Causal Contribution Research Articles

Genetic manipulation of gut microbes enables single-gene interrogation in a complex microbiome

Hundreds of microbiota genes are associated with host biology/disease. Unraveling the causal contribution of a microbiota gene to host biology remains difficult because many are encoded by nonmodel gut commensals and not genetically targetable. A general approach to identify their gene transfer methodology and build their gene manipulation tools would enable mechanistic dissections of their impact on host physiology. We developed a pipeline that identifies the gene transfer methods for multiple nonmodel microbes spanning five phyla, and we demonstrated the utility of their genetic tools by modulating microbiome-derived short-chain fatty acids and bile acids invitro and in the host. In a proof-of-principle study, by deleting a commensal gene for bile acid synthesis in a complex microbiome, we discovered an intriguing role of this gene in regulating colon inflammation. This technology will enable genetically engineering the nonmodel gut microbiome and facilitate mechanistic dissection of microbiota-host interactions.

Study on Causal Nexus between Export, mport and Economic Growth byFrequency-Domain Approach: Evidence from Selected East and Southeast Asian Economies

In this study, frequency domain Granger causality test and generalized forecast error variance decomposition are employed to check the causal direction and contribution of exports and imports to economic growth for eight economies. Granger results show: in the short run, (a) Japan, Indonesia, and Thailand support growth-led import, Malaysia supports import-led growth, and Singapore supports bidirectional causal connection between imports and economic growth; (b) Indonesia supports growth-led export, the Philippines and Thailand support export-led growth, and Hong Kong SAR and Singapore support mutual causality between exports and economic growth; in the long run, (c) Indonesia and Thailand support growth-led import, Japan, Hong Kong SAR, and Singapore support import-led growth, and South Korea supports a two-way causality nexus between imports and economic growth; (d) South Korea and Indonesia support growth-led export, Japan, Hong Kong SAR, and Singapore support export-led growth, and Thailand supports bidirectional causality between exports and economic growth. Variance decomposition results indicated that in Japan, South Korea, Malaysia, Indonesia, and the Philippines, imports explain a larger part of economic growth than exports; in Hong Kong SAR and Singapore, exports have a larger impact than imports on economy; in Thailand, exports and imports are almost at the same importance level.

Stunting and Underweight, but not Wasting are Associated with Delay in Child Development in Southwest Ethiopia.

BackgroundStimulating care during childhood is the foundation for optimal health, learning, productivity, and social well-being throughout the life course. In addition, malnutrition is a major public health concern affecting up to half of children under-five years in Ethiopia. However, evidence on the causal contribution of malnutrition to delay in child development is poorly understood in Ethiopia.ObjectiveTo identify the relationship between different forms of malnutrition and delay in child development among children in Southwest Ethiopia.MethodsA community-based survey was conducted among 507 randomly selected mother–child pairs in the Guraghe Zone, Southwest Ethiopia. A pretested tool and validated anthropometric measurements were used. Anthropometric indices (WFH, WFA, and HFA) were calculated in Anthros software. The data were summarized in mean, median, standard deviation, tables and charts. Bivariable and multivariable binary logistic regression (stepwise backward regression) models were fitted with nutritional status (wasting, stunting and underweight) and other potential factors associated with delay in child developmental. Adjusted odds ratios with 95% confidence intervals and p-values were reported.ResultsA total of 507 mother–child (12–59 months) pairs were included in the survey (97% response rate). The mean ASQ-3 score was 150 (± 23.4), with a minimum and maximum score of 45 and 270, respectively. A total of 149 (29.4%; 95% CI: 25.4–33.4) children had developmental delays, where 17.2%, 16.8%, 13.4%, 10.8%, and 10.1% had delays in gross motor, communication, problem-solving, personal-social, and fine motor skills, respectively. Children of working mothers (AOR=2.9; 1.8, 4.8), preterm births (AOR=3.2; 1.4, 7.0), early initiation of complementary feeding (AOR=2.5; 1.37, 4.6), stunting (AOR=3.0; 1.9, 4.7), underweight (AOR= 2.3; 1.1, 4.7) and low dietary diversity score (AOR=3.1; 1.3, 7.5), were predictors of developmental delay.ConclusionChild development delay is a public health concern and it is strongly associated with stunting, underweight, undiversified dietary consumption, and suboptimal infant and young child feeding practices.

