Adversity Interpreted: A Scoping Review of Adversity Appraisal Measurement.

Although evidence suggests that individuals' appraisals (i.e., subjective interpretations) of adverse or traumatic life events may serve as a mechanism accounting for differences in adversity exposure and psychological adjustment, understanding this mechanism is contingent on our ability to reliably and consistently measure appraisals. However, measures have varied widely between studies, making conclusions about how best to measure appraisal a challenge for the field. To address this issue, the present study reviewed 88 articles from three research databases, assessing adults' appraisals of adversity. To be included in the scoping review, articles had to meet the following criteria: (1) published no earlier than 1999, (2) available in English, (3) published as a primary source manuscript, and (4) included a measure assessing for adults' (over the age of 18) subjective primary and/or secondary interpretations of adversity. Each article was thoroughly reviewed and coded based on the following information: study demographics, appraisal measurement tool(s), category of appraisal, appraisal dimensions (e.g., self-blame, impact, and threat), and the tool's reliability and validity. Further, information was coded according to the type of adversity appraised, the time in which the appraised event occurred, and which outcomes were assessed in relation to appraisal. Results highlight the importance of continued examination of adversity appraisals and reveal which appraisal tools, categories, and dimensions are most commonly assessed for. These results provide guidance to researchers in how to examine adversity appraisals and what gaps among the measurement of adversity appraisal which need to be addressed in the future research.

Connecting post-release mortality to the physiological stress response of large coastal sharks in a commercial longline fishery.

Bycatch mortality is a major factor contributing to shark population declines. Post-release mortality (PRM) is particularly difficult to quantify, limiting the accuracy of stock assessments. We paired blood-stress physiology with animal-borne accelerometers to quantify PRM rates of sharks caught in a commercial bottom longline fishery. Blood was sampled from the same individuals that were tagged, providing direct correlation between stress physiology and animal fate for sandbar (Carcharhinus plumbeus, N = 130), blacktip (C. limbatus, N = 105), tiger (Galeocerdo cuvier, N = 52), spinner (C. brevipinna, N = 14), and bull sharks (C. leucas, N = 14). PRM rates ranged from 2% and 3% PRM in tiger and sandbar sharks to 42% and 71% PRM in blacktip and spinner sharks, respectively. Decision trees based on blood values predicted mortality with >67% accuracy in blacktip and spinner sharks, and >99% accuracy in sandbar sharks. Ninety percent of PRM occurred within 5 h after release and 59% within 2 h. Blood physiology indicated that PRM was primarily associated with acidosis and increases in plasma potassium levels. Total fishing mortality reached 62% for blacktip and 89% for spinner sharks, which may be under-estimates given that some soak times were shortened to focus on PRM. Our findings suggest that no-take regulations may be beneficial for sandbar, tiger, and bull sharks, but less effective for more susceptible species such as blacktip and spinner sharks.

The effects of elevated potassium, acidosis, reduced oxygen levels, and temperature on the functional properties of isolated myocardium from three elasmobranch fishes: clearnose skate (Rostroraja eglanteria), smooth dogfish (Mustelus canis), and sandbar shark (Carcharhinus plumbeus).

Elevated plasma potassium levels (hyperkalemia), reduced plasma pH (acidosis), reduced blood oxygen content, and elevated temperatures are associated with species-specific rates of at-vessel and post-release mortality in elasmobranch fishes. The mechanism linking these physiological disturbances to mortality remains undetermined however, and we hypothesize that the proximate cause is reduced myocardial function. We measured changes in the functional properties of isolated ventricular myocardial strips from clearnose skate (Rostroraja eglanteria), smooth dogfish (Mustelus canis), and sandbar shark (Carcharhinus plumbeus) when subjected to the following stressors (both in isolation and in combination): hyperkalemia (7.4 mM K+), acidosis (from 7.9 to 7.1), and reduced oxygen (to 31% O2 saturation) applied at temperatures 5 °C above and below holding temperatures. We selected these species based on phylogenetic distance, diverse routine activity levels, and their tolerance to capture and transport. Stressors had a few significant species-specific detrimental impacts on myocardial function (e.g., a 33-45% decrease in net force under acidosis + low O2). Net force production of myocardial strips from clearnose skate and smooth dogfish approximately doubled following exposure to isoproterenol, demonstrating that these species possess beta-adrenergic receptors and that their stimulation could provide a mechanism for preservation of cardiac function during stress. Our results suggest that disruption of physiological homeostasis associated with capture may fatally impair cardiac function in some elasmobranch species, although research with more severe stressors is needed.

