Experience-dependent Tip60 nucleocytoplasmic transport is regulated by its NLS/NES sequences for neuroplasticity gene control.

Nucleocytoplasmic transport (NCT) in neurons is critical for enabling proteins to enter the nucleus and regulate plasticity genes in response to environmental cues. Such experience-dependent (ED) neural plasticity is central for establishing memory formation and cognitive function and can influence the severity of neurodegenerative disorders like Alzheimer's disease (AD). ED neural plasticity is driven by histone acetylation (HA) mediated epigenetic mechanisms that regulate dynamic activity-dependent gene transcription profiles in response to neuronal stimulation. Yet, how histone acetyltransferases (HATs) respond to extracellular cues in the in vivo brain to drive HA-mediated activity-dependent gene control remains unclear. We previously demonstrated that extracellular stimulation of rat hippocampal neurons in vitro triggers Tip60 HAT nuclear import with concomitant synaptic gene induction. Here, we focus on investigating Tip60 HAT subcellular localization and NCT specifically in neuronal activity-dependent gene control by using the learning and memory mushroom body (MB) region of the Drosophila brain as a powerful in vivo cognitive model system. We used immunohistochemistry (IHC) to compare the subcellular localization of Tip60 HAT in the Drosophila brain under normal conditions and in response to stimulation of fly brain neurons in vivo either by genetically inducing potassium channels activation or by exposure to natural positive ED conditions. Furthermore, we found that both inducible and ED condition-mediated neural induction triggered Tip60 nuclear import with concomitant induction of previously identified Tip60 target genes and that Tip60 levels in both the nucleus and cytoplasm were significantly decreased in our well-characterized Drosophila AD model. Mutagenesis of a putative nuclear localization signal (NLS) sequence and nuclear export signal (NES) sequence that we identified in the Drosophila Tip60 protein revealed that both are functionally required for appropriate Tip60 subcellular localization. Our results support a model by which neuronal stimulation triggers Tip60 NCT via its NLS and NES sequences to promote induction of activity-dependent neuroplasticity gene transcription and that this process may be disrupted in AD.

Hip Range of Motion During Passive and 1-Leg Exercises Is Greater in Women: A Meta-analysis and Systematic Review.

PURPOSE: To summarize sex-related differences in hip range of motion (ROM), including flexion, extension, abduction, adduction, internal rotation, and external rotation. METHODS: We performed a systematic search of 3 databases (PubMed, CINAHL [Cumulative Index to Nursing and Allied Health Literature], and Embase). The search terms were as follows: hip, pelvis, range of motion, kinematic, men, and women. Included studies reported sex-specific data on hip ROM in healthy, uninjured adults. To generate hip ROM mean differences, a DerSimonian-Laird random-effects model was used. Effect sizes were pooled for each exercise. Subgroup analyses compared hip ROM by physical activity group: passive ROM, 1-leg hop or jump, 2-leg hop or jump, 2-leg drop or landing, 1-leg squat, 2-leg squat, walking, and jogging/running. Positive effect sizes represent greater ROM in women. RESULTS: Thirty-eight studies with 3,234 total subjects were included; of these subjects, 1,639 were women (50.1%). The mean age was 25.3 years. An effect difference was considered statistically significant if P < .05 and clinically significant if the mean difference was greater than 4.0°. Women showed statistically and clinically significantly greater hip flexion in passive ROM (mean difference, 6.4°) and during the 1-leg hop or jump exercise (mean difference, 6.5°). Women also showed statistically and clinically significantly greater hip adduction during the 1-leg hop or jump (mean difference, 4.5°) and 1-leg squat (mean difference, 4.4°) exercises, as well as statistically and clinically significantly greater hip internal rotation in passive ROM (mean difference, 8.2°). In contrast, men showed statistically and clinically significantly greater flexion during the 2-leg hop or jump exercise (mean difference, -9.1°). No clinically significant differences in extension, abduction, or external rotation were found between women and men. CONCLUSIONS: On average, women showed statistically and clinically significantly greater flexion, adduction, and internal rotation during passive and 1-leg exercises whereas men showed statistically and clinically significantly greater flexion during the 2-leg hop or jump exercise. LEVEL OF EVIDENCE: Level IV, meta-analysis and systematic review of Level II-IV studies.

Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.

Through their capacity to sense danger signals and to generate active interleukin-1ß (IL-1ß), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1ß, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1ß was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders.