Mob Rules: Toward a Causal Model of Social Structure

AbstractThis essay enriches causal models capturing the propagation of prejudice, bias, and other aggregative social mechanisms, negative or positive. These explananda include the reinforcement of economic inequality, “mob-like” behavior, peer pressure, and the establishment of social norms. The stage is set by introducing various forms of redundant causation and discussing some difficulties with mainstream preemption. Next the main proposal extends current representations of aggregative social mechanisms in two respects. First, it is more nuanced, as it identifies three distinct kinds of inferences: relevance of causes to effects, degree of redundancy of an effect, and the influence that causes exert on other causes. Second, it offers a quantitative—as opposed to merely qualitative—distinction between the causal contribution of preempting and preempted causes.

Dysbiosis of the Human Urinary Microbiome and its Association to Diseases Affecting the Urinary System.

The human urinary microbiome, also termed urobiome, has been overlooked due to the clinical dogma of sterile urine, as reported by routine culture. However, evolving sensitive tools such as expanded quantitative urine culture, 16S ribosomal RNA gene sequencing, and next-generation sequencing have discovered a vast number of microorganisms present in urine, even in healthy individuals. Microbiome dysbiosis and its links to disease is a heavily explored area in several microbial niches. Presently, urobiome dysbiosis and its correlation to urinary system-related diseases is at its infancy but rapidly emerging, as it provides potential therapeutic insights. This review outlines the changes in the human urinary microbiome concerning globally prevalent diseases affecting kidney function, such as chronic kidney disease (CKD), diabetes mellitus (DM), hypertension (HT), and urinary tract infection (UTI). Alterations to urine microbial diversity, including differences in the abundance and species richness of particular microbial genera, notably Lactobacillus, Prevotella, Streptococcus, Staphylococcus, Klebsiella, Enterococcus, between diseased and healthy samples are discussed utilising studies to date. Subsequent research needs to move beyond correlation to understand the roles of the urinary microbiota in diseases, thereby clarifying whether urinary dysbiosis has causal contributions that may provide important insight for diagnostics, pathophysiology, and therapy in renal pathologies.

Abstract 10816: Causal Effect of Atrial Fibrillation on Cardiovascular Diseases - A Mendelian Randomization Analysis in the Million Veteran Program

Introduction: Observational studies have implicated atrial fibrillation (AF) as a risk factor for a number of cardiovascular diseases (CVD). Whether AF is causally related to these CVD is unknown. Methods: We included participants with both electronic health record-derived phenotypes and imputed genotype data in this study. A genetic instrument for AF consisting of 406 common variants was derived using a pruning and thresholding method (r2<0.3; p-value <5x10-8) on the 2018 AF Genetics Consortium GWAS summary statistics. 1- and 2-sample MR analyses were performed. In 2-sample MR, the inverse-variance weighted method was used as the primary analysis. Additional sensitivity analyses were performed to account for potential violations of the instrumental variable assumptions. Results: We included 615,635 participants in the study (440,690 European, 118,531 African, 48,908 Hispanic, 7,506 Asian ancestry). Genetic risk of AF was associated with heart failure in both 1-sample (OR/log odds of genetically predicted AF =1.18, 95% CI 1.15 - 1.20) and 2-sample MR (OR/log odds of genetically predicted AF =1.13, 95% CI 1.11 - 1.15). Additionally, genetic risk of AF was associated with heart failure subtypes and non-ischemic cardiomyopathy. There was no association between genetic risk of AF and pulmonary embolism (PE) or deep venous thrombosis (DVT), however, genetic risk of AF was associated with PE after excluding individuals with concurrent or prior DVT (OR1-sample MR 1.08, 95% CI 1.01 - 1.15; OR2-sample MR 1.06, 95% CI 1.03 - 1.08). Lastly, we confirmed an association between genetic risk of AF and ischemic stroke but not all-cause dementia. Our results were robust to a number of sensitivity analyses. Conclusions: In a large multi-ancestry study, we delineate the potential causal contribution of AF to a number of CVD and highlight support for a causal association between AF and isolated PE. Our findings inform how prevention and treatment of AF may affect CVD incidence and outcomes.

