1 Department of Surgery, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts
2 Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
3 Department ...of Molecular Genetics and Microbiology, Gainsville, Florida
4 Center for Surgical Research, University of Alabama, Birmingham, Alabama
5 Stanford University, Stanford, California
6 Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
A primary objective of the large collaborative project entitled "Inflammation and the Host Response to Injury" was to identify leukocyte genes that are differentially expressed after two different types of injury in mouse models and to test the hypothesis that both forms of injury would induce similar changes in gene expression. We report here the genes that are expressed in white blood cells (WBCs) and in splenocytes at 2 h, 1 day, 3 days, and 7 days after burn and sham injury or trauma-hemorrhage (T-H) and sham T-H. Affymetrix Mouse Genome 430 2.0 GeneChips were used to profile gene expression, and the results were analyzed by dCHIP, BRB Array Tools, and Ingenuity Pathway Analysis (IPA) software. We found that the highest number of genes differentially expressed following burn injury were at day 1 for both WBCs (4,989) and for splenocytes (4,715) and at day 1 for WBCs (1,167) and at day 3 for splenocytes (1,117) following T-H. The maximum overlap of genes that were expressed after both forms of injury were at day 1 in WBCs (136 genes) and at day 7 in splenocytes (433 genes). IPA revealed that the cell-to-cell signaling, cell death, immune response, antiapoptosis, and cell cycle control pathways were affected most significantly. In summary, this report provides a database of genes that are modulated in WBCs and splenocytes at sequential time points after burn or T-H in mice and reveals that relatively few leukocyte genes are expressed in common after these two forms of injury.
inflammation; gene microarray; immune response; gene microarray analysis; pathway analysis
WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown.
...We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID).
We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition.
Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Among industrialized nations, the United States has a unique system for providing social welfare, as corporations supplement the basic and comparatively small Medicare and Social Security benefits ...(Esping-Andersen, 1990). One result of this system is that the employment relationship takes on increasing importance as one's access to health care and retirement benefits is inextricably linked to her job. This dissertation offers a multi-method investigation of a key welfare provision, employer-sponsored retirement, from its emergence as an institutionalized practice to its present state of decline. Study 1, examines a key historical event in the diffusion of company-sponsored retirement plans—when the United Automobile Workers (UAW) union began bargaining for such benefits in 1949–50. Because negotiating over welfare provision was a strategic departure for the Union, I compare the rhetoric used to frame these demands with that used to bargain over price control of automobiles in 1945–46. The findings show that the UAW used relatively consistent framing efforts across the two negotiating rounds, suggesting that once leaders develop a discursive repertoire consistent with the organization's ideology, leaders explain, rationalize and legitimize their organizational strategies using the same set of previously established frames. Study 2 examines firm-level factors that have led to the decline in defined benefit (DB) pensions and the growth of defined contribution (DC) retirement plans and argues that corporate choices around retirement are shaped by power differences at the firm level. Firm ownership by financial investors negatively affects DB plan participation, while passive financial ownership promotes DC participation and active financial ownership hinders it. Manager and employee power promote DC participation and the findings suggest they also have a positive impact on DB participation. In sum, different organizational constituents have particular interests as it pertains to a firm's retirement strategy—the extent to which these constituent groups have power, the better able they are to protect those interests. Together, these studies enlighten our understanding of the US's unique form of welfare provision and show how decisions made at the organizational level can have significant societal impact.
The Pacific decadal oscillation (PDO), the dominant year-round pattern of monthly North Pacific sea surface temperature (SST) variability, is an important target of ongoing research within ...themeteorological and climate dynamics communities and is central to the work of many geologists, ecologists, natural resource managers, and social scientists. Research over the last 15 years has led to an emerging consensus: the PDO is not a single phenomenon, but is instead the result of a combination of different physical processes, including both remote tropical forcing and local North Pacific atmosphere–ocean interactions, which operate on different time scales to drive similar PDO-like SST anomaly patterns. How these processes combine to generate the observed PDO evolution, including apparent regime shifts, is shown using simple autoregressive models of increasing spatial complexity. Simulations of recent climate in coupled GCMs are able to capture many aspects of the PDO, but do so based on a balance of processes often more independent of the tropics than is observed. Finally, it is suggested that the assessment of PDO-related regional climate impacts, reconstruction of PDO-related variability into the past with proxy records, and diagnosis of Pacific variability within coupled GCMs should all account for the effects of these different processes, which only partly represent the direct forcing of the atmosphere by North Pacific Ocean SSTs.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Evidence suggests a link between smaller hippocampal volume (HV) and post-traumatic stress disorder (PTSD). However, there has been little prospective research testing this question directly and it ...remains unclear whether smaller HV confers risk or is a consequence of traumatization and PTSD.