Transferring the sandwich principle to instructional videos: is it worth the effort?

BACKGROUND: The sandwich principle is an educational concept that regularly alternates between collective and individual learning phases within one learning unit. Applying sandwich principle to lectures has proven to be more effective for learning outcomes than classical lectures. Supposedly, this teaching format also leads to a beneficial knowledge transfer when applied to other teaching formats. Therefore, the aim of this study was to investigate the effect of the sandwich principle on instructional videos and how its use was evaluated by students. METHODS: Participants (n = 51) were randomly allocated into two groups. Both groups were given a test to assess the baseline level of knowledge. Afterwards, the control group watched the normal instructional video on cleft lips and palates, while the sandwich group watched the same video modified according to the sandwich principle. The participants then had to answer 30 single-choice questions to assess their knowledge gain and evaluate the instructional video. Long-term retention of the knowledge was tested again 6 months later using the same test questions. The unpaired t-test and ANOVA were used to compare the results. RESULTS: Comparison of the pre-test and post-test results of both groups showed significantly increased test scores (p < 0.0001). Regarding long-term retention, the mean test scores were still significantly higher in both groups than before watching the video (p < 0.0001). For all test results, there was no significant difference between the groups (p > 0.05). The evaluation showed that the students highly appreciated the modified video and found the interruptions for repetition of previously learned knowledge useful. CONCLUSION: The hypothesis that the modification of instructional videos according to the sandwich principle would lead to an improved learning outcome could not be proved subjectively or objectively. Nevertheless, the teaching format was highly appreciated by the students and may have increased their motivation to learn with instructional videos.

Pattern recognition receptor function in neutrophils.

Previously, neutrophils were largely ignored in the pattern recognition receptor (PRR) signaling field. However, interest in neutrophil biology has been revitalized by emerging roles for neutrophils in promoting protective and pathogenic T helper (Th)17-driven immune responses and in orchestrating innate and adaptive immunity via cytokine/chemokine production. Although it was originally assumed that neutrophils are transcriptionally inert and their short lifespan limits their ability to respond to PRR agonists, the past 5 years has seen tremendous advances in neutrophil PRR signaling that have shifted this paradigm. Here, we review recent findings that demonstrate that neutrophils express a broad repertoire of PRRs, respond dynamically to their stimulation during infection and inflammation, and that neutrophil PRRs are key regulators of in vivo host immune responses.

The inflammasome: an integrated view.

An inflammasome is a multiprotein complex that serves as a platform for caspase-1 activation and caspase-1-dependent proteolytic maturation and secretion of interleukin-1ß (IL-1ß). Though a number of inflammasomes have been described, the NLRP3 inflammasome is the most extensively studied but also the most elusive. It is unique in that it responds to numerous physically and chemically diverse stimuli. The potent proinflammatory and pyrogenic activities of IL-1ß necessitate that inflammasome activity is tightly controlled. To this end, a priming step is first required to induce the expression of both NLRP3 and proIL-1ß. This event renders the cell competent for NLRP3 inflammasome activation and IL-1ß secretion, and it is highly regulated by negative feedback loops. Despite the wide array of NLRP3 activators, the actual triggering of NLRP3 is controlled by integration a comparatively small number of signals that are common to nearly all activators. Minimally, these include potassium efflux, elevated levels of reactive oxygen species (ROS), and, for certain activators, lysosomal destabilization. Further investigation of how these and potentially other as yet uncharacterized signals are integrated by the NLRP3 inflammasome and the relevance of these biochemical events in vivo should provide new insight into the mechanisms of host defense and autoinflammatory conditions.

Advance Care Planning Practice Patterns Before and During a Pandemic.

Introduction: The COVID-19 pandemic resulted in introspection of the United States health care infrastructure, especially with advance care planning (ACP). Methods: This is a retrospective chart review assessing the frequency of ACP discussions and formal documents reflecting ACP wishes in an outpatient palliative medicine (PM) practice. The study site was at University Medical Center New Orleans from pre-COVID-19 surge (November 2019-February 2020) to months during and post-COVID-19 surge (March-April 2020). Results: Results showed an increase in ACP discussions during the post-COVID-19 months. Patients seen during the surge and post-COVID-19 months were more likely to discuss medical power of attorney (odds ratio [OR] = 1.78, p = 0.045) and preferred code status (OR = 2.82, p < 0.001). Conclusion: Our study showed that more ACP discussions were conducted post-COVID-19 versus pre-COVID-19. However, formal documents reflecting these wishes were lacking. These results can help guide ACP use in crisis periods and improve understanding of ACP discussions in an outpatient PM clinic.