TMS Reveals Dynamic Interaction between Inferior Frontal Gyrus and Posterior Middle Temporal Gyrus in Gesture-Speech Semantic Integration.

Semantic processing is an amodal process with modality-specific information integrated in supramodal "convergence zones" or "semantic hub" with executive mechanisms that tailor semantic representation in a task-appropriate way. One unsolved question is how frontal control region dynamically interacts with temporal representation region in semantic integration. The present study addressed this issue by using inhibitory double-pulse transcranial magnetic stimulation over the left inferior frontal gyrus (IFG) or left posterior middle temporal gyrus (pMTG) in one of eight 40 ms time windows (TWs) (3 TWs before and 5 TWs after the identification point of speech), when human participants (12 females, 14 males) were presented with semantically congruent or incongruent gesture-speech pairs but merely identified the gender of speech. We found a TW-selective disruption of gesture-speech integration, indexed by the semantic congruency effect (i.e., a cost of reaction time because of semantic conflict), when stimulating the left pMTG in TW1, TW2, and TW7 but when stimulating the left IFG in TW3 and TW6. Based on the timing relationship, we hypothesize a two-stage gesture-speech integration circuit with a pMTG-to-IFG sequential involvement in the prelexical stage for activating gesture semantics and top-down constraining the phonological processing of speech. In the postlexical stage, an IFG-to-pMTG feedback signal might be implicated for the control of goal-directed representations and multimodal semantic unification. Our findings provide new insights into the dynamic brain network of multimodal semantic processing by causally revealing the temporal dynamics of frontal control and temporal representation regions.SIGNIFICANCE STATEMENT Previous research has identified differential functions of left inferior frontal gyrus (IFG) and posterior middle temporal gyrus (pMTG) in semantic control and semantic representation, respectively, and a causal contribution of both regions in gesture-speech integration. However, it remains largely unclear how the two regions dynamically interact in semantic processing. By using double-pulse transcranial magnetic stimulation to disrupt regional activity at specific time, this study for the first time revealed critical time windows when the two areas were causally involved in integrating gesture and speech semantics. Findings suggest a pMTG-IFG-pMTG neurocircuit loop in gesture-speech integration, which deepens current knowledge and inspires future investigation of the temporal dynamics and cognitive processes of the amodal semantic network.

Purinergic signalling in the urinary bladder - When function becomes dysfunction.

Knowledge of the participation of ATP and related purines in urinary tract physiology has been established over the last five decades through the work of many independent groups, inspired by, and building on the pioneering studies of Professor Geoffrey Burnstock and his coworkers. As part of a series of reviews in this tribute edition, the present article summarises our current understanding of purines and purinergic signalling in modulating and regulating urinary tract function. Purinergic mechanisms underlying the origin of bladder pain; sensations of bladder filling and urinary tract motility; and regulation of detrusor smooth muscle contraction are described, encompassing the relevant history of discovery and consolidation of knowledge as methodologies and pharmacological tools have developed. We consider normal physiology, including development and ageing and then move to pathophysiology, discussing the causal and consequential contribution of purinergic signalling mechanism and their constituent components (receptors, signal transduction, effector molecules) to bladder dysfunction.

