Abstract Background Mindfulness meditation training interventions have been shown to improve markers of health, but the underlying neurobiological mechanisms are not known. Building on initial ...cross-sectional research showing that mindfulness meditation may increase default mode network (DMN) resting state functional connectivity (rsFC) with regions important in top-down executive control (dorsolateral prefrontal cortex, dlPFC), here we test whether mindfulness meditation training increases DMN-dlPFC rsFC, and whether these rsFC alterations prospectively explain improvements in interleukin-6 (IL-6) in a randomized controlled trial. Method Stressed job-seeking unemployed community adults (N=35) were randomized to either a 3-day intensive residential mindfulness meditation or relaxation training program. Participants completed a five-minute resting state scan before and after the intervention program. Participants also provided blood samples at pre-intervention and at 4-month follow-up, which were assayed for circulating IL-6, a biomarker of systemic inflammation. Results We tested for alterations in DMN rsFC using a posterior cingulate cortex (PCC) seed-based analysis, and found that mindfulness meditation training, and not relaxation training, increased PCC rsFC with left dlPFC ( p <.05, corrected). These pre-post training alterations in PCC-dlPFC rsFC statistically mediated mindfulness meditation training improvements in IL-6 at 4-month follow-up. Specifically, these alterations in rsFC statistically explained 30% of the overall mindfulness meditation training effects on IL-6 at follow-up. Conclusions These findings provide the first evidence that mindfulness meditation training functionally couples the DMN with a region known to be important in top-down executive control at rest (left dlPFC), which in turn is associated with improvements in a marker of inflammatory disease risk. Trial Registration The RCT is registered on clinicaltrials.gov (#NCT01628809)
Mindfulness interventions have garnered significant attention as a complementary health treatment for many physical and psychological conditions. While some research has shown that mindfulness ...training can decrease psychological and physiological stress responses, it remains unclear whether mindfulness training impacts inflammation-a predictor of poor health outcomes. In addition, little research has examined the active components of mindfulness that may drive health-related improvements. Here, we provide data from two 3-arm randomized controlled trials that examined the effect of mindfulness training on inflammation in stressed community adults. Specifically, we examined whether training individuals to have an accepting attitude towards present moment experiences is a key emotion regulation skill that can lead to decreases in inflammation. Both studies randomly assigned participants to one of three conditions: mindfulness training that taught both attention monitoring and acceptance skills (Monitor+Accept); mindfulness training teaching monitoring without the acceptance component (Monitor Only); or a control condition. Study 1 employed a novel 2-week smartphone-based intervention and Study 2 employed a standard 8-week Mindfulness-Based Stress Reduction (MBSR) intervention. We hypothesized that Monitor+Accept training would lead to reductions in the inflammatory biomarker C-Reactive Protein (CRP) compared to Monitor Only training and control groups. Contrary to this hypothesis, we found that Monitor+Accept mindfulness training did not lead to reductions in CRP. Exploratory analyses combining study subsamples, however, suggest that both mindfulness interventions may reduce CRP in populations at risk for systemic inflammation-midlife-to-older adults and individuals with high BMI. Overall, the present studies contribute significantly to the question of whether mindfulness interventions can reduce systemic markers of low-grade inflammation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Monotremes (echidna and platypus) are egg-laying mammals. One of their most unique characteristic is that males have venom/crural glands that are seasonally active. Male platypuses produce venom ...during the breeding season, delivered via spurs, to aid in competition against other males. Echidnas are not able to erect their spurs, but a milky secretion is produced by the gland during the breeding season. The function and molecular composition of echidna venom is as yet unknown. Hence, we compared the deeply sequenced transcriptome of an in-season echidna crural gland to that of a platypus and searched for putative venom genes to provide clues into the function of echidna venom and the evolutionary history of monotreme venom. We found that the echidna venom gland transcriptome was markedly different from the platypus with no correlation between the top 50 most highly expressed genes. Four peptides found in the venom of the platypus were detected in the echidna transcriptome. However, these genes were not highly expressed in echidna, suggesting that they are the remnants of the evolutionary history of the ancestral venom gland. Gene ontology terms associated with the top 100 most highly expressed genes in echidna, showed functional terms associated with steroidal and fatty acid production, suggesting that echidna "venom" may play a role in scent communication during the breeding season. The loss of the ability to erect the spur and other unknown evolutionary forces acting in the echidna lineage resulted in the gradual decay of venom components and the evolution of a new role for the crural gland.