Candidate Mechanism Research Articles

Identifying cognitive, affective, and developmental mechanisms linking threat and deprivation with adolescent psychopathology.

The mechanisms linking early-life adversity with psychopathology over the life-course are complex. In this prospective study, we collectively examined cognitive, affective, and developmental mediators previously found to individually link childhood threat and deprivation experiences to adolescent psychopathology to identify the most potent mechanisms. Data came from a community sample of 227 children (mean child age 11.5 ± 0.5 years, 48.5% female) from the Seattle metro area with recruitment designed to reflect diversity in family income. Candidate mechanisms included self-rated pubertal development and task-measured attention bias to threat, emotion regulation, theory of mind, fear learning, inhibitory control, language ability, reasoning, and reward sensitivity. Using a high-dimensional mediation approach, we determined which mediating pathways linking threat and deprivation to psychopathology persisted after controlling for all candidate mechanisms associated with psychopathology. Models additionally controlled for the child's age, sex, early-childhood emotional and behavioral symptoms, poverty, and maternal depression. Blunted reward sensitivity mediated the prospective relationship between threat and internalizing psychopathology, explaining 17.25% (95% CI 1.08%, 69.96%) of this association. Advanced pubertal development was associated with increases in internalizing and externalizing symptoms (standardized associations of 0.16 (95% CI 0.03, 0.29) and 0.17 (95% CI 0.05, 0.29), respectively), but not with adversity. Although deprivation was strongly related to psychopathology, no mechanisms were empirically identified. In a well-characterized community sample, we isolated reward sensitivity as a robust mediator of the prospective association between early-life threat and adolescent internalizing psychopathology. Interventions aimed at bolstering reward sensitivity may mitigate the impact of early-life threat experiences on internalizing problems.

Regulation of BCR-dependent germinal center B-cell formation by HGAL and insight into its emerging myeloid ortholog, C1ORF150.

The specificity of cytokine and immunoreceptor signaling frequently depends upon receptor recruitment of select adaptor proteins and specifically engaged effectors. This review focuses on the orthologous adaptor proteins, HGAL and C1ORF150, and aims to provide insight into their respective modulation of lymphoid and myeloid cell signaling, formation, and function. HGAL acts predominantly within germinal center B cells as an important BCR signal transducer. Effects on BCR signalosome assembly involve HGAL's localization to the plasma membrane via its lipidation, initial interactions with SYK, the pY-phosphorylation of HGAL including its recruitment of GRB2, and HGAL engagement of PDZ-RhoGEF and RhoA signaling. At ligated BCRs, this includes HGAL(-GRB2) stimulation of SYK kinase, attenuation of calcium flux-dependent and NF-κB expression, promotion of cSMAC formation, and cytoskeletal remodeling associated with HGAL-attenuated cell migration. HGAL and partnered effectors also impact on DLBCL pathogenesis, and studies are summarized on HGAL's actions (using DLBCL and Burkitt lymphoma B cells) including cell migration effects, HGAL modulation of cytoskeletal components, and insightful HGAL transgenic mouse and xenograft models. For C1ORF150, its HGAL-homologous subdomains are considered, together with studies that demonstrate C1OR150's FcϵRI- and KIT-mediated expression and phosphorylation in primary human mast cells. Intriguingly, recent GWAS studies have identified a C1ORF150 in-frame splice variant that is strongly associated with urticaria. Candidate mechanisms via which the encoded "C1ORF150-Δexon2" isoform affects mast cell degranulation are considered, including FcϵR1 and/or KIT receptor connections, and candidate "myristoylation switch" mechanisms.

Correction to “cross-cultural differences in memory specificity: Investigation of candidate mechanisms” by Leger and Gutchess (2021).

Correction to “cross-cultural differences in memory specificity: Investigation of candidate mechanisms” by Leger and Gutchess (2021).