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

GADD34 attenuates HIV-1 replication by viral 5'-UTR TAR RNA-mediated translational inhibition.

Role of GADD34, a protein that is induced following cellular stress, in HIV-1 replication was investigated. GADD34 was induced during the late phase of HIV-1 infection. siRNA-knockdown of GADD34 stimulated whereas overexpression of GADD34 inhibited HIV-1 replication. GADD34 N-terminal ER-binding-helix amino acid region 1-192 alone was found to be sufficient for the inhibition of HIV-1 replication whereas protein-phosphatase -1-binding domain and eIF-2α-phosphatase activity of GADD34 were not crucial for anti-HIV-1 activity. GADD34 did not alter the HIV-1 RNA levels but reduced the viral protein expression suggesting that GADD34 interferes in HIV protein synthesis. Studies on the effect of HIV-1-5'-UTR and its mutants on a human promoter-driven luciferase expression indicated that GADD34-inhibition was mediated by 5'-UTR/TAR RNA, probably by modulating TAR RNA structure. In summary, our data support a novel function of GADD34 as a putative anti-HIV-1 restriction factor.

Occupational Gradients in Work-Related Insecurity and Health: Interrogating the Links.

Traditional work-related securities that constitute the career-job model of employment have been in steep decline for several decades, affecting workers across industries and occupations. Still, insecure employment remains unequally distributed across the working population according to the major axes of social stratification, namely age, gender, race, and socioeconomic class. This study investigates patterns of exposure to work-related insecurity across the occupational hierarchy and whether these contribute to occupational gradients in health outcomes. Drawing on data from a national panel survey of the Canadian workforce, a multilevel growth curve modeling approach is used to examine the relationship between work-insecurity exposures and workers' self-rated health trajectories over 5 years. Findings show that work-related insecurity is associated with declines in self-rated health, although the type of insecurity as well as the magnitude, direction, and duration of the effect varies by occupational status-position. The application of pseudo-R2 tests confirmed this study's central hypothesis that gradients in health outcomes across occupational hierarchies are due, in part, to differences in exposure to work-related insecurity. Going forward, the development of effective health promotion interventions that can modify work-related health gradients, must work toward mitigating the risk of exposure to adverse work circumstances that is systemic to occupational hierarchies.

N-Cadherin-Expressing Bone and Marrow Stromal Progenitor Cells Maintain Reserve Hematopoietic Stem Cells.

Regulation of hematopoietic stem cells (HSCs) by bone marrow (BM) niches has been extensively studied; however, whether and how HSC subpopulations are distinctively regulated by BM niches remain unclear. Here, we functionally distinguished reserve HSCs (rHSCs) from primed HSCs (pHSCs) based on their response to chemotherapy and examined how they are dichotomously regulated by BM niches. Both pHSCs and rHSCs supported long-term hematopoiesis in homeostasis; however, pHSCs were sensitive but rHSCs were resistant to chemotherapy. Surviving rHSCs restored the HSC pool and supported hematopoietic regeneration after chemotherapy. The rHSCs were preferentially maintained in the endosteal region that enriches N-cadherin+ (N-cad+) bone-lining cells in homeostasis and post-chemotherapy. N-cad+ cells were functional bone and marrow stromal progenitor cells (BMSPCs), giving rise to osteoblasts, adipocytes, and chondrocytes in vitro and in vivo. Finally, ablation of N-cad+ niche cells or deletion of SCF from N-cad+ niche cells impaired rHSC maintenance during homeostasis and regeneration.

Labor market and health trajectories during periods of economic recession and expansion in the United States, 1988‒2011.