The role of ventromedial and dorsolateral prefrontal cortex in attention and interpretation biases in individuals with general anxiety disorder (GAD): A tDCS study

Backgroundand purpose of the study: Individuals with general anxiety disorder (GAD) have deficits in emotional and cognitive processing, including cognitive bias, which plays a causal role in anxiety. Hyperactivity of the ventromedial prefrontal cortex (vmPFC) and dorsolateral prefrontal cortex (dlPFC) is assumed to be involved in cognitive bias. We aimed to explore the causal contribution of the dorsolateral and ventromedial prefrontal cortices (dlPFC, vmPFC) on cognitive bias via non-invasive brain stimulation, and expected a bias-reducing effect of cortical activity enhancement over these areas in GAD, with a larger contribution of the vmPFC to perceptual, and of the dlPFC to interpretation bias. Material and methodsThe study was conducted in a randomized, single-blinded, and complete crossover design. Thirty-four adults with GAD, received transcranial direct current stimulation (tDCS) in 5 separate sessions (1.5 mA, 20 min) with the following electrode montages: anodal dlPFC/cathodal vmPFC, anodal vmPFC/cathodal dlPFC, anodal dlPFC/cathodal right shoulder, anodal vmPFC/cathodal left shoulder, and sham stimulation. During stimulation, in each session, participants performed the Dot-Probe and Reading Mind from Eyes tests to measure attention and interpretation biases. ResultsA significant effect of stimulation condition on attention and interpretation biases was observed. Anodal vmPFC and dlPFC stimulation coupled with an extracranial cathodal electrode reduced attention bias to threat-related stimuli in the dot-probe test. Furthermore, anodal dlPFC/cathodal vmPFC stimulation reduced negative interpretation bias in reading from eyes test. ConclusionAs suggested by the results of this study, both dlPFC and vmPFC are involved in cognitive bias in GAD, but with partially different roles. Anodal stimulation over the right vmPFC and the left dlPFC reduced attention bias, supporting the relevance of these areas for attention bias. For interpretation bias, the significant effect of anodal dlPFC/cathodal vmPFC stimulation, but only trendwise effect of anodal tDCS over the dlPFC combined with an extracephalic return electrode is in accordance with a predominant effect of the dlPFC on interpretation bias, but does not rule out an additional minor involvement of the vmPFC. Based on these results, a new model is suggested for the neural underpinnings of anxiety symptoms.

Mitochondrial dysfunction in adult midbrain dopamine neurons triggers an early immune response.

Dopamine (DA) neurons of the midbrain are at risk to become affected by mitochondrial damage over time and mitochondrial defects have been frequently reported in Parkinson’s disease (PD) patients. However, the causal contribution of adult-onset mitochondrial dysfunction to PD remains uncertain. Here, we developed a mouse model lacking Mitofusin 2 (MFN2), a key regulator of mitochondrial network homeostasis, in adult midbrain DA neurons. The knockout mice develop severe and progressive DA neuron-specific mitochondrial dysfunction resulting in neurodegeneration and parkinsonism. To gain further insights into pathophysiological events, we performed transcriptomic analyses of isolated DA neurons and found that mitochondrial dysfunction triggers an early onset immune response, which precedes mitochondrial swelling, mtDNA depletion, respiratory chain deficiency and cell death. Our experiments show that the immune response is an early pathological event when mitochondrial dysfunction is induced in adult midbrain DA neurons and that neuronal death may be promoted non-cell autonomously by the cross-talk and activation of surrounding glial cells.

Lesion Evidence for a Causal Role of the Insula in Aversion to Social Inequity.

Humans resist unequal distributions of goods in their social interactions, even if it requires foregoing personal gains. Functional neuroimaging studies implicate the insula in this aversion to social inequity and in fairness-related decisions, but a causal contribution has not yet been established. We compared the responses of 30 patients with lesions to the insula on a multiple-trial version of the one-shot Ultimatum Game, a neuroeconomic social exchange paradigm where a sum of money is split between two players, to those of 30 matched patients with brain injuries sparing the insula. Insula lesion patients accepted offers of an unequal disadvantageous split significantly more often than comparison lesion patients. Computational modeling confirmed that this difference in choice behavior was due to decreased aversion to disadvantageous inequity following insula damage, rather than due to increased decision noise or non-consideration of inequity. Our results provide novel evidence that the insula is causally involved in aversion to inequity and in value-based choices in the context of social interactions.

