Comparative physiology reveals heat stress disrupts acid-base homeostasis independent of symbiotic state in the model cnidarian Exaiptasia diaphana.

Climate change threatens the survival of symbiotic cnidarians by causing photosymbiosis breakdown in a process known as bleaching. Direct effects of temperature on cnidarian host physiology remain difficult to describe because heatwaves depress symbiont performance, leading to host stress and starvation. The symbiotic sea anemone Exaiptasia diaphana provides an opportune system to disentangle direct versus indirect heat effects on the host, as it can survive indefinitely without symbionts. We tested the hypothesis that heat directly impairs cnidarian physiology by comparing symbiotic and aposymbiotic individuals of two laboratory subpopulations of a commonly used clonal strain of E. diaphana, CC7. We exposed anemones to a range of temperatures (ambient, +2°C, +4°C and +6°C) for 15-18 days, then measured their symbiont population densities, autotrophic carbon assimilation and translocation, photosynthesis, respiration and host intracellular pH (pHi). Symbiotic anemones from the two subpopulations differed in size and symbiont density and exhibited distinct heat stress responses, highlighting the importance of acclimation to different laboratory conditions. Specifically, the cohort with higher initial symbiont densities experienced dose-dependent symbiont loss with increasing temperature and a corresponding decline in host photosynthate accumulation. In contrast, the cohort with lower initial symbiont densities did not lose symbionts or assimilate less photosynthate when heated, similar to the response of aposymbiotic anemones. However, anemone pHi decreased at higher temperatures regardless of cohort, symbiont presence or photosynthate translocation, indicating that heat consistently disrupts cnidarian acid-base homeostasis independent of symbiotic status or mutualism breakdown. Thus, pH regulation may be a critical vulnerability for cnidarians in a changing climate.

Acute heat priming promotes short-term climate resilience of early life stages in a model sea anemone.

Across diverse taxa, sublethal exposure to abiotic stressors early in life can lead to benefits such as increased stress tolerance upon repeat exposure. This phenomenon, known as hormetic priming, is largely unexplored in early life stages of marine invertebrates, which are increasingly threatened by anthropogenic climate change. To investigate this phenomenon, larvae of the sea anemone and model marine invertebrate Nematostella vectensis were exposed to control (18 °C) or elevated (24 °C, 30 °C, 35 °C, or 39 °C) temperatures for 1 h at 3 days post-fertilization (DPF), followed by return to control temperatures (18 °C). The animals were then assessed for growth, development, metabolic rates, and heat tolerance at 4, 7, and 11 DPF. Priming at intermediately elevated temperatures (24 °C, 30 °C, or 35 °C) augmented growth and development compared to controls or priming at 39 °C. Indeed, priming at 39 °C hampered developmental progression, with around 40% of larvae still in the planula stage at 11 DPF, in contrast to 0% for all other groups. Total protein content, a proxy for biomass, and respiration rates were not significantly affected by priming, suggesting metabolic resilience. Heat tolerance was quantified with acute heat stress exposures, and was significantly higher for animals primed at intermediate temperatures (24 °C, 30 °C, or 35 °C) compared to controls or those primed at 39 °C at all time points. To investigate a possible molecular mechanism for the observed changes in heat tolerance, the expression of heat shock protein 70 (HSP70) was quantified at 11 DPF. Expression of HSP70 significantly increased with increasing priming temperature, with the presence of a doublet band for larvae primed at 39 °C, suggesting persistent negative effects of priming on protein homeostasis. Interestingly, primed larvae in a second cohort cultured to 6 weeks post-fertilization continued to display hormetic growth responses, whereas benefits for heat tolerance were lost; in contrast, negative effects of short-term exposure to extreme heat stress (39 °C) persisted. These results demonstrate that some dose-dependent effects of priming waned over time while others persisted, resulting in heterogeneity in organismal performance across ontogeny following priming. Overall, these findings suggest that heat priming may augment the climate resilience of marine invertebrate early life stages via the modulation of key developmental and physiological phenotypes, while also affirming the need to limit further anthropogenic ocean warming.

A kinome-wide CRISPR screen identifies CK1α as a target to overcome enzalutamide resistance of prostate cancer.