Objectives We examined associations between labor market and health (LM-H) trajectories in the United States between 1988 and 2011 and whether associations differed across macroeconomic expansion/recession periods. Methods Working-age cohorts, derived from the US Panel Study of Income Dynamics, were followed over time to characterize LM-H trajectories. Poisson regression provided relative risks (RR) with robust 95% confidence intervals (CI) for the association between trajectories, adjusting for demographic and socioeconomic variables. Results LM trajectories ending in unemployment (RR 1.7‒2.5 across periods) or inactivity (RR 2.3-3.2) had a greater risk of worsening health trajectories, compared to stable employment. In contrast, RR for individuals returning to work following an intermediary period of unemployment/inactivity were attenuated across most periods. Stable-employed individuals had the highest probability of remaining in good health, whereas trajectories ending in unemployment or inactivity had the lowest probability. These overall relationships were consistent across macroeconomic periods. Conclusions We found strong and consistent relationships between LM-H trajectories across macroeconomic periods. The attenuated (but not eliminated) risk among individuals returning to work following a period of unemployment/inactivity suggests that health outcomes are not only dependent on the LM end-state, but also on the distinct pattern over time.

Evaluating the Use of Mobile Health Technology in Older Adults With Heart Failure: Mixed-Methods Study.

BACKGROUND: Heart failure (HF) is associated with high rates of hospitalizations, morbidity, mortality, and costs. Remote patient monitoring (mobile health, mHealth) shows promise in improving self-care and HF management, thus increasing quality of care while reducing hospitalizations and costs; however, limited information exists regarding perceptions of older adults with HF about mHealth use. OBJECTIVE: This study aimed to compare perspectives of older adults with HF who were randomized to either (1) mHealth equipment connected to a 24-hour call center, (2) digital home equipment, or (3) standard care, with regard to ease and satisfaction with equipment, provider communication and engagement, and ability to self-monitor and manage their disease. METHODS: We performed a pilot study using a mixed-methods descriptive design with pre- and postsurveys, following participants for 12 weeks. We augmented these data with semistructured qualitative interviews to learn more about feasibility, satisfaction, communication, and self-management. RESULTS: We enrolled 28 patients with HF aged 55 years and above, with 57% (16/28) male, 79% (22/28) non-Hispanic white, and with multiple comorbid conditions. At baseline, 50% (14/28) rated their health fair or poor and 36% (10/28) and 25% (7/28) were very often/always frustrated and discouraged by their health. At baseline, 46% (13/28) did not monitor their weight, 29% (8/28) did not monitor their blood pressure, and 68% (19/28) did not monitor for symptoms. Post intervention, 100% of the equipment groups home monitored daily. For technology anxiety, 36% (10/28) indicated technology made them nervous, and 32% (9/28) reported fear of technology, without significant changes post intervention. Technology usability post intervention scored high (91/100), reflecting ease of use. A majority indicated that a health care provider should be managing their health, and 71% reported that one should trust and not question the provider. Moreover, 57% (16/28) believed it was better to seek professional help than caring for oneself. Post intervention, mHealth users relied more on themselves, which was not mirrored in the home equipment or standard care groups. Participants were satisfied with communication and engagement with providers, yet many described access problems. Distressing symptoms were unpredictable and prevailed over the 12 weeks with 79 provider visits and 7 visits to emergency departments. The nurse call center received 872 readings, and we completed 289 telephone calls with participants. Narrative data revealed the following main themes: (1) traditional communication and engagement with providers prevailed, delaying access to care; (2) home monitoring with technology was described as useful, and mHealth users felt secure knowing that someone was observing them; (3) equipment groups felt more confident in self-monitoring and managing; and finally, (4) uncertainty and frustration with persistent health problems. CONCLUSIONS: mHealth equipment is feasible with potential to improve patient-centered outcomes and increase self-management in older adults with HF.

Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice.

Bardet-Biedl syndrome (BBS) is a heterogeneous disease characterized by deficiencies in various organs that are caused by defects in genes involved in the genesis, structural maintenance, and protein trafficking of cilia. Leucine zipper transcription factor-like 1 (LZTFL1) has been identified as a BBS protein (BBS17), because patients with mutations in this gene exhibit the common BBS phenotypes. In this study, we generated a knockout mouse model to investigate the effects of LZTFL1 depletion. Lztfl1 knockout mice were born with low birth weight, reached similar weight to those of wild-type mice at 10 weeks of age, and later gained more weight than their wild-type counterparts. LZTFL1 was localized to the primary cilium of kidney cells, and the absence of LZTFL1 increased the ciliary localization of BBS9. Moreover, in the retinas of Lztfl1 knockout mice, the photoreceptor outer segment was shortened, the distal axoneme of photoreceptor connecting cilium was significantly enlarged, and rhodopsin was targeted to the outer nuclear layer. TUNEL assay showed that many of these abnormal photoreceptor cells in Lztfl1 knockout mice underwent apoptosis. Interestingly, the absence of LZTFL1 caused an abnormal increase of the adaptor protein complex 1 (AP1) in some photoreceptor cells. Based on these data, we conclude that LZTFL1 is a cilium protein and regulates animal weight and photoreceptor connecting cilium function probably by controlling microtubule assembly and protein trafficking in cilia.