Modeling magnetic field amplification in supernova remnants driven by laser

Abstract The origin of magnetic fields and their amplification have always been hot topics in fields such as astrophysics and high-energy-density physics. Among them, the turbulent dynamo effect is an important candidate mechanism, and the interaction between supernova remnants (SNRs) is an important carrier for studying the amplification effect of turbulent magnetic fields. In this paper, we use the radiation magnetohydrodynamic simulation program to carry out a scaling simulation study on the amplification effect of turbulent magnetic fields in the interaction of SNRs driven by powerful lasers. We investigate and compare the evolution of turbulence under different laser driving methods, different directions, and different intensities of initial external environmental magnetic fields. Here, we carefully identify the contributions of Biermann self-generated magnetic fields and environmental magnetic fields in the process of magnetic field amplification, present magnetic energy spectra, and magnetic field amplification factors, and analyze the influence of radiative cooling effect on turbulence and magnetic field evolution. The results show that the collision direction component of the environmental magnetic field dominates the process of magnetic field amplification, and the frequency spectrum of turbulence is consistent with Kolmogorov’s law. The research results are necessary for sorting out and elucidating the physical mechanism of magnetic field amplification in SNRs, and have reference significance for regulating turbulence in strong magnetic fields in the future.

Recording morphogen signals reveals mechanisms underlying gastruloid symmetry breaking.

Aggregates of stem cells can break symmetry and self-organize into embryo-like structures with complex morphologies and gene expression patterns. Mechanisms including reaction-diffusion Turing patterns and cell sorting have been proposed to explain symmetry breaking but distinguishing between these candidate mechanisms of self-organization requires identifying which early asymmetries evolve into subsequent tissue patterns and cell fates. Here we use synthetic 'signal-recording' gene circuits to trace the evolution of signalling patterns in gastruloids, three-dimensional stem cell aggregates that form an anterior-posterior axis and structures resembling the mammalian primitive streak and tailbud. We find that cell sorting rearranges patchy domains of Wnt activity into a single pole that defines the gastruloid anterior-posterior axis. We also trace the emergence of Wnt domains to earlier heterogeneity in Nodal activity even before Wnt activity is detectable. Our study defines a mechanism through which aggregates of stem cells can form a patterning axis even in the absence of external spatial cues.

Hybrid-Vlasov Modelling of Ion Velocity Distribution Functions Associated with the Kelvin–Helmholtz Instability with a Density and Temperature Asymmetry

The Kelvin–Helmholtz instability (KHI), characterized by vortices forming at a perturbed velocity shear layer, is a prominent candidate mechanism for mass, momentum, and energy transport across boundaries with velocity shear in various space plasma environments. It is of particular interest at the flanks of Earth’s magnetopause, which separates the plasma of the magnetosphere from the adjacent shocked solar wind flow in the magnetosheath. In the present study, we use local hybrid-Vlasov simulations to investigate the ion velocity distribution functions (VDFs) associated with KHI in a magnetopause-like, transverse velocity shear layer setting (magnetic field perpendicular to the shear plane). We look for signatures of ion finite Larmor radius (FLR) effects, which could be utilized in spacecraft measurements to recognize when such effects are active, influencing KHI evolution and driving plasma mixing. We show that when a density/temperature asymmetry exists across the shear layer, FLR effects produce a heat flux along the vortex edges. With a magnitude (≳0.1 mW m−2) that is a significant fraction of the total magnetosheath energy flux, the heat flux provides a distinct signature that could be measured with a single spacecraft. During the late nonlinear stage of KHI, mixed non-Maxwellian ion VDFs are additionally found within the vortices. Our results are also valid in the presence of a small magnetic shear across the magnetopause.

Stability Conditions and Stiffness Variability of General Tensegrity Systems with Kinematic Joints

Abstract Tensegrity systems represent promising candidate mechanisms with in-situ stiffness variability through changing the cables' prestress levels. However, prestress-based stiffness behaviors of tensegrity systems with arbitrary kinematic joints have not been analyzed systematically. This paper adopts the natural absolute coordinates for static modeling of tensegrity systems consisting of rigid members and tension elements. Then, a generic stiffness analysis method is developed to formulate the reduced-basis tangent stiffness matrix, which is found to include three parts: positive semi-definite material and geometric stiffness matrices, and an indefinite constraint stiffness matrix. Based on these findings, a systematic stability-checking procedure is derived to determine prestress and super stability, which are qualitative indicators of the softening and stiffening effects in different tensegrity systems. Then, we proceed to quantify the range of prestress-based stiffness variability by formulating semidefinite programming problems that numerically pinpoint the maximum and zero stiffness points. Furthermore, this paper reveals the composable nature of multiple self-stress states, enabling the composability of stiffness properties in mechanism designs. Several numerical examples verify the efficacy and versatility of the proposed method and demonstrate interesting stiffness behaviors of tensegrity systems with kinematic joints.