Enzalutamide (ENZA), a second-generation androgen receptor antagonist, has significantly increased progression-free and overall survival of patients with metastatic prostate cancer (PCa). However, resistance remains a prominent obstacle in treatment. Utilizing a kinome-wide CRISPR-Cas9 knockout screen, we identified casein kinase 1α (CK1α) as a therapeutic target to overcome ENZA resistance. Depletion or pharmacologic inhibition of CK1α enhanced ENZA efficacy in ENZA-resistant cells and patient-derived xenografts. Mechanistically, CK1α phosphorylates the serine residue S1270 and modulates the protein abundance of ataxia telangiectasia mutated (ATM), a primary initiator of DNA double-strand break (DSB)-response signaling, which is compromised in ENZA-resistant cells and patients. Inhibition of CK1α stabilizes ATM, resulting in the restoration of DSB signaling, and thus increases ENZA-induced cell death and growth arrest. Our study details a therapeutic approach for ENZA-resistant PCa and characterizes a particular perspective for the function of CK1α in the regulation of DNA-damage response.

Strategies to increase couples HIV testing and counselling in sub-Saharan Africa: a systematic review.

INTRODUCTION: Couple HIV testing and counselling (CHTC) is associated with measurable benefits for HIV prevention and treatment. However, the uptake remains limited in much of sub-Saharan Africa, despite an expanded range of strategies designed to promote access. METHODS: Following PRIMSA guidelines, we conducted a systematic review to characterize CHTC uptake strategies. Five databases were searched. Full-text articles were included if they were: conducted in sub-Saharan Africa during the study period (1980-2019), targeted heterosexual couples, reported at least one strategy to promote CHTC and provided a quantifiable measure of CHTC uptake. After the initial and full-text screening, key features of the studies were abstracted and synthesized. RESULTS: Of the 6188 unique records found in our search, 365 underwent full-text review with 29 distinct studies included and synthesized. Most studies recruited couples through antenatal care (n = 11) or community venues (n = 8) and used provider-based HIV testing (n = 25). The primary demand creation strategies included home-based CHTC (n = 7); integration of CHTC into clinical settings (n = 4); distribution of HIV self-testing kits (n = 4); verbal or written invitations (n = 4); community recruiters (n = 3); partner tracing (n = 2); relationship counselling (n = 2); financial incentives (n = 1); group education with CHTC coupons (n = 1); and HIV testing at other community venues (n = 1). CHTC uptake ranged from negligible to nearly universal. DISCUSSION: We thematically categorized a diverse range of strategies with varying levels of intensity and resources used across sub-Saharan Africa to promote CHTC. Offering CHTC within couples' homes was the most common approach, followed by the integration of CHTC into clinical settings. Due to heterogeneity in study characteristics, we were unable to compare the effectiveness across studies, but several trends were observed, including the high prevalence of CHTC promotion strategies in antenatal settings and the promising effects of home-based CHTC, distribution of HIV self-tests and integration of CHTC into routine health services. Since 2019, an updated literature search found that combining partner notification and secondary distribution of HIV self-test kits may be an additionally effective CHTC strategy. CONCLUSIONS: There are many effective, feasible and scalable approaches to promote CHTC that should be considered by national programmes according to local needs, cultural context and available resources.

Diptoindonesin G antagonizes AR signaling and enhances the efficacy of antiandrogen therapy in prostate cancer.

BACKGROUND: The androgen receptor (AR) signaling pathway has been well demonstrated to play a crucial role in the development, progression, and drug resistance of prostate cancer. Although the current anti-androgen therapy could significantly benefit prostate cancer patients initially, the efficacy of the single drug usually lasts for a relatively short period, as drug resistance quickly emerges. METHODS: We have performed an unbiased bioinformatics analysis using the RNA-seq results in 22Rv1 cells to identify the cell response toward Dip G treatment. The RNA-seq results were validated by qRT-PCR. Protein levels were detected by western blot or staining. Cell viability was measured by Aquabluer and colony formation assay. RESULTS: Here, we identified that Diptoindonesin G (Dip G), a natural extracted compound, could promote the proteasome degradation of AR and polo-like kinase 1 (PLK1) through modulating the activation of CHIP E3 ligase. Administration of Dip G has shown a profound efficiency in the suppression of AR and PLK1, not only in androgen-dependent LNCaP cells but also in castration-resistant and enzalutamide-resistant cells in a CHIP-dependent manner. Through co-targeting the AR signaling, Dip G robustly improved the efficacy of HSP90 inhibitors and enzalutamide in both human prostate cancer cells and in vivo xenograft mouse model. CONCLUSIONS: Our results revealed that Dip G-mediated AR degradation would be a promising and valuable therapeutic strategy in the clinic.