LZTFL1 Upregulated by All-Trans Retinoic Acid during CD4+ T Cell Activation Enhances IL-5 Production.

Retinoic acids, which are metabolites of vitamin A, have been shown to be involved in multiple T cell effector responses through their binding to the retinoic acid receptor, a ligand-activated transcription factor. Because the molecular mechanism of regulation by retinoic acid is still not fully uncovered, we investigated the gene expression profile of all-trans retinoic acid (ATRA)-treated human CD4(+) T cells. Leucine zipper transcription factor-like 1 (LZTFL1) was upregulated by ATRA in a dose- and time-dependent manner. The expression of LZTFL1 depended on both ATRA and TCR signaling. LZTFL1 accumulated in the plasma membrane compartment of human CD4(+) T cells, and, during immunological synapse formation, it transiently redistributed to the T cell and APC contact zone, indicating its role in T cell activation. Live-cell imaging demonstrates that at the initial stage of immunological synapse formation, LZTFL1 is concentrated at the APC contact site, and, during later stages, it relocates to the distal pole. Knockdown of LZTFL1 reduced the basal- and ATRA-induced levels of IL-5 in CD4(+) T cells, and overexpression of LZTFL1 enhanced the TCR-mediated NFAT signaling, suggesting that LZTFL1 is an important regulator of ATRA-induced T cell response. Together, these data indicate that LZTFL1 modulates T cell activation and IL-5 levels.

The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection.

The transcription factor T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during viral infection. We find that, at high concentrations, T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential.

The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells.

The differentiation of CD4(+) helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and sufficient to shift differentiation away from Tfh cells, instead promoting that of Th1 cells. These findings were not the result of generalized signaling attenuation in Tfh cells, because they retained the ability to flux calcium and activate NFAT-transcription-factor-dependent cytokine production. These data identify the interleukin-2 (IL-2)-mTORc1 axis as a critical orchestrator of the reciprocal balance between Tfh and Th1 cell fates and their respective metabolic activities after acute viral infection.

The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa.

T follicular helper cells (Tfh) are crucial for the initiation and maintenance of germinal center (GC) reactions and high affinity, isotype-switched antibody responses. In this study, we demonstrate that direct TGF-ß signaling to CD4 T cells is important for the formation of influenza-specific Tfh cells, GC reactions, and development of isotype-switched, flu-specific antibody responses. Early during infection, TGF-ß signaling suppressed the expression of the high affinity IL-2 receptor α chain (CD25) on virus-specific CD4 T cells, which tempered IL-2 signaling and STAT5 and mammalian target of rapamycin (mTOR) activation in Tfh precursor CD4 T cells. Inhibition of mTOR allowed for the differentiation of Tfh cells in the absence of TGF-ßR signaling, suggesting that TGF-ß insulates Tfh progenitor cells from IL-2-delivered mTOR signals, thereby promoting Tfh differentiation during acute viral infection. These findings identify a new pathway critical for the generation of Tfh cells and humoral responses during respiratory viral infections.

The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection.

Protein kinase B (also known as AKT) and the mechanistic target of rapamycin (mTOR) are central regulators of T cell differentiation, proliferation, metabolism, and survival. Here, we show that during chronic murine lymphocytic choriomeningitis virus infection, activation of AKT and mTOR are impaired in antiviral cytotoxic T lymphocytes (CTLs), resulting in enhanced activity of the transcription factor FoxO1. Blockade of inhibitory receptor programmed cell death protein 1 (PD-1) in vivo increased mTOR activity in virus-specific CTLs, and its therapeutic effects were abrogated by the mTOR inhibitor rapamycin. FoxO1 functioned as a transcriptional activator of PD-1 that promoted the differentiation of terminally exhausted CTLs. Importantly, FoxO1-null CTLs failed to persist and control chronic viral infection. Collectively, this study shows that CTLs adapt to persistent infection through a positive feedback pathway (PD-1?FoxO1?PD-1) that functions to both desensitize virus-specific CTLs to antigen and support their survival during chronic viral infection.