Alternative activation of macrophages by IL-4 requires SHIP degradation.

Alternatively activated macrophages are critical in host defense against parasites and are protective in inflammatory bowel disease, but contribute to pathology in asthma and solid tumors. The mechanisms underlying alternative activation of macrophages are only partially understood and little is known about their amenability to manipulation in pathophysiological conditions. Herein, we demonstrate that Src homology 2-domain-containing inositol-5'-phosphatase (SHIP)-deficient murine macrophages are more sensitive to IL-4-mediated skewing to an alternatively activated phenotype. Moreover, SHIP levels are decreased in macrophages treated with IL-4 and in murine GM-CSF-derived and tumor-associated macrophages. Loss of SHIP and induction of alternatively activated macrophage markers, Ym1 and arginase I (argI), were dependent on phosphatidylinositol 3-kinase (PI3K) activity and argI induction was dependent on the class IA PI3Kp110δ isoform. STAT6 was required to reduce SHIP protein levels, but reduced SHIP levels did not increase STAT6 phosphorylation. STAT6 transcription was inhibited by PI3K inhibitors and enhanced when SHIP was reduced using siRNA. Importantly, reducing SHIP levels enhanced, whereas SHIP overexpression or blocking SHIP degradation reduced, IL-4-induced argI activity. These findings identify SHIP and the PI3K pathway as critical regulators of alternative macrophage activation and SHIP as a target for manipulation in diseases where macrophage phenotype contributes to pathology.

Telehealth Interventions to Improve Diabetes Management Among Black and Hispanic Patients: a Systematic Review and Meta-Analysis.

BACKGROUND: Previous systematic reviews have found that telehealth is an effective strategy for implementing interventions to improve glycemic control and other clinical outcomes for diabetes patients. However, these reviews have not meaningfully focused on Black and Hispanic patients-partly because of the lack of adequate representation of people from racial and ethnic minority groups in clinical trials. It is unclear whether telehealth interventions are effective at improving glycemic control among Black and Hispanic patients given the disproportionate number of barriers they face accessing health care. OBJECTIVES: A systematic review and meta-analysis of randomized control trials that used telehealth interventions for improving glycemic control among Black and Hispanic diabetes patients. METHODS: We reviewed PubMed, Embase, Web of Science, CINAHL, PsycINFO, and clinicalTrials.gov from inception to March 2021. We used a narrative summary approach to describe key study characteristics and graded the quality of studies using two reviewers. The pooled net change in HbA1c values was estimated across studies using a random-effects model. RESULTS: We identified 10 studies that met our inclusion and exclusion criteria. Nine studies were included in the meta-analysis. Only one study was rated as having low bias. Telehealth interventions were primarily delivered by telephone calls, text messages, web-based portals, and virtual visits. Most interventions involved delivering diabetes self-management education. Telehealth intervention pooled across studies with a mix of Black and Hispanic participants (> 50% sample) was associated with a - 0.465 ([CI: - 0.648 to - 0.282], p = 0.000) reduction in HbA1c. CONCLUSIONS: Our findings suggest telehealth interventions are effective at improving glycemic control among Black and Hispanic diabetes patients.

SHIP prevents lipopolysaccharide from triggering an antiviral response in mice.

Gram-negative bacterial infections, unlike viral infections, do not typically protect against subsequent viral infections. This is puzzling given that lipopolysaccharide (LPS) and double-stranded (ds) RNA both activate the TIR domain-containing adaptor-inducing interferon beta (TRIF) pathway and, thus, are both capable of eliciting an antiviral response by stimulating type I interferon (IFN) production. We demonstrate herein that SH2-containing inositol-5'-phosphatase (SHIP) protein levels are dramatically increased in murine macrophages via the MyD88-dependent pathway, by up-regulating autocrine-acting transforming growth factor-beta (TGFbeta). The increased SHIP then mediates, via inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway, cytosine-phosphate-guanosine (CPG)- and LPS-induced tolerance and cross-tolerance and restrains IFN-beta production induced by a subsequent exposure to LPS or dsRNA. Intriguingly, we found, using isoform-specific PI3K inhibitors, that LPS- or cytosine-phosphate-guanosine-induced interleukin-6 (IL-6) is positively regulated by p110alpha, -gamma, and -delta but negatively regulated by p110beta. This may explain some of the controversy concerning the role of PI3K in Toll-like receptor-induced cytokine production. Consistent with our in vitro findings, SHIP(-/-) mice overproduce IFN-beta in response to LPS, and this leads to antiviral hypothermia. Thus, up-regulation of SHIP in response to Gram-negative bacterial infections probably explains the inability of such infections to protect against subsequent viral infections.