Pre- and Postsynaptic MEF2C Promotes Experience-Dependent, Input-Specific Development of Cortical Layer 4 to Layer 2/3 Excitatory Synapses and Regulates Activity-Dependent Expression of Synaptic Cell Adhesion Molecules.

Experience- and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here, we demonstrate that the activity-dependent transcription factor myocyte enhancer factor 2C (MEF2C) is required in both presynaptic layer (L) 4 and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or the ipsilateral frontal/motor cortex. Similarly, homozygous or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function, and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory-deprived mice. Together, these results suggest that experience- and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. Additionally, MEF2C regulates the expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits.

Nonthermal Observations of a Flare Loop-top Using IRIS Fe xxi: Implications for Turbulence and Electron Acceleration

The excess broadening of high-temperature spectral lines, long observed near the tops of flare arcades, is widely considered to result from magnetohydrodynamic turbulence. According to different theories, plasma turbulence is also believed to be a candidate mechanism for particle acceleration during solar flares. However, the degree to which this broadening is connected to the acceleration of nonthermal electrons remains largely unexplored outside of recent work, and many observations have been limited by limited spatial resolution and cadence. Using the Interface Region Imaging Spectrometer, we present spatially resolved observations of loop-top (LT) broadenings using hot (≈11 MK) Fe xxi 1354.1 Å line emission at ≈9 s cadence during the 2022 March 30 X1.3 flare. We find nonthermal velocities upward of 65 km s−1 that decay linearly with time, indicating the presence and subsequent dissipation of plasma turbulence. Moreover, the initial Fe xxi signal was found to be cospatial and cotemporal with microwave emission measured by the Expanded Owens Valley Solar Array, placing a population of nonthermal electrons in the same region as the LT turbulence. Evidence of electron acceleration at this time is further supported by hard X-ray measurements from the Spectrometer/Telescope for Imaging X-rays on board Solar Orbiter. Using the decay of nonthermal broadenings as a proxy for turbulent dissipation, we found the rate of energy dissipation to be consistent with the power of nonthermal electrons deposited into the chromosphere, suggesting a possible connection between turbulence and electron acceleration.

Opening the Black Box: The Underlying Working Mechanisms in Virtual-Reality Exposure Therapy for Anxiety Disorders

Although research on virtual-reality (VR) exposure therapy (VRET) in anxiety disorders has primarily focused on effectiveness and acceptability, the underlying working mechanisms have received scant attention. To fill this knowledge gap, we discuss potential theoretical underpinnings of VRET based on three dominant theoretical accounts on exposure: inhibitory-learning theory (expectancy violation), emotional-processing theory (habituation), and self-efficacy theory. Whereas theoretically speaking, habituation and self-efficacy seem plausible candidate mechanisms to explain the effects of VRET, the role of expectancy violation is less straightforward. Because of the simulated nature of VR, some feared outcomes cannot occur, and therefore, possibilities to violate expectancies about their occurrence may be compromised. Empirical evidence on the working mechanisms of VRET is scarce and has important limitations. Avenues for future research are provided. Insights into the mechanisms of VRET not only are of theoretical importance but also can provide theory-based directions to optimize the application of VRET.

Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1

In glioblastoma (GB) cells oxidative stress is induced by both, conditions of the tumor microenvironment as well as by therapeutic interventions. Upregulation of superoxide dismutase 1 (SOD1), a key enzyme for oxidative defense and downstream target of mammalian target of rapamycin complex 1 (mTORC1) is a candidate mechanism to sustain survival and proliferation of tumor cells. SOD1 was inhibited by shRNA mediated gene suppression, CRISPR/Cas9 knockout and pharmacological inhibition in human (primary) GB cells. SOD1 activity was determined by SOD1/2 activity assay. ROS levels, cell death and the NADPH/NADP-ratio were measured under normal and starvation conditions. To study the mTORC1-SOD1 axis, mTORC1 activated TSC2 knockdown cells (TSC2sh) were analyzed. Genetic and pharmacological inhibition of SOD1 correlated with decreased SOD1 activity, increased ROS and enhanced the sensitivity of glioma cells towards starvation- and hypoxia-induced cell death. This was accompanied by a decreased NADPH/NADP-ratio. Furthermore, combination therapy of SOD1 and mTORC1 inhibition partially rescued the protective effect of mTORC1 inhibitor monotherapy. SOD1 mediates adaptation of GB cells to stress conditions in the tumor microenvironment in a mTORC1-dependent manner. Moreover, SOD1 activation contributes to the cell death resistance conferred by mTORC1 inhibitors under hypoxic conditions.