Transcranial Direct Current Stimulation of the Ventromedial Prefrontal Cortex Modulates Perceptual and Neural Patterns of Fear Generalization

BackgroundOvergeneralization of fear is a pathogenic marker of anxiety and stress-related disorders and has been linked with perceptual discrimination deficits, reduced fear inhibition, and prefrontal hyporeactivity to safety-signaling stimuli. We aimed to examine whether behavioral and neural patterns of fear generalization are influenced by the fear-inhibiting ventromedial prefrontal cortex (vmPFC). MethodsThree groups of healthy participants received excitatory (n = 27), inhibitory (n = 26), or sham (n = 26) transcranial direct current stimulation of the vmPFC after a fear conditioning phase and before a fear generalization phase. We obtained, as dependent variables, fear ratings and unconditioned stimulus–expectancy ratings, perceptual aspects of fear generalization (perceptual discrimination), pupil dilations, and source estimations of event-related fields elicited by conditioned and generalization stimuli. ResultsAfter inhibitory (compared with excitatory and sham) vmPFC stimulation, we observed reduced performance in perceptual discrimination and less negative inhibitory gradients in frontal structures at midlatency and late time intervals. Fear and unconditioned stimulus–expectancy ratings as well as pupil dilation remained unaffected by stimulation. ConclusionsThese findings reveal a causal contribution of vmPFC reactivity to generalization patterns and suggest that vmPFC hyporeactivity consequent on inhibitory vmPFC stimulation may serve as a model for pathological processes of fear generalization (reduced discrimination, impaired fear inhibition via frontal brain structures). This encourages further basic and clinical research on the potential of targeted brain stimulation to modulate fear generalization and overgeneralization.

Game-theoretical mapping of fundamental brain functions based on lesion deficits in acute stroke.

Lesion analysis is a fundamental and classical approach for inferring the causal contributions of brain regions to brain function. However, many studies have been limited by the shortcomings of methodology or clinical data. Aiming to overcome these limitations, we here use an objective multivariate approach based on game theory, Multi-perturbation Shapley value Analysis, in conjunction with data from a large cohort of 394 acute stroke patients, to derive causal contributions of brain regions to four principal functional components of the widely used National Institutes of Health Stroke Score measure. The analysis was based on a high-resolution parcellation of the brain into 294 grey and white matter regions. Through initial lesion symptom mapping for identifying all potential candidate regions and repeated iterations of the game-theoretical approach to remove non-significant contributions, the analysis derived the smallest sets of regions contributing to each of the four principal functional components as well as functional interactions among the regions. Specifically, the factor ‘language and consciousness’ was related to contributions of cortical regions in the left hemisphere, including the prefrontal gyrus, the middle frontal gyrus, the ventromedial putamen and the inferior frontal gyrus. Right and left motor functions were associated with contributions of the left and right dorsolateral putamen and the posterior limb of the internal capsule, correspondingly. Moreover, the superior corona radiata and the paracentral lobe of the right hemisphere as well as the right caudal area 23 of the cingulate gyrus were mainly related to left motor function, while the prefrontal gyrus, the external capsule and the sagittal stratum fasciculi of the left hemisphere contributed to right motor function.Our approach demonstrates a practically feasible strategy for applying an objective lesion inference method to a high-resolution map of the human brain and distilling a small, characteristic set of grey and white matter structures contributing to fundamental brain functions. In addition, we present novel findings of synergistic interactions between brain regions that provide insight into the functional organization of brain networks.

Governing from the opposition?’: tracing the impact of EFF’s ‘niche populist politics’ on ANC policy shifts

ABSTRACT In December 2017, South Africa’s ruling party, the ANC, announced that they will adopt expropriation of land without compensation and free higher education for 90% of students. These policy positions had been associated with the radical left-wing EFF party. This article asks whether the EFF influenced the ANC policy shifts and if they did, how? Leveraging Williams (2006)’s theory of peripheral party impact and the process tracing method, the study finds evidence of EFF direct causal contribution on ANC policy shift on land reform and strong grounds for inferring indirect influence of the EFF on ANC policy shift on higher education funding. Data sources included policy documents, manifestos, speeches by ANC and EFF political leaders and parliamentary motions. The study contributes to the literature on peripheral party impact and understanding populism in Africa.

