The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone production that occurs in most mammalian species. In rodents and nonhuman primates, estrogen and progesterone’s ...impact on the brain is evident across a range of spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain networks at rest in a woman who underwent brain imaging and venipuncture for 30 consecutive days. Standardized regression analyses illustrate estrogen and progesterone’s widespread associations with functional connectivity. Time-lagged analyses examined the temporal directionality of these relationships and suggest that cortical network dynamics (particularly in the Default Mode and Dorsal Attention Networks, whose hubs are densely populated with estrogen receptors) are preceded—and perhaps driven—by hormonal fluctuations. A similar pattern of associations was observed in a follow-up study one year later. Together, these results reveal the rhythmic nature in which brain networks reorganize across the human menstrual cycle. Neuroimaging studies that densely sample the individual connectome have begun to transform our understanding of the brain’s functional organization. As these results indicate, taking endocrine factors into account is critical for fully understanding the intrinsic dynamics of the human brain.
•Intrinsic fluctuations in sex hormones shape the brain’s functional architecture.•Estradiol facilitates tighter coherence within whole-brain functional networks.•Progesterone has the opposite, reductive effect.•Ovulation (via estradiol) modulates variation in topological network states.•Effects are pronounced in network hubs densely populated with estrogen receptors.
Low levels of type I interferon (IFN-I) are thought to be a driving force for immune activation and T-cell exhaustion in HIV-1 infected individuals on combination antiretroviral therapy (cART), ...though the causative mechanisms for persistent IFN-I signaling have remained unclear. Here, we show Rev-CRM1-dependent nuclear export and peripheral membrane association of intron-containing HIV-1 RNA, independent of primary viral sequence or viral protein expression, is subject to sensing and signaling via MAVS, resulting in IFN-I-dependent pro-inflammatory responses in macrophages. Additionally, HIV-1 intron-containing-RNA-induced innate immune activation of macrophages leads to upregulation of inhibitory receptor expression and functional immune exhaustion of co-cultured T cells. Our findings suggest that persistent expression of HIV-1 intron-containing RNA in macrophages contributes to chronic immune activation and T-cell dysfunction and that use of HIV RNA expression inhibitors as adjunct therapy might abrogate aberrant inflammation and restore immune function in HIV-infected individuals on cART.
A hallmark pathological feature of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is the depletion of RNA-binding protein TDP-43 from the nucleus ...of neurons in the brain and spinal cord
. A major function of TDP-43 is as a repressor of cryptic exon inclusion during RNA splicing
. Single nucleotide polymorphisms in UNC13A are among the strongest hits associated with FTD and ALS in human genome-wide association studies
, but how those variants increase risk for disease is unknown. Here we show that TDP-43 represses a cryptic exon-splicing event in UNC13A. Loss of TDP-43 from the nucleus in human brain, neuronal cell lines and motor neurons derived from induced pluripotent stem cells resulted in the inclusion of a cryptic exon in UNC13A mRNA and reduced UNC13A protein expression. The top variants associated with FTD or ALS risk in humans are located in the intron harbouring the cryptic exon, and we show that they increase UNC13A cryptic exon splicing in the face of TDP-43 dysfunction. Together, our data provide a direct functional link between one of the strongest genetic risk factors for FTD and ALS (UNC13A genetic variants), and loss of TDP-43 function.
Despite progress in interdisciplinary research, difficulties remain. In this paper, we argue that scholars, educators, and practitioners need to critically rethink the ways in which interdisciplinary ...research and training are conducted. We present epistemological pluralism as an approach for conducting innovative, collaborative research and study. Epistemological pluralism recognizes that, in any given research context, there may be several valuable ways of knowing, and that accommodating this plurality can lead to more successful integrated study. This approach is particularly useful in the study and management of social–ecological systems. Through resilience theory's adaptive cycle, we demonstrate how a focus on epistemological pluralism can facilitate the reorganization of interdisciplinary research and avoid the build-up of significant, but insufficiently integrative, disciplinary-dominated research. Finally, using two case studies—urban ecology and social–ecological research in Alaska—we highlight how interdisciplinary work is impeded when divergent epistemologies are not recognized and valued, and that by incorporating a pluralistic framework, these issues can be better explored, resulting in more integrated understanding.
Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to PPP2R1A, which encodes the ...predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30% to 40% of USC cases, the clinical actionability of these mutations has not been studied. Using a high-throughput screening approach, we showed that mutations in Aα results in synthetic lethality following treatment with inhibitors of ribonucleotide reductase (RNR). In vivo, multiple models of Aα mutant uterine serous tumors were sensitive to clofarabine, an RNR inhibitor (RNRi). Aα-mutant cells displayed impaired checkpoint signaling upon RNRi treatment and subsequently accumulated more DNA damage than wild-type (WT) cells. Consistently, inhibition of PP2A activity using LB-100, a catalytic inhibitor, sensitized WT USC cells to RNRi. Analysis of The Cancer Genome Atlas data indicated that inactivation of PP2A, through loss of PP2A subunit expression, was prevalent in USC, with 88% of patients with USC harboring loss of at least one PP2A gene. In contrast, loss of PP2A subunit expression was rare in uterine endometrioid carcinomas. While RNRi are not routinely used for uterine cancers, a retrospective analysis of patients treated with gemcitabine as a second- or later-line therapy revealed a trend for improved outcomes in patients with USC treated with RNRi gemcitabine compared with patients with endometrioid histology. Overall, our data provide experimental evidence to support the use of ribonucleotide reductase inhibitors for the treatment of USC.
A drug repurposing screen identifies synthetic lethal interactions in PP2A-deficient uterine serous carcinoma, providing potential therapeutic avenues for treating this deadly endometrial cancer.
Methylmercury (MeHg) is a bioaccumulative toxic contaminant in many ecosystems, but factors governing its production are poorly understood. Recent work has shown that the anaerobic microbial ...conversion of mercury (Hg) to MeHg requires the Hg-methylation genes hgcAB and that these genes can be used as biomarkers in PCR-based estimators of Hg-methylator abundance. In an effort to determine reliable methods for assessing hgcA abundance and diversity and linking them to MeHg concentrations, multiple approaches were compared including metagenomic shotgun sequencing, 16S rRNA gene pyrosequencing and cloning/sequencing hgcAB gene products. Hg-methylator abundance was also determined by quantitative hgcA qPCR amplification and metaproteomics for comparison to the above measurements. Samples from eight sites were examined covering a range of total Hg (HgT; 0.03–14 mg kg–1 dry wt. soil) and MeHg (0.05–27 μg kg–1 dry wt. soil) concentrations. In the metagenome and amplicon sequencing of hgcAB diversity, the Deltaproteobacteria were the dominant Hg-methylators while Firmicutes and methanogenic Archaea were typically ∼50% less abundant. This was consistent with metaproteomics estimates where the Deltaproteobacteria were steadily higher. The 16S rRNA gene pyrosequencing did not have sufficient resolution to identify hgcAB + species. Metagenomic and hgcAB results were similar for Hg-methylator diversity and clade-specific qPCR-based approaches for hgcA are only appropriate when comparing the abundance of a particular clade across various samples. Weak correlations between Hg-methylating bacteria and soil Hg concentrations were observed for similar environmental samples, but overall total Hg and MeHg concentrations poorly correlated with Hg-cycling genes.
Objective
This pilot study tested the efficacy of two brief, phone‐administered, behavioral interventions derived from behavioral activation in reducing burnout among doctoral students.
Methods
...Sixty‐six doctoral students demonstrating current high burnout were randomly assigned to one of three intervention conditions: (1) Reward: increasing pleasant, rewarding behaviors, (2) Approach: approaching important goals that they have been avoiding, or (3) Control: monitoring only.
Results
Results indicated that doctoral students treated with the approach intervention reported significantly lower burnout compared to participants in the control condition immediately after the intervention and at a 1‐week follow‐up. Results also suggested that students in the approach intervention also reported higher well‐being compared to students in the control condition.
Conclusion
These findings suggest that this approach intervention is an effective treatment for school burnout for doctoral students that can be delivered remotely through phone and web technology.