Pramipexole Hyperactivates the External Globus Pallidus and Impairs Decision-Making in a Mouse Model of Parkinson's Disease.

In patients with Parkinson's disease (PD), dopamine replacement therapy with dopamine D2/D3 receptor agonists induces impairments in decision-making, including pathological gambling. The neurobiological mechanisms underlying these adverse effects remain elusive. Here, in a mouse model of PD, we investigated the effects of the dopamine D3 receptor (D3R)-preferring agonist pramipexole (PPX) on decision-making. PD model mice were generated using a bilateral injection of the toxin 6-hydroxydopamine into the dorsolateral striatum. Subsequent treatment with PPX increased disadvantageous choices characterized by a high-risk/high-reward in the touchscreen-based Iowa Gambling Task. This effect was blocked by treatment with the selective D3R antagonist PG-01037. In model mice treated with PPX, the number of c-Fos-positive cells was increased in the external globus pallidus (GPe), indicating dysregulation of the indirect pathway in the corticothalamic-basal ganglia circuitry. In accordance, chemogenetic inhibition of the GPe restored normal c-Fos activation and rescued PPX-induced disadvantageous choices. These findings demonstrate that the hyperactivation of GPe neurons in the indirect pathway impairs decision-making in PD model mice. The results provide a candidate mechanism and therapeutic target for pathological gambling observed during D2/D3 receptor pharmacotherapy in PD patients.

Attentional dynamics of evidence accumulation explain why more numerate people make better decisions under risk

In decisions under risk, more numerate people are typically more likely to choose the option with the highest expected value (EV) than less numerate ones. Prior research indicates that this finding cannot be explained by differences in the reliance on explicit EV calculation. The current work uses the attentional Drift Diffusion Model as a unified computational framework to formalize three candidate mechanisms of pre-decisional information search and processing—namely, attention allocation, amount of deliberation, and distorted processing of value—which may differ between more and less numerate people and explain differences in decision quality. Computational modeling of an eye-tracking experiment on risky choice demonstrates that numeracy is linked to how people allocate their attention across the options, how much evidence they require before committing to a choice, and also how strongly they distort currently non-attended information during preference formation. Together, especially the latter two mechanisms largely mediate the effect of numeracy on decision quality. Overall, the current work disentangles and quantifies latent aspects of the dynamics of preference formation, explicates how their interplay may give rise to manifest differences in decision quality, and thereby provides a fully formalized, mechanistic explanation for the link between numeracy and decision quality in risky choice.

Impact of cognitive behavioural therapy on neural, inflammatory, & autonomic markers in a sample with PTSD and cardiovascular risk: protocol for a pilot randomised controlled trial

ABSTRACT Background: Individuals with posttraumatic stress disorder (PTSD) are at heightened risk for cardiovascular disease (CVD) compared to the general population. Inflammation and autonomic dysfunction are candidate mechanisms of CVD risk in PTSD; however, these mechanisms have not been well-characterised in the PTSD-CVD link. Further, these mechanisms may operate through altered stress-related neural activity (SNA). Yet, it remains unknown if changes in PTSD are associated with changes in CVD risk mechanisms. Objective: This manuscript describes the design and procedures of a pilot randomised controlled trial to assess the impact of a first-line treatment for PTSD (Cognitive Processing Therapy; CPT) versus waitlist control on mechanisms of CVD risk. Further, this study will test the hypothesis that CPT reduces CVD risk through its effects on inflammation and autonomic function and that these changes are driven by changes in SNA. Methods: Adults with PTSD and CVD risk (N = 30) will be randomised to CPT or waitlist control. Participants complete two laboratory visits (baseline and post-treatment) that include surveys, brain and peripheral imaging via 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), and resting measures of autonomic function. Primary outcomes include arterial inflammation and heart rate variability. Secondary outcomes include leukopoiesis (bone marrow uptake), heart rate, and blood pressure. The indirect effects of PTSD treatment on changes in inflammation and autonomic function through SNA will also be examined. Conclusions: This study seeks to characterise candidate neuroimmune mechanisms of the PTSD-CVD link to identify treatment targets and develop personalised interventions to reduce CVD events in PTSD populations. Trial registration: ClinicalTrials.gov identifier: NCT06429293..