Antibiotic-induced disruption of the microbiome exacerbates chemotherapy-induced diarrhoea and can be mitigated with autologous faecal microbiota transplantation

BackgroundChemotherapy is well documented to disrupt the gut microbiome, leading to poor treatment outcomes and a heightened risk of adverse toxicity. Although strong associations exist between its composition and gastrointestinal toxicity, its causal contribution remains unclear. Our inability to move beyond association has limited the development and implementation of microbial-based therapeutics in chemotherapy adjuncts with no clear rationale of how and when to deliver them. Methods/ResultsHere, we investigate the impact of augmenting the gut microbiome on gastrointestinal toxicity caused by the chemotherapeutic agent, methotrexate (MTX). Faecal microbiome transplantation (FMT) delivered after MTX had no appreciable impact on gastrointestinal toxicity. In contrast, disruption of the microbiome with antibiotics administered before chemotherapy exacerbated gastrointestinal toxicity, impairing mucosal recovery (P < 0.0001) whilst increasing diarrhoea severity (P = 0.0007) and treatment-related mortality (P = 0.0045). Importantly, these detrimental effects were reversed when the microbiome was restored using autologous FMT (P = 0.03), a phenomenon dictated by the uptake and subsequent expansion of Muribaculaceae. ConclusionsThese are the first data to show that clinically impactful symptoms of gastrointestinal toxicity are dictated by the microbiome and provide a clear rationale for how and when to target the microbiome to mitigate the acute and chronic complications caused by disruption of the gastrointestinal microenvironment. Translation of this new knowledge should focus on stabilising and strengthening the gut microbiome before chemotherapy and developing new microbial approaches to accelerate recovery of the mucosa. By controlling the depth and duration of mucosal injury, secondary consequences of gastrointestinal toxicity may be avoided.

Using Mendelian Randomisation methods to understand whether diurnal preference is causally related to mental health

Late diurnal preference has been linked to poorer mental health outcomes, but the understanding of the causal role of diurnal preference on mental health and wellbeing is currently limited. Late diurnal preference is often associated with circadian misalignment (a mismatch between the timing of the endogenous circadian system and behavioural rhythms), so that evening people live more frequently against their internal clock. This study aims to quantify the causal contribution of diurnal preference on mental health outcomes, including anxiety, depression and general wellbeing and test the hypothesis that more misaligned individuals have poorer mental health and wellbeing using an actigraphy-based measure of circadian misalignment. Multiple Mendelian Randomisation (MR) approaches were used to test causal pathways between diurnal preference and seven well-validated mental health and wellbeing outcomes in up to 451,025 individuals. In addition, observational analyses tested the association between a novel, objective measure of behavioural misalignment (Composite Phase Deviation, CPD) and seven mental health and wellbeing outcomes. Using genetic instruments identified in the largest GWAS for diurnal preference, we provide robust evidence that early diurnal preference is protective for depression and improves wellbeing. For example, using one-sample MR, a twofold higher genetic liability of morningness was associated with lower odds of depressive symptoms (OR: 0.92, 95% CI: 0.88, 0.97). It is possible that behavioural factors including circadian misalignment may contribute in the chronotype depression relationship, but further work is needed to confirm these findings.

Transcranial direct current stimulation with functional magnetic resonance imaging: a detailed validation and operational guide.