In coastal wetlands, one of the most striking examples of climate change is the poleward range expansion of mangrove forests in response to warming winters. In North America, the Cedar Key region has ...often been considered the range limit for mangroves along the western coast of Florida (USA). However, within the past several decades, robust stands of
Avicennia germinans
and
Rhizophora mangle
have been observed in the Apalachicola Bay region, which is 200 km northwest of Cedar Key. Here, we combined field vegetation surveys, historical herbarium records, and analyses of past temperature data (station-based and gridded) to examine the distribution and structure of these two mangrove species in the Apalachicola Bay region. Historical records indicate that mangroves have been present for at least 150 years. However, our abundance and structural data indicate that mangroves are currently reaching heights, densities, and reproductive stages not historically reported. We found a surprisingly broad distribution and high number of
R. mangle
individuals, which is unlike
A. germinans
–dominated mangrove range limits in Louisiana and Texas. Using cold temperature tolerance thresholds and gridded temperature data, we show that
A. germinans
and
R. mangle
distributions can be influenced by spatial variation in the frequency of extreme freeze events, which can be used to spatially depict the risk of mangrove cold damage. Given the rapid pace of change and the potential for abrupt landscape-scale transformation, our findings reinforce the pressing need to advance understanding of mangrove expansion dynamics near northern range limits in the southeastern United States.
Premise
As Baker’s law suggests, the successful colonization of oceanic islands is often associated with uniparental reproduction (self‐fertility), but the high incidence of dimorphism (dioecy, ...gynodioecy) on islands complicates this idea. Lycium carolinianum is widespread, occurring on the North American mainland and the Hawaiian Islands. We examined Baker's ideas for mainland and island populations of L. carolinianum and examined inbreeding depression as a possible contributor to the evolution of gynodioecy on Maui.
Methods
Controlled crosses were conducted in two mainland populations and two populations in Hawaii. Treatments included self and cross pollination, unmanipulated controls, and autogamy/agamospermy. Alleles from the self‐incompatibility S‐RNase gene were isolated and compared between mainland and island populations. Given self‐compatibility in Hawaii, we germinated seeds from self‐ and cross‐ treatments and estimated inbreeding depression using seven traits and a measure of cumulative fitness.
Results
Mainland populations of Lycium carolinianum are predominately self‐incompatible with some polymorphism for self‐fertility, whereas Hawaiian populations are self‐compatible. Concordantly, S‐RNase allelic diversity is reduced in Hawaii compared to the mainland. Hawaiian populations also exhibit significant inbreeding depression.
Conclusions
Self‐compatibility in Hawaii and individual variation in self‐fertility in mainland populations suggests that a colonization filter promoting uniparental reproduction may be acting in this system. Comparison of S‐RNase variation suggests a collapse of allelic diversity and heterozygosity at the S‐RNase locus in Hawaii, which likely contributed to mate limitation upon arrival to the Pacific. Inbreeding depression coupled with autonomous self‐fertilization may have led to the evolution of gynodioecy on Maui.
Preliminary evidence has demonstrated the benefits of targeting self-compassion in the treatment of posttraumatic stress disorder (PTSD). However, survivors of childhood maltreatment may present with ...unique challenges that compromise the effectiveness of these and other PTSD treatments. Specifically, childhood maltreatment victims often exhibit a marked fear and active resistance of self-kindness and warmth (i.e., fear of self-compassion). Victims may also attempt to control distressing internal experiences in a way that hinders engagement in value-based actions (i.e., psychological inflexibility). Research suggests that psychological inflexibility exacerbates the negative effects of fear of self-compassion. The present study expanded on previous research by examining the relations among childhood maltreatment, fear of self-compassion, psychological inflexibility, and PTSD symptom severity in 288 college women. As expected, moderate to severe levels of childhood maltreatment were associated with greater fear of self-compassion, psychological inflexibility, and PTSD symptom severity compared to minimal or no childhood maltreatment. A mediation analysis showed that childhood maltreatment had a significant indirect effect on PTSD symptom severity via fear of self-compassion, although a conditional process analysis did not support psychological inflexibility as a moderator of this indirect effect. A post hoc multiple mediator analysis showed a significant indirect effect of childhood maltreatment on PTSD symptom severity via psychological inflexibility, but not fear of self-compassion. These findings highlight the importance of addressing fear of self-compassion and psychological inflexibility as barriers to treatment for female survivors of childhood maltreatment.
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