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Individuals chronically infected with HIV-1 harbor complex viral populations within their bloodstreams. Recently, it has come to light that when these people infect others, the new infection is ...typically established by only one or a small number of virions from within this complex viral swarm. An important goal is to characterize the biological properties of HIV-1 virions that seed and exist early in new human infections because these are potentially the only viruses against which a prophylactic HIV-1 vaccine would need to elicit protection. This includes understanding how the Envelope (Env) protein of these virions interacts with the T-cell receptor CD4, which supports attachment and entry of HIV-1 into target cells. We examined early HIV-1 isolates for their ability to infect cells via the CD4 receptor of 15 different primate species. Primates were the original source of HIV-1 and now serve as valuable animal models for studying HIV-1. We find that most primary isolates of HIV-1 from the blood, including early isolates, are highly selective and enter cells through some primate CD4 receptor orthologs but not others. This phenotype is remarkably consistent, regardless of route of transmission, viral subtype, or time of isolation post infection. We show that the weak CD4 binding affinity of blood-derived HIV-1 isolates is what makes them sensitive to the small sequence differences in CD4 from one primate species to the next. To substantiate this, we engineered an early HIV-1 Env to have high, medium, or low binding affinity to CD4, and we show that it loses the ability to enter cells via the CD4 receptor of many primate species as the binding affinity gets weaker. Based on the phenotype of selective use of primate CD4, we find that weak CD4 binding appears to be a nearly universal property of HIV-1 circulating in the bloodstream. Therefore, weak binding to CD4 must be a selected and important property in the biology of HIV-1 in the body. We identify six primate species that encode CD4 receptors that fully support the entry of early HIV-1 isolates despite their low binding affinity for CD4. These findings will help inform long-standing efforts to model HIV-1 transmission and early disease in primates.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Splenosis is a benign condition caused by implant of splenic tissue after trauma or surgery. It is usually an incidental finding, but may be commonly confused as metastatic cancer on abdominal ...imaging. This is a case of a 48-year-old female with a history of splenectomy after a motor vehicle accident 40 years ago, who presented to the hospital with a 1 week history of epigastric pain, diarrhea, and a 10 pound weight loss. Physical examination revealed epigastric tenderness. Laboratory tests were normal and stool studies negative. CT scan confirmed a 3.3 x 3.0 x 2.9 cm intrapancreatic tail mass, 2 small masses in the left upper quadrant adjacent to the colon and between the stomach and colon, a 4.3 x 3.3 x 4.8 cm extrinsic mass in the midline right upper quadrant anteriorly adjacent to the left hepatic lobe with mass effect on the liver, 3 small low-attenuation lesions within the liver, 4.6 cm peripherally calcified uterine mass, and 4 cm right adnexal mass. There was a concern for metastatic cancer. CA 19-9, CEA, CA 125, AFP were normal. With the patient's history of splenectomy, splenosis was a consideration and a sulfur colloid scan showed normal uptake by the liver, a few small areas of increased activity in the left upper quadrant compatible with splenosis, however there was a space-occupying cold defect overlying the left lobe of the liver corresponding to the CT finding which did not represent splenosis. Biopsy of this lesion confirmed benign lymphoid tissue with small lymphocytes. On outpatient follow up, she underwent EUS with pancreatic mass biopsy which showed benign tissue and biopsy of the liver, grade I neurendocrine tumor. Further work up is in progress. Splenosis should be considered in the differential diagnosis when multiple tumor-like lesions appear on abdominal imaging in a patient with a splenic injury or splenectomy previously. They are usually asymptomatic, but may be a cause of hemorrhage or small bowel obstruction. Splenic implants may be located anywhere in the peritoneal cavity. Novel, noninvasive radiologogic testing modalities such as the Technetium (Tc) 99m radionuclide scanning, can assist in the diagnosis of splenosis. Once the diagnosis is made, no further testing needs to be completed unless the patient is symptomatic. Although rare, splenosis is a differential diagnosis to keep in mind in patients with the appropriate risk factors. In this patient, she interestingly had concomitant malignancy in addition to splenosis.
Summary
Mature urban trees improve air quality, reduce storm water run‐off and sequester carbon. Municipal agencies establish forests of native juvenile trees to enhance these and other ecosystem ...services to cities. Little data exist, however, regarding whether these trees will form mature, native forests.
We review urban forestry research that deals specifically with the growth, survival and recruitment of new native urban forests and use these data to identify knowledge gaps and propose research needed to create and maintain native urban forests.
Experimental urban forestry studies are few and most are of durations ≤5 years, shorter than the 10–25 year time frame required to understand forest stand dynamics. Studies capturing initial dynamics of urban afforestation (≤5 years) identify invasive species as the primary threat to native tree establishment. Data exploring longer‐term dynamics are needed to evaluate whether early‐stage afforestation dynamics can be used to infer the composition and function of mature urban forests.