Epigenetics in prostate cancer treatment.

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men, and the progression of this disease results in fewer treatment options available to clinical patients. It highlights the vital necessity for discovering novel therapeutic approaches and expanding the current understanding of molecular mechanisms. Epigenetic alternations such as DNA methylation models and histone modifications have been associated as key drivers in the development and advancement of PCa. Several studies have been conducted and demonstrated that targeting these epigenetic enzymes or regulatory proteins has been strongly associated with the regulation of cancer cell growth. Due to the success rate of these therapeutic routes in pre-clinical settings, many drugs have now advanced to clinical testing, where efficacy will be measured. This review will discuss the role of epigenetic modifications in PCa development and its function in the progression of the disease to resistant forms and introduce therapeutic strategies that have demonstrated successful results as PCa treatment.

Immunoglobulin M in Health and Diseases: How Far Have We Come and What Next?

B lymphocytes are important in secreting antibodies that protect against invading pathogens such as viruses, bacteria, parasites, and also in mediating pathogenesis of allergic diseases and autoimmunity. B lymphocytes develop in the bone marrow and contain heavy and light chains, which upon ligation form an immunoglobulin M (IgM) B cell receptor (BCR) expressed on the surface of naïve immature B cells. Naïve B cells expressing either IgM or IgD isotypes are thought to play interchangeable functions in antibody responses to T cell-dependent and T cell-independent antigens. IgM short-lived plasma cells (SLPCs) and antigen-specific IgM memory B cells (MBCs-M) are critical in the first few days of infection, as well as long-term memory induced by vaccination, respectively. At mucosal surfaces, IgM is thought to play a critical part in promoting mucosal tolerance and shaping microbiota together with IgA. In this review, we explore how IgM structure and BCR signaling shapes B cell development, self and non-self-antigen-specific antibody responses, responses to infectious (such as viruses, parasites, and fungal) and non-communicable diseases (such as autoimmunity and allergic asthma). We also explore how metabolism could influence other B cell functions such as mucosal tolerance and class switching. Finally, we discuss some of the outstanding critical research questions in both experimental and clinical settings targeting IgM.

Reducing exposure to ultraviolet radiation from the sun and indoor tanning: A meta-analysis.

Objective: Skin cancer is the most frequently diagnosed cancer and rates are increasing because of global warming. This article reports a meta-analysis of randomized controlled trials of behavioral interventions to reduce exposure to ultraviolet radiation (UVR). The review aimed to (a) quantify the magnitude of intervention effects on indoor tanning, sun exposure, and sunscreen use, and (b) determine which intervention strategies maximize behavior change. Method: Out of 17,437 records identified via literature searches, 190 independent tests (N = 89,365) met the inclusion criteria. Sample, intervention, and methodological characteristics, and change techniques were coded, and random effects meta-analyses and metaregressions were conducted. Results: The sample-weighted average effect size across all studies was d+ = .193 (95% confidence interval, CI [.161, .226]), and there were significant effects on indoor tanning, sun exposure, and sunscreen use (d+ = .080, .149, and .196, respectively). However, there was evidence of publication bias, and trim and fill analyses indicated that the corrected effects for sun exposure and sunscreen use were of very small magnitude (d+ ~ .06) and were not significantly different from zero for indoor tanning (d+ = -.011, 95% CI [-.096, .074]). Metaregression analyses identified several intervention strategies that predicted effect sizes. For instance, interventions delivered individually that promoted alternatives to tanning were associated with larger effect sizes for indoor tanning. Conclusion: Interventions to date have had only a modest impact on behavioral exposure to UVR. The present findings offer new insights into how the effectiveness of future interventions can be improved. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

What works in smoking cessation interventions for cancer survivors? A meta-analysis.

