Mindfulness meditation training alters stress-related amygdala resting state functional connectivity: a randomized controlled trial

Recent studies indicate that mindfulness meditation training interventions reduce stress and improve stress-related health outcomes, but the neural pathways for these effects are unknown. The present research evaluates whether mindfulness meditation training alters resting state functional connectivity (rsFC) of the amygdala, a region known to coordinate stress processing and physiological stress responses. We show in an initial discovery study that higher perceived stress over the past month is associated with greater bilateral amygdala-subgenual anterior cingulate cortex (sgACC) rsFC in a sample of community adults (n = 130). A follow-up, single-blind randomized controlled trial shows that a 3-day intensive mindfulness meditation training intervention (relative to a well-matched 3-day relaxation training intervention without a mindfulness component) reduced right amygdala-sgACC rsFC in a sample of stressed unemployed community adults (n = 35). Although stress may increase amygdala-sgACC rsFC, brief training in mindfulness meditation could reverse these effects. This work provides an initial indication that mindfulness meditation training promotes functional neuroplastic changes, suggesting an amygdala-sgACC pathway for stress reduction effects.     

Neural responses to maternal criticism in healthy youth

Parental criticism can have positive and negative effects on children’s and adolescents’ behavior; yet, it is unclear how youth react to, understand and process parental criticism. We proposed that youth would engage three sets of neural processes in response to parental criticism including the following: (i) activating emotional reactions, (ii) regulating those reactions and (iii) social cognitive processing (e.g. understanding the parent’s mental state). To examine neural processes associated with both emotional and social processing of parental criticism in personally relevant and ecologically valid social contexts, typically developing youth were scanned while they listened to their mother providing critical, praising and neutral statements. In response to maternal criticism, youth showed increased brain activity in affective networks (e.g. subcortical–limbic regions including lentiform nucleus and posterior insula), but decreased activity in cognitive control networks (e.g. dorsolateral prefrontal cortex and caudal anterior cingulate cortex) and social cognitive networks (e.g. temporoparietal junction and posterior cingulate cortex/precuneus). These results suggest that youth may respond to maternal criticism with increased emotional reactivity but decreased cognitive control and social cognitive processing. A better understanding of children’s responses to parental criticism may provide insights into the ways that parental feedback can be modified to be more helpful to behavior and development in youth.     

Neural changes with attention bias modification for anxiety: a randomized trial

Attention bias modification (ABM) procedures typically reduce anxiety symptoms, yet little is known about the neural changes associated with this behavioral treatment. Healthy adults with high social anxiety symptoms (n = 53) were randomized to receive either active or placebo ABM. Unlike placebo ABM, active ABM aimed to train individuals’ attention away from threat. Using the dot-probe task, threat-related attention bias was measured during magnetic resonance imaging before and after acute and extended training over 4 weeks. A subset of participants completed all procedures (n = 30, 15 per group). Group differences in neural activation were identified using standard analyses. Linear regression tested predictive factors of symptom reduction (i.e., training group, baseline indices of threat bias). The active and placebo groups exhibited different patterns of right and left amygdala activation with training. Across all participants irrespective of group, individuals with greater left amygdala activation in the threat-bias contrast prior to training exhibited greater symptom reduction. After accounting for baseline amygdala activation, greater symptom reduction was associated with assignment to the active training group. Greater left amygdala activation at baseline predicted reductions in social anxiety symptoms following ABM. Further research is needed to clarify brain-behavior mechanisms associated with ABM training.     

A neural correlate of visceral emotional responses: evidence from fMRI of the thoracic spinal cord

Functional magnetic resonance imaging (fMRI) of thoracic spinal cord neurons was used to examine the neural correlates of visceral emotional responses. Participants completed four spinal fMRI runs involving passive viewing (i.e. no movement) and motoric responses to negative or neutral images. Negative images, particularly in the movement condition, elicited robust activity in motoric nuclei, indicating ‘action preparedness’. These images also enhanced activity in autonomic and sensory nuclei, thus providing a clear neural representation of visceral responses to emotional stimuli.     

Adaptive differentiation and rapid evolution of a soil bacterium along a climate gradient

Microbial community responses to environmental change are largely associated with ecological processes; however, the potential for microbes to rapidly evolve and adapt remains relatively unexplored in natural environments. To assess how ecological and evolutionary processes simultaneously alter the genetic diversity of a microbiome, we conducted two concurrent experiments in the leaf litter layer of soil over 18 mo across a climate gradient in Southern California. In the first experiment, we reciprocally transplanted microbial communities from five sites to test whether ecological shifts in ecotypes of the abundant bacterium, Curtobacterium, corresponded to past adaptive differentiation. In the transplanted communities, ecotypes converged toward that of the native communities growing on a common litter substrate. Moreover, these shifts were correlated with community-weighted mean trait values of the Curtobacterium ecotypes, indicating that some of the trait variation among ecotypes could be explained by local adaptation to climate conditions. In the second experiment, we transplanted an isogenic Curtobacterium strain and tracked genomic mutations associated with the sites across the same climate gradient. Using a combination of genomic and metagenomic approaches, we identified a variety of nonrandom, parallel mutations associated with transplantation, including mutations in genes related to nutrient acquisition, stress response, and exopolysaccharide production. Together, the field experiments demonstrate how both demographic shifts of previously adapted ecotypes and contemporary evolution can alter the diversity of a soil microbiome on the same timescale.