Achieving Occam's razor: Deep learning for optimal model reduction.

All fields of science depend on mathematical models. Occam's razor refers to the principle that good models should exclude parameters beyond those minimally required to describe the systems they represent. This is because redundancy can lead to incorrect estimates of model parameters from data, and thus inaccurate or ambiguous conclusions. Here, we show how deep learning can be powerfully leveraged to apply Occam's razor to model parameters. Our method, FixFit, uses a feedforward deep neural network with a bottleneck layer to characterize and predict the behavior of a given model from its input parameters. FixFit has three major benefits. First, it provides a metric to quantify the original model's degree of complexity. Second, it allows for the unique fitting of data. Third, it provides an unbiased way to discriminate between experimental hypotheses that add value versus those that do not. In three use cases, we demonstrate the broad applicability of this method across scientific domains. To validate the method using a known system, we apply FixFit to recover known composite parameters for the Kepler orbit model and a dynamic model of blood glucose regulation. In the latter, we demonstrate the ability to fit the latent parameters to real data. To illustrate how the method can be applied to less well-established fields, we use it to identify parameters for a multi-scale brain model and reduce the search space for viable candidate mechanisms.

Early 2-Factor Transcription Factors Associated with Progression and Recurrence in Bevacizumab-Responsive Subtypes of Glioblastoma.

The early 2-factor (E2F) family of transcription factors, including E2F1 through 8, plays a critical role in apoptosis, metabolism, proliferation, and angiogenesis within glioblastoma (GBM). However, the specific functions of E2F transcription factors (E2Fs) and their impact on the malignancy of Bevacizumab (BVZ)-responsive GBM subtypes remain unclear. This study used data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI), and Gene Expression Omnibus (GEO) to explore the impact of eight E2F family members on the clinical characteristics of BVZ-responsive GBM subtypes and possible mechanisms of recurrence after BVZ treatment. Using machine learning algorithms, including TreeBagger and deep neural networks, we systematically predicted and validated GBM patient survival terms based on the expression profiles of E2Fs across BVZ-responsive GBM subtypes. Our bioinformatics analyses suggested that a significant increase in E2F8 post-BVZ treatment may enhance the function of angiogenesis and stem cell proliferation, implicating this factor as a candidate mechanism of GBM recurrence after treatment. In addition, BVZ treatment in unresponsive GBM patients may potentially worsen disease progression. These insights underscore that E2F family members play important roles in GBM malignancy and BVZ treatment response, highlighting their potential as prognostic biomarkers, therapeutic targets, and recommending precision BVZ treatment to individual GBM patients.

Androgen effects on mesoprefrontal dopamine systems in the adult male brain

Epidemiological data show that males are more often and/or more severely affected by symptoms of prefrontal cortical dysfunction in schizophrenia, Parkinson’s disease and other disorders in which dopamine circuits associated with the prefrontal cortex are dysregulated. This review focuses on research showing that these dopamine circuits are powerfully regulated by androgens. It begins with a brief overview of the sex differences that distinguish prefrontal function in health and prefrontal dysfunction or decline in aging and/or neuropsychiatric disease. This review article then spotlights data from human subjects and animal models that specifically identify androgens as potent modulators of prefrontal cortical operations and of closely related, functionally critical measures of prefrontal dopamine level or tone. Candidate mechanisms by which androgens dynamically control mesoprefrontal dopamine systems and impact prefrontal states of hypo- and hyper-dopaminergia in aging and disease are then considered. This is followed by discussion of a working model that identifies a key locus for androgen modulation of mesoprefrontal dopamine systems as residing within the prefrontal cortex itself. The last sections of this review critically consider the ways in which the organization and regulation of mesoprefrontal dopamine circuits differ in the adult male and female brain, and highlights gaps where more research is needed.