OBJECTIVE: We conducted a meta-analysis of randomized controlled trials designed to promote smoking cessation among cancer survivors to (a) assess how effective interventions are at increasing quit rates, and (b) determine which intervention strategies are associated with effect sizes. METHODS: Out of 10,848 records that were located using computerized searches and informal sources, 21 interventions met the inclusion criteria for the review. We developed a bespoke taxonomy of 36 categories of techniques designed to change smoking behavior, and coded sample, intervention, and methodological characteristics. Random effects meta-analysis and metaregressions were conducted. RESULTS: The sample-weighted average effect size for smoking cessation was d+ = .030, and was not significantly different from zero (95%CI = -.042 to .101). Effect sizes exhibited both publication bias and small sample bias. Metaregressions indicated that, out of the many potential moderators that were tested, just a single intervention feature was associated with effect sizes. Interventions delivered solely by nurses exhibited larger effects compared to interventions from other sources. CONCLUSION: The present review indicates that current smoking cessation interventions for cancer survivors are ineffective. High-quality and effective interventions are needed. We offer suggestions regarding promising intervention strategies. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Promoting physical activity among cancer survivors: Meta-analysis and meta-CART analysis of randomized controlled trials.

OBJECTIVE: We conducted a meta-analysis of physical activity interventions among cancer survivors to (a) quantify the magnitude of intervention effects on physical activity and (b) determine what combination of intervention strategies maximizes behavior change. METHOD: Out of 32,626 records that were located using computerized searches, 138 independent tests (N = 13,050) met the inclusion criteria for the review. We developed a bespoke taxonomy of 34 categories of techniques designed to promote psychological change, and categorized sample, intervention, and methodological characteristics. Random effects meta-analysis and metaregressions were conducted; effect size data were also submitted to meta-analysis with classification and regression trees (i.e., meta-CART). RESULTS: The sample-weighted average effect size for physical activity interventions was d+ = .35, equivalent to an increase of 1,149 steps per day. Effect sizes exhibited both publication bias and small sample bias but remained significantly different from zero, albeit of smaller magnitude (d+ ≥ .20), after correction for bias. Meta-CART indicated that the major difference in effectiveness was attributable to supervised versus unsupervised programs (d+ = .49 vs. .26). Greater contact time was associated with larger effects in supervised programs. For unsupervised programs, establishing outcome expectations, greater contact time, and targeting overweight or sedentary participants each predicted greater program effectiveness, whereas prompting barrier identification and providing workbooks were associated with smaller effect sizes. CONCLUSION: The present review indicates that interventions have a small but significant effect on physical activity among cancer survivors and offers insights into how the effectiveness of future interventions might be improved. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

When does risk perception predict protection motivation for health threats? A person-by-situation analysis.

Although risk perception is a key concept in many health behavior theories, little research has explicitly tested when risk perception predicts motivation to take protective action against a health threat (protection motivation). The present study tackled this question by (a) adopting a multidimensional model of risk perception that comprises deliberative, affective, and experiential components (the TRIRISK model), and (b) taking a person-by-situation approach. We leveraged a highly intensive within-subjects paradigm to test features of the health threat (i.e., perceived severity) and individual differences (e.g., emotion reappraisal) as moderators of the relationship between the three types of risk perception and protection motivation in a within-subjects design. Multi-level modeling of 2968 observations (32 health threats across 94 participants) showed interactions among the TRIRISK components and moderation both by person-level and situational factors. For instance, affective risk perception better predicted protection motivation when deliberative risk perception was high, when the threat was less severe, and among participants who engage less in emotional reappraisal. These findings support the TRIRISK model and offer new insights into when risk perceptions predict protection motivation.

Situation selection is a particularly effective emotion regulation strategy for people who need help regulating their emotions.

Situation selection involves choosing situations based on their likely emotional impact and may be less cognitively taxing or challenging to implement compared to other strategies for regulating emotion, which require people to regulate their emotions "in the moment"; we thus predicted that individuals who chronically experience intense emotions or who are not particularly competent at employing other emotion regulation strategies would be especially likely to benefit from situation selection. Consistent with this idea, we found that the use of situation selection interacted with individual differences in emotional reactivity and competence at emotion regulation to predict emotional outcomes in both a correlational (Study 1; N = 301) and an experimental field study (Study 2; N = 125). Taken together, the findings suggest that situation selection is an effective strategy for regulating emotions, especially for individuals who otherwise struggle to do so.