Introduction:Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique used to modulate human brain and behavioural function in both research and clinical interventions. The combination of functional magnetic resonance imaging (fMRI) with tDCS enables researchers to directly test causal contributions of stimulated brain regions, answering questions about the physiology and neural mechanisms underlying behaviour. Despite the promise of the technique, advances have been hampered by technical challenges and methodological variability between studies, confounding comparability/replicability. Methods:Here tDCS-fMRI at 3T was developed for a series of experiments investigating language recovery after stroke. To validate the method, one healthy volunteer completed an fMRI paradigm with three conditions: (i) No-tDCS, (ii) Sham-tDCS, (iii) 2mA Anodal-tDCS. MR data were analysed in SPM12 with region-of-interest (ROI) analyses of the two electrodes and reference sites. Results: Quality assessment indicated no visible signal dropouts or distortions introduced by the tDCS equipment. After modelling scanner drift, motion-related variance, and temporal autocorrelation, we found no field inhomogeneity in functional sensitivity metrics across conditions in grey matter and in the three ROIs. Discussion:Key safety factors and risk mitigation strategies that must be taken into consideration when integrating tDCS into an fMRI environment are outlined. To obtain reliable results, we provide practical solutions to technical challenges and complications of the method. It is hoped that sharing these data and SOP will promote methodological replication in future studies, enhancing the quality of tDCS-fMRI application, and improve the reliability of scientific results in this field. Conclusions: The method and data provided here provide a technically safe, reliable tDCS-fMRI procedure to obtain high quality MR data. The detailed framework of the Standard Operation Procedure SOP ( https://doi.org/10.5281/zenodo.4606564)systematically reports the technical and procedural elements of our tDCS-fMRI approach, which we hope can be adopted and prove useful in future studies.

The Mental Element in Equitable Accessory Liability

Abstract There has been heated debate over the test of dishonesty since it was first laid down in Royal Brunei Airlines v Tan. This paper argues that the essence of ‘dishonest’ assistance is willing participation in a breach of trust, that is, assistants endorse or accept their causal role in bringing it about. Three implications follow. First, the mental element should be fixed at the minimum level necessary to reflect endorsement rather than varying by the degree of causal contribution to the primary wrong. Second, the test of neither dishonesty nor knowledge fully captures the requisite mental element for endorsement. Third, a test framed in terms of intention and belief concerning the core elements of a breach would better identify the mental element of accessory liability in equity. This reformulated test would add much-needed transparency to mental element determination for equitable accessory liability.

Bodily self-perception during voluntary actions: The causal contribution of premotor cortex and cerebellum

Voluntary actions are accompanied by the experience of controlling one's own movements (sense of agency) and the feeling that the moving body part belongs to one's self (sense of body ownership). So far, agency and body ownership have been investigated separately, leaving the neural underpinnings of the relation between the two largely unexplored. The aim of this study was to explore the causal role of two multisensory brain regions, that is the premotor cortex (PMc) and the cerebellum, in agency and body ownership concurrently on the same behavioral task, i.e., the moving Rubber Hand Illusion (mRHI). Participants watched a rubber hand while moving their hidden hand. The type of movement (active or passive) and posture of the rubber hand (congruent or incongruent) differed in three conditions (active congruent, passive congruent, active incongruent), so that agency and ownership could be elicited either separately or concurrently. Agency and ownership were measured by subjective report and proprioceptive drift. Sham and anodal transcranial direct current stimulation (tDCS) were delivered to the PMc (Experiment 1) or the cerebellum (Experiment 2) prior to the mRHI task. Independent of the site or type of tDCS, subjective reports revealed that both agency and ownership were evoked in the active congruent condition, ownership but not agency in the passive congruent condition, and agency but not ownership in the active incongruent condition. The proprioceptive drift was evoked in the active congruent and the passive congruent condition. Anodal tDCS over the PMc reduced the feeling of agency in the active congruent condition, while it enhanced proprioceptive drift when applied over the cerebellum. These findings suggest a specific causal contribution of the PMc and the cerebellum to bodily self-perception during voluntary movement, with the PMc mainly involved in awareness of action and the cerebellum in proprioceptive adaptation of body position in space.

Retention and Engagement of Human Capital: Causal Contribution of Perceived Organizational Prestige and Job Characteristics

Reducing turnover intention and increasing work engagement is not just "nice-to-have" but has been shown to relate to financial and behavioural gains. The present study focused on investigating the causal contribution of perceived organizational prestige (POP) and job characteristics in turnover intention and work engagement. The study involved 107 mid-level managers. Results revealed that POP explained a significant variance in turnover intention and work engagement. Meaningfulness and autonomy were substantial in increasing work engagement, whereas feedback was instrumental in reducing turnover intention. The findings are important for HR executives who seek ways to sustain human capital and foster employee engagement.