Social episodic memory in severe alcohol use disorder: Positive encoding bias and negative bias in accessibility of interpersonal information.

Alterations in higher-order social cognition are well documented in individuals with severe alcohol use disorder (SAUD). However, the basic mechanisms underpinning them are not well understood. This knowledge gap hampers the development of targeted therapeutic interventions. Here, we investigated whether individuals with SAUD show abnormalities in social episodic memory processes, which may represent relevant candidate mechanisms for alterations in social cognition. Recently detoxified patients with SAUD and matched healthy controls (HCs) completed two experimental tasks. We first used a Social Recognition Task in 40 SAUD patients and 40 HCs to measure the participants' ability to implicitly memorize the facial identity and emotion of novel interpersonal cues (i.e., dynamic facial expressions of anger and happiness). We then used a Social Memory Accessibility Task in 29 SAUD patients and 30 HCs) to measure participants' access to and fluency for already existing social memories by asking them to retrieve as many specific positive and negative interpersonal events as possible within equal time limits. In the Social Recognition Task, we found that, compared to HCs, patients with SAUD had a globally lower recognition performance for the facial identities of novel social stimuli, but a preserved bias toward positive information. Conversely, in the social memory accessibility task, patients showed greater access to and fluency for negative interpersonal memories than controls (no group differences were observed for positive ones), resulting in a negative accessibility bias. This exploration of episodic social memory in individuals with SAUD showed (1) a preserved bias for the encoding of positive versus negative novel social information, and (2) greater access to negative than positive interpersonal memories. These results enhance our understanding of socio-affective processing in individuals with SAUD and identify social memory alterations that may contribute to social cognition and interpersonal difficulties.

Female‐biased population sex ratios caused by genetic rather than ecological mechanisms in dwarf willow (Salix herbacea L.)

Abstract Biased sex ratios among reproductive individuals are common in plants, but the underlying mechanisms, as well as the evolutionary consequences, are not well understood. The classical theory of Düsing and Fisher predicts an equal primary sex ratio at seed production, based on the selective advantage of the rare sex. Biased sex ratios among reproductive plants can arise from sexual dimorphism in survival and flowering. Sex ratio biases can also be present from the seed stage; in these cases, assumptions of Düsing's and Fisher's theory, for example, random mating or demographic equilibrium, are thought to be violated. We investigated mechanisms leading to female‐biased sex ratios in the arctic‐alpine dwarf willow Salix herbacea L. We studied sex ratios in three natural populations over 3 years as well as in 29 crosses (full‐sib families) under controlled conditions over four growth periods. We tested whether sex ratio was associated with habitat parameters (elevation and snowmelt time), or with germination, survival or flowering, and whether females and males differed in size or flowering that may cause observation bias. We detected a strong and consistent female bias, both in natural populations (sex ratio [proportion of females]: 0.71–0.82) and in our controlled experiment (overall sex ratio: 0.70–0‐72). Female bias became more pronounced with increasing elevation. Our data did not support sexual dimorphism in size or flowering. Family sex ratios varied largely (from 0.25 to 1), including many female‐biased families, unbiased families and two male‐biased families. Families with lower germination, seedling establishment, survival or flowering did not have stronger female bias, indicating that intrinsically higher survival or flowering in females does not explain overall female bias. Synthesis. Our results suggest that sex ratio bias in S. herbacea is already present in seeds and does not arise through intrinsic differences between sexes. Candidate mechanisms that can lead to both overall female bias and variation in sex ratio among families are meiotic drive or cyto‐nuclear interactions. The pioneer habit of Salix may lead to non‐equilibrium population dynamics that allow for the long‐term persistence of variable genetic sex ratio distortion systems that arise from genetic conflict.

211-OR: Massively Parallel Characterization of Thousands of Type 2 Diabetes–Associated Variants in Multiple Cell Types Nominates Candidate Causal Regulatory Alleles and Mechanisms

211-OR: Massively Parallel Characterization of Thousands of Type 2 Diabetes–Associated Variants in Multiple Cell Types Nominates Candidate Causal Regulatory Alleles and Mechanisms