Long-term mortality risk in individuals with permanent work-related impairment.

OBJECTIVES: Recent estimates indicate that at least one in five activity-limiting injuries occurs at work. Of individuals who suffer these injuries approximately 10% experience some degree of functional impairment. We were interested in investigating long-term mortality risk in individuals with permanent impairment from work injury and to examine whether work disability is a significant explanatory factor. METHODS: We used a retrospective matched cohort methodology to examine differences in mortality rates between individuals with permanent impairment from a work injury and a group of non-injured controls over a 19-year period. We used a sample of impaired workers to investigate the impact of work disability on mortality risk using percentage of earnings recovery after injury as the key proxy measure. All analyses were stratified by sex. RESULTS: Permanent impairment from a work injury was predictive of premature mortality in both male and female claimants, though the risk was slightly higher among women. Work disability was a key explanatory factor in the rate of death among impaired workers, the effects being more pronounced in men. We also found that higher impairment level was associated with mortality in men but not in women. CONCLUSION: The study demonstrates the impact of permanent work-related impairment on longevity and identifies work disability as an important determinant of mortality risk. Given the disconnect between impairment ratings derived from standard diagnostic tools and labour-market activity after accident, more research is needed on the specific factors that contribute to work disability, particularly those related to psycho-social health and well-being.

CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection.

Tissue-resident memory T (Trm) cells provide enhanced protection against infection at mucosal sites. Here we found that CD4(+) T cells are important for the formation of functional lung-resident CD8(+) T cells after influenza virus infection. In the absence of CD4(+) T cells, CD8(+) T cells displayed reduced expression of CD103 (Itgae), were mislocalized away from airway epithelia, and demonstrated an impaired ability to recruit CD8(+) T cells to the lung airways upon heterosubtypic challenge. CD4(+) T cell-derived interferon-γ was necessary for generating lung-resident CD103(+) CD8(+) Trm cells. Furthermore, expression of the transcription factor T-bet was increased in "unhelped" lung Trm cells, and a reduction in T-bet rescued CD103 expression in the absence of CD4(+) T cell help. Thus, CD4(+) T cell-dependent signals are important to limit expression of T-bet and allow for the development of CD103(+) CD8(+) Trm cells in the lung airways following respiratory infection.

Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells.

Multiple bone marrow stromal cell types have been identified as hematopoietic stem cell (HSC)-regulating niche cells. However, whether HSC progeny can serve directly as HSC niche cells has not previously been shown. Here we report a dichotomous role of megakaryocytes (MKs) in both maintaining HSC quiescence during homeostasis and promoting HSC regeneration after chemotherapeutic stress. We show that MKs are physically associated with HSCs in the bone marrow of mice and that MK ablation led to activation of quiescent HSCs and increased HSC proliferation. RNA sequencing (RNA-seq) analysis revealed that transforming growth factor ß1 (encoded by Tgfb1) is expressed at higher levels in MKs as compared to other stromal niche cells. MK ablation led to reduced levels of biologically active TGF-ß1 protein in the bone marrow and nuclear-localized phosphorylated SMAD2/3 (pSMAD2/3) in HSCs, suggesting that MKs maintain HSC quiescence through TGF-ß-SMAD signaling. Indeed, TGF-ß1 injection into mice in which MKs had been ablated restored HSC quiescence, and conditional deletion of Tgfb1 in MKs increased HSC activation and proliferation. These data demonstrate that TGF-ß1 is a dominant signal emanating from MKs that maintains HSC quiescence. However, under conditions of chemotherapeutic challenge, MK ablation resulted in a severe defect in HSC expansion. In response to stress, fibroblast growth factor 1 (FGF1) signaling from MKs transiently dominates over TGF-ß inhibitory signaling to stimulate HSC expansion. Overall, these observations demonstrate that MKs serve as HSC-derived niche cells to dynamically regulate HSC function.