Microbial communities respond quickly to environmental change (1, 2). These responses are typically associated with ecological processes; however, the potential for microbes to evolve and adapt to changes in the environment on ecological timescales remains largely unexplored in natural ecosystems. While evolutionary processes are typically considered over longer timescales, the short generation times, large populations, and high mutation rates indicative of microorganisms may allow for rapid adaptation. Laboratory studies have repeatedly demonstrated rapid evolution of bacterial populations (3) with consequences for organismal physiology (4), yet it remains unclear how these in vitro studies extend to in situ communities (5).Both ecological and evolutionary processes likely contribute simultaneously (6, 7) to the response of a microbiome to changing environmental conditions (8). However, separating these processes for bacteria can be difficult as they occur along a continuum of temporal and genetic scales. In terms of ecological processes, microbiome composition can respond demographically, as selective forces promote the growth and survival of differentially adapted taxa within the bacterial community. Certainly, many studies have observed such shifts in taxonomic composition of 16S ribosomal RNA (rRNA)–defined taxa in response to simulated global changes (9), and these responses are considered an ecological process (e.g., species sorting). Few examples, however, link these responses to trait differences among bacterial taxa (10–13), precluding direct insights into whether these ecological shifts are due to adaptive differentiation among taxa as a result of past evolutionary divergence. Concurrently, the same selective forces can also shift the abundance of conspecific strains and alter the allele frequencies of preexisting genetic variation, which at this genetic scale is defined as an evolutionary process (14). Finally, evolution through de novo mutation can provide a new source of genetic variation that may allow for further adaptation to environmental change.In this study, we aimed to capture this continuum of ecological and evolutionary processes that together produce the response of a microbiome’s diversity to environmental change (Fig. 1A). Studying evolution in microbial communities in situ, however, is challenging. For one, variation in highly conserved marker genes used in many microbiome studies (e.g., 16S rRNA) represents distant evolutionary divergences, and thus these regions are too conserved to detect locally adapted lineages (11, 12, 15), let alone recent evolutionary change within communities (16). To overcome this limitation, studies have leveraged shotgun metagenomic data (17, 18) and genome sequences of co-occurring, closely related strains (19, 20) to characterize evolutionary processes (e.g., recombination and gene flow) structuring the genetic diversity of bacterial lineages. However, these studies are also limited by an inherent challenge in microbiome research: delineating population boundaries, the fundamental unit of evolution. While progress has been made in defining microbial species (21–23), the high genetic heterogeneity within diverse microbial communities, such as soils, convolute the boundaries of the fine-scale patterns of genetic diversity within microbial taxonomic units (12). For instance, metagenome-assembled genomes are often composed of a composite of strains forming a large population of mosaic genomes (24) that may not fully capture the diversity of the local population (25). As such, it remains difficult to study evolutionary rates within microbial communities (however, see refs. 26, 27), and the extent and time scale at which evolutionary processes contribute to both standing and new genetic variation relative to ecological processes.Open in a separate windowFig. 1.Microbial community transplant experiment. (A) Changes in microbial community composition can be due to a continuum of ecological and evolutionary processes. For instance, shifts in standing genetic variation can be attributed to both ecological and evolutionary processes depending on the level of biological resolution, while de novo mutations can be a result from evolutionary adaptation. (B) A schematic of the two parallel transplant experiments at the community and strain level. Inoculated litterbags were transplanted to all sites along an elevation gradient that covaried in temperature and precipitation. Site codes: D=Desert; Sc=Scrubland; G=Grassland; P=Pine-Oak; S=Subalpine.Here, we asked the following question: can we characterize the ecological and evolutionary processes that are contributing concurrently to the response of a soil bacterial community to a changing environment? To answer this question, we utilized a field-based experimental approach to quantify the influence of both ecological and evolutionary processes on one focal soil bacterium in its natural environment, the genus Curtobacterium (28). Specifically, we transplanted the bacterium across an elevation gradient on a common resource (leaf litter) substrate (29) to assess its response to new climates in two parallel experiments over the same 18 mo time period (Fig. 1B). In both experiments, we used microbial cages [nylon mesh bags that allow for nutrient transport (30)] to manipulate microbial composition while restricting microbial migration to eliminate the introduction of new alleles and/or variants from dispersal (31). A reciprocal transplant design allowed for direct testing of microbial adaptation to abiotic conditions (i.e., moisture and temperature) in a natural setting.In the first experiment, we conducted a reciprocal transplant of the entire microbial community (32) and tracked the ecological response of Curtobacterium ecotypes (33). A bacterial ecotype is defined as highly clustered genotypic and phenotypic strains occupying the same ecological niche, somewhat equivalent to a eukaryotic species (34). To test the hypothesis that Curtobacterium ecotypes are locally adapted to their climate conditions, we assessed the convergence of ecotype composition in the transplanted communities to that of control communities (those that remained in their native environment; Fig. 1B). We further hypothesized that the demographic shifts were due to differential adaptation to local climates as a result of trait variation among the ecotypes. Thus, we expected that the climate gradient would select for a strong trait–environment relationship (assessed by community-weighted mean (CWM) trait values) as typically observed in plant communities (35, 36).In parallel, we conducted an in situ evolution experiment by transplanting an isogenic Curtobacterium strain across the same gradient to investigate the potential for rapid evolution on the same timescales. We hypothesized that a variety of genomic mutations would be associated with adaptation to local climate conditions. Therefore, we expected fewer genetic changes when the strain was transplanted to its original environment, the midelevation Grassland site, while the extreme sites of the gradient would impose stronger selective pressures resulting in greater genetic changes. We further expected to observe parallel mutations among replicates within a site, which would be indicative of adaptive events (37). Variation in such mutations across sites would suggest selection differences across the climate gradient. Together, the two experiments capture the simultaneous effects of both ecological and evolutionary processes on the response of a soil bacterium to new climates in the field.     

TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region

Treacher Collins Syndrome (TCS) is the most common of the human mandibulofacial dysostosis disorders. Recently, a partial TCOF1 cDNA was identified and shown to contain mutations in TCS families. Here we present the entire exon/intron genomic structure and the complete coding sequence of TCOF1. TCOF1 encodes a low complexity protein of 1,411 amino acids, whose predicted protein structure reveals repeated motifs that mirror the organization of its exons. These motifs are shared with nucleolar trafficking proteins in other species and are predicted to be highly phosphorylated by casein kinase. Consistent with this, the full-length TCOF1 protein sequence also contains putative nuclear and nucleolar localization signals. Throughout the open reading frame, we detected an additional eight mutations in TCS families and several polymorphisms. We postulate that TCS results from defects in a nucleolar trafficking protein that is critically required during human craniofacial development.     

Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ

The application of allogeneic stem cell transplantation (alloSCT) is limited by graft-versus-host disease (GVHD). GVHD can be divided into acute and chronic forms that likely have different requirements for initiation and pathogenesis mechanisms. In prior studies we demonstrated that residual host antigen-presenting cells (APCs) were required to initiate acute GVHD (aGVHD) mediated by CD8 T cells. In contrast, here we demonstrate that either donor or host APCs can initiate CD4-mediated GVHD in a model that has features of chronic GVHD (cGVHD). Both donor and host APCs must provide CD80/86-dependent costimulation to elicit maximal cGVHD, and there is no GVHD when both donor and host lack CD80/86. Finally, we were surprised to find that, although either donor or host APCs are sufficient to stimulate skin cGVHD, donor APCs play a dominant role in intestinal cGVHD. Both CD40 and CD80/86 are critical for donor APC function in intestinal cGVHD, but only CD80/86 is required for skin cGVHD. Thus, there are target-tissue-specific differences in APC requirements. These results identify differences in APC requirements between CD8-mediated aGVHD and CD4-mediated cGVHD. They further highlight donor APCs as additional targets for GVHD therapy.     

Chronic HIV-2 infection protects against total CD4+ cell depletion and rapid disease progression induced by SHIV89.6p challenge

OBJECTIVE: To better understand HIV-1 sexual transmission risk, we have studied the susceptibility of HIV-2-exposed, uninfected (EU) female pig-tailed macaques to intravaginal (IVAG) re-challenge with the homologous HIV-2 strain, followed by heterologous SHIV89.6p. METHODS: Nine female macaques, previously protected by a post-exposure prophylaxis (PEP) regimen, along with one mock-treated EU animal, were re-exposed to HIV-2 by the IVAG route approximately 1.5 years later. A single follow-up challenge was performed approximately 1 year later with SHIV89.6p to assess susceptibility of chronic HIV-2-infected animals to further re-infection and pathogenic effects with a heterologous virus, somewhat mimicking HIV-1. RESULTS: Eight of ten macaques (80%) became infected systemically with HIV-2, and plasma or cervicovaginal vRNA levels did not appreciably differ from prior historic non-PEP control macaques. Interestingly, all eight HIV-2-infected females were susceptible to SHIV89.6p infection by either intravenous (n = 4) or IVAG exposure (n = 4) after one inoculation. Plasma vRNA levels in these groups were controlled by week 8 and there were no decrease in CD4+ T cells > 50%. The remaining two HIV-2 EU macaques, inoculated intrarectally with SHIV89.6p, were unable to control virus replication and succumbed to disease by week 25 or week 61. CONCLUSIONS: Our findings demonstrate that successful PEP regimens to prevent an initial infection do not have any lasting protective effects. The observed lack of cross-protection against SHIV89.6p transmission among chronic HIV-2-infected macaques provides modeling support for limited epidemiologic data indicating that human HIV-2 infection does not protect against HIV-1 infection, but may serve to alter overt clinical outcome.