U.S. soldiers (
= 107) completed a battery of clinical assessments, including structural magnetic resonance imaging pre-deployment. Once deployed they completed monthly assessments of traumatic-stressors and symptoms. We hypothesized that smaller HV would potentiate the effects of traumatic stressors on PTSD symptoms in theater. Analyses evaluated whether total HV, lateral (right
left) HV, or HV asymmetry (right - left) moderated the effects of stressor-exposure during deployment on PTSD symptoms.
Findings revealed no interaction between total HV and average monthly traumatic-stressors on PTSD symptoms
= -0.028,
= 0.681 95% confidence interval (CI) -0.167 to 0.100. However, in the context of greater exposure to average monthly traumatic stressors, greater right HV was associated with fewer PTSD symptoms
= -0.467,
= 0.023 (95% CI -0.786 to -0.013), whereas greater left HV was unexpectedly associated with greater PTSD symptoms
= 0.435,
= 0.024 (95% CI 0.028-0.715).
Our findings highlight the importance of considering the complex role of HV, in particular HV asymmetry, in predicting the emergence of PTSD symptoms in response to war-zone trauma.
Abstract
Background
Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive–compulsive, and trauma- and stressor-related disorders; however, many patients do not improve, ...resulting in prolonged suffering and poorly used resources. Basic research on fear extinction may inform the development of a biomarker for the selection of exposure-based therapy. Growing evidence links orexin system activity to deficits in fear extinction and we have demonstrated that reactivity to an inhaled carbon dioxide (CO
2
) challenge—a safe, affordable, and easy-to-implement procedure—can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents. Building upon this basic research, the goal for the proposed study is to validate CO
2
reactivity as a biomarker of exposure-based therapy non-response.
Methods
We will assess CO
2
reactivity in 600 adults meeting criteria for one or more fear- or anxiety-related disorders prior to providing open exposure-based therapy. By incorporating CO
2
reactivity into a multivariate model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related predictor variables, we will establish the mechanistic specificity and the additive predictive utility of the potential CO
2
reactivity biomarker. By developing models independently within two study sites (University of Texas at Austin and Boston University) and predicting the other site’s data, we will validate that the results are likely to generalize to future clinical samples.
Discussion
Representing a necessary stage in translating basic research, this investigation addresses an important public health issue by testing an accessible clinical assessment strategy that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders, and enhanced understanding of the mechanisms governing exposure-based therapy.
Trial registration
ClinicalTrials.gov Identifier: NCT05467683 (20/07/2022).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•tDCS enhanced gains from a single session of in vivo exposure therapy.•Augmentation effects from a single active tDCS session persisted through 1-month.•Greater severity and a poorer early response ...predicted better gains from active tDCS.•tDCS may be indicated for those who are resistant to standard exposure.•Further investigation using tDCS as an exposure augmentation is warranted.
Exposure therapy is highly effective for anxiety-related disorders, but there is a need for enhancement. Recent trials of adjunctive neuromodulation have shown promise, warranting evaluation of transcranial direct current stimulation (tDCS) as an augmentation. In a double-blind, placebo-controlled trial, contamination- and animal-phobic participants (N = 49) were randomized to active tDCS (1.7 mA, 20 min; n = 27), or sham tDCS (1.7 mA, 30 s; n = 22), followed by 30 min of in-vivo exposure. Active tDCS targeted excitation of the left mPFC and inhibition of the right dlPFC; polarity was counterbalanced for controls. We predicted tDCS would result in accelerated and better maintained gains, contingent on the subsequent in-session response, and baseline negative prognostic indicators. Consistent with predictions, tDCS promoted engagement and reductions in threat appraisals during exposure, and greater reductions in distress and threat appraisals through 1-month, although effects did not uniformly generalize. tDCS was most beneficial given high phobic severity, anxiety sensitivity, and a suboptimal early response. tDCS may promote engagement and response among individuals who are resistant or refractory to standard treatment. tDCS should be applied to more severe anxiety-related disorders, with parameters yoked to individual differences to improve outcomes in exposure-based interventions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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