Synthesis and applications. Urban afforestation approaches – from natural colonization to large‐scale plantings – represent a trade‐off in cost vs. efficacy for establishing native forests. A major cost‐saving strategy would be to determine whether exotics and natives can co‐exist and provide the intended ecosystem services.
Urban afforestation approaches – from natural colonization to large‐scale plantings – represent a trade‐off in cost vs. efficacy for establishing native forests. A major cost‐saving strategy would be to determine whether exotics and natives can co‐exist and provide the intended ecosystem services.
A networked multiagent system is tasked to cooperatively track a mobile target, where agents experience random loss of sensing due to occlusions resulting from the target moving in a complex ...environment. A directed random graph is used to model the time-varying availability of the target states to agents, where the connection of the directed edge in the graph is assumed to be probabilistic and evolves according to a two-state Markov Model. An almost sure consensus algorithm is developed for all agents to achieve consensus on the target position. Due to limited communication capabilities (i.e., the agents can only communicate within a certain range), agent motion may result in a disconnected communication network, leading to the failure of consensus to the target states. Motivated to preserve the graph connectivity of the position-dependent communication network, an algebraic-connectivity-based distributed motion controller is developed to ensure that the communication network remains connected during cooperative target tracking. Compared to existing results, our approach allows agents to break existing links when necessary as long as the algebraic connectivity remains positive, which provides more motion freedom for agents in mission operation. Moreover, our approach only requires information exchange within two-hop neighbors to preserve the network connectivity, which eliminates the need of iterative estimation of the algebraic connectivity.
Rare DNA alterations that cause heritable diseases are only partially resolvable by clinical next-generation sequencing due to the difficulty of detecting structural variation (SV) in all genomic ...contexts. Long-read, high fidelity genome sequencing (HiFi-GS) detects SVs with increased sensitivity and enables assembling personal and graph genomes. We leverage standard reference genomes, public assemblies (n = 94) and a large collection of HiFi-GS data from a rare disease program (Genomic Answers for Kids, GA4K, n = 574 assemblies) to build a graph genome representing a unified SV callset in GA4K, identify common variation and prioritize SVs that are more likely to cause genetic disease (MAF < 0.01). Using graphs, we obtain a higher level of reproducibility than the standard reference approach. We observe over 200,000 SV alleles unique to GA4K, including nearly 1000 rare variants that impact coding sequence. With improved specificity for rare SVs, we isolate 30 candidate SVs in phenotypically prioritized genes, including known disease SVs. We isolate a novel diagnostic SV in KMT2E, demonstrating use of personal assemblies coupled with pangenome graphs for rare disease genomics. The community may interrogate our pangenome with additional assemblies to discover new SVs within the allele frequency spectrum relevant to genetic diseases.
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system
. We have previously shown that ...the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells
, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10
GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly
. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Neurodevelopmental disorders present with synaptic alterations that disrupt the balance between excitatory and inhibitory signaling. For example, hyperexcitability of cortical neurons is associated ...with both epilepsy and autism spectrum disorders. However, the mechanisms that initially establish the balance between excitatory and inhibitory signaling in brain development are not well understood. Here, we sought to determine how the extracellular matrix directs synapse formation and regulates synaptic function in a model of human cortical brain development. The extracellular matrix, making up twenty percent of brain volume, is largely comprised of hyaluronan. Hyaluronan acts as both a scaffold of the extracellular matrix and a space-filling molecule. Hyaluronan is present from the onset of brain development, beginning with neural crest cell migration. Through acute perturbation of hyaluronan levels during synaptogenesis, we sought to determine how hyaluronan impacts the ratio of excitatory to inhibitory synapse formation and the resulting neural activity. We used 3-D cortical spheroids derived from human induced pluripotent stem cells to replicate this neurodevelopmental window. Our results demonstrate that hyaluronan preferentially surrounds nascent excitatory synapses. Removal of hyaluronan increases the expression of excitatory synapse markers and results in a corresponding increase in the formation of excitatory synapses, while also decreasing inhibitory synapse formation. This increased excitatory synapse formation elevates network activity, as demonstrated by microelectrode array analysis. In contrast, the addition of purified hyaluronan suppresses excitatory synapse formation. These results establish that the hyaluronan extracellular matrix surrounds developing excitatory synapses, where it critically regulates synapse formation and the resulting balance between excitatory to inhibitory signaling.
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