-knockdown resulted in similar, profound effects on global H2A.Z distribution. H2A.Z in the gene body of stress-responsive genes was negatively correlated with gene expression, and this was more apparent in response to Pi deficiency. In contrast, the role of H2A.Z at the transcription start site (TSS) was more context dependent, acting as a repressor of some stress-responsive genes, but an activator of some genes with housekeeping functions. This was especially evident upon OsARP6-knockdown, which resulted in down-regulation of a number of genes linked to chloroplast function that contained decreases in H2A.Z at the TSS. Consistently, OsARP6-RNAi plants exhibited lower chlorophyll content relative to the wild-type. Our results demonstrate that gene body-localized H2A.Z plays a prominent role in repressing stress-responsive genes under non-inductive conditions, whereas H2A.Z at the TSS functions as a positive or negative regulator of transcription.

The role of 'jackpot' stimuli in maladaptive decision-making: dissociable effects of D1/D2 receptor agonists and antagonists.

RATIONALE: Laboratory experiments often model risk through a choice between a large, uncertain (LU) reward against a small, certain (SC) reward as an index of an individual's risk tolerance. An important factor generally lacking from these procedures are reward-associated cues that may modulate risk preferences. OBJECTIVE: We tested whether the addition of cues signaling 'jackpot' wins to LU choices would modulate risk preferences and if these cue effects were mediated by dopaminergic signaling. METHODS: Three groups of rats chose between LU and SC rewards for which the LU probability of reward decreased across blocks. The unsignaled group received a non-informative stimulus of trial outcome. The signaled group received a jackpot signal prior to reward delivery and blackout on losses. The signaled-light group received a similar jackpot for wins, but a salient loss signal distinct from the win signal. RESULTS: Presenting win signals decreased the discounting of LU value for both signaled groups regardless of loss signal, while the unsignaled group showed discounting similar to previous research without cues. Pharmacological challenges with D1/D2 agonists and antagonists revealed that D1 antagonism increased and decreased sensitives to the relative probability of reward for unsignaled and signaled groups, respectively, while D2 agonists decreased sensitivities to the relative magnitude of reward. CONCLUSION: The results highlight how signals predictive of wins can promote maladaptive risk taking in individuals, while loss signals have reduced effect. Additionally, the presence of reward-predictive cues may change the underlying neurobehavioral mechanisms mediating decision-making under risk.

Rice nucleosome patterns undergo remodeling coincident with stress-induced gene expression.

BACKGROUND: Formation of nucleosomes along eukaryotic DNA has an impact on transcription. Major transcriptional changes occur in response to low external phosphate (Pi) in plants, but the involvement of chromatin-level mechanisms in Pi starvation responses have not been investigated. RESULTS: We mapped nucleosomes along with transcriptional changes after 24-h of Pi starvation in rice (Oryza sativa) by deep sequencing of micrococcal nuclease digested chromatin and ribosome-depleted RNA. We demonstrated that nucleosome patterns at rice genes were affected by both cis- and trans-determinants, including GC content and transcription. Also, categorizing rice genes by nucleosome patterns across the transcription start site (TSS) revealed nucleosome patterns that correlated with distinct functional categories of genes. We further demonstrated that Pi starvation resulted in numerous dynamic nucleosomes, which were enhanced at genes differentially expressed in response to Pi starvation. CONCLUSIONS: We demonstrate that rice nucleosome patterns are suggestive of gene functions, and reveal a link between chromatin remodeling and transcriptional changes in response to deficiency of a major macronutrient. Our findings help to enhance the understanding towards eukaryotic gene regulation at the chromatin level.

Gambling-like behavior in pigeons: 'jackpot' signals promote maladaptive risky choice.

Individuals often face choices that have uncertain outcomes and have important consequences. As a model of this environment, laboratory experiments often offer a choice between an uncertain, large reward that varies in its probability of delivery against a certain but smaller reward as a measure of an individual's risk aversion. An important factor generally lacking from these procedures are gambling related cues that may moderate risk preferences. The present experiment offered pigeons choices between unreliable and certain rewards but, for the Signaled group on winning choices, presented a 'jackpot' signal prior to reward delivery. The Unsignaled group received an ambiguous stimulus not informative of choice outcomes. For the Signaled group, presenting win signals effectively blocked value discounting for the large, uncertain outcome as the probability of a loss increased, whereas the Unsignaled group showed regular preference changes similar to previous research lacking gambling related cues. These maladaptive choices were further shown to be unaffected by more salient loss signals and resistant to response cost increases. The results suggest an important role of an individual's sensitivity to outcome-correlated cues in influencing risky choices that may moderate gambling behaviors in humans, particularly in casino and other gambling-specific environments.

Art, Objects, and Beautiful Stories: A "New" Approach to Spiritual Care.

The use of story, and the use of art or various arts-based techniques have become popular in a number of helping professions, including spiritual care. There remains a gap in the literature, however, in which an approach comprised of both story and art or objects is explored. This paper addresses this gap by discussing the experience, theory, benefits, and technique of combining story and art or object-based techniques for the provision of spiritual care.