Neuro-oncology Multidisciplinary Clinic and Improvements in Patient Outcome.

BACKGROUND: Neuro-oncology care is becoming increasingly complex and patients often see multiple specialists. Multidisciplinary clinic (MDC) is a patient-centric option to allow multiple specialists to be involved where patients see multiple providers on the same day. OBJECTIVE: The objective of this study was to evaluate the role of a neuro-oncology MDC on patient outcomes. MATERIALS AND METHODS: Retrospective study was performed on consecutive patients who received radiosurgery for central nervous system (CNS) disease. We evaluated patients 2 years before and 2 years after the implementation of a MDC. RESULTS: A total of 351 patients were analyzed, 163 patients before MDC and 188 after implementation of MDC. Before MDC the median follow-up was dependent on which department ordered follow-up radiographic imaging. This discrepancy decreased after the MDC. Overall survival for patients with CNS metastatic disease improved in the MDC cohort (median survival of 248 before MDC and 315 d after, P<0.027). CONCLUSION: We found that neuro-oncology MDC improved follow-up across disciplines and improved overall survival for patients with CNS metastatic disease.

Environmental Drivers of Questing Activity of Juvenile Black-Legged Ticks (Acari: Ixodidae): Temperature, Desiccation Risk, and Diel Cycles.

Vector feeding behavior can have a profound influence on the transmission of vector-borne diseases. In the case of black-legged ticks, Ixodes scapularis Say, which vectors the agents of Lyme disease, babesiosis, and other pathogens, the timing and propensity of questing can determine which hosts are fed upon as well as the risk of contact with humans. Yet we know little about the controls and constraints on tick host-finding behavior under natural conditions. Ticks must balance the need to quest for blood meal hosts with the risk of desiccation, all on a fixed energy budget. Prior research, primarily in the laboratory, has shown that questing activity varies with conditions (e.g., temperature, relative humidity), light-dark cycles, and energy reserves, but the findings have been idiosyncratic and the dominant factor(s) in nature remains unknown. We measured questing activity of nymphs and larvae throughout the day and night and over several weeks in enclosures across a range of suitable tick habitats within a site in the Northeast. Activity of nymphs increased slightly during dawn and dusk, opposite of larvae, and declined slightly with air temperature and rain, but these patterns were weak and inconsistent among replicate sites. Rather it appears a fraction of ticks were questing most of the time, regardless of conditions. Our study suggests neither climatic conditions or light-dark cycles have appreciable influence on tick questing behavior.

The impact of residual mitral regurgitation after MitraClip therapy in functional mitral regurgitation.

AIMS: MitraClip therapy for the treatment of functional mitral regurgitation (FMR) is an increasingly used intervention for high-risk surgical patients. The aim of this observational study was to assess the impact of residual mitral regurgitation (rMR) at discharge on long-term outcome after MitraClip therapy in patients with FMR. METHODS AND RESULTS: Overall, 458 patients (mean age 73.8 ± 8.9 years) underwent MitraClip implantation between September 2008 and December 2017. The impact of rMR ≤ 1+ at discharge (n = 251) was retrospectively compared to patients graded as rMR 2+ (n = 173) and rMR ≥3+ (n = 34) at discharge. Median follow-up time was 5.09 years (5.00-5.26) with maximum follow-up of 10.02 years. The primary outcome was survival, and Kaplan-Meier analyses revealed significant differences among all rMR subgroups with highest survival rates for rMR ≤ 1+ patients. This was further confirmed by composite outcome analyses (P < 0.02). The inferior outcomes of rMR 2+ and rMR ≥ 3+ at discharge were confirmed by increased adjusted hazard ratios when rMR 2+ (1.54, P = 0.0039) and rMR ≥ 3+ (2.16, P = 0.011) were compared to rMR ≤ 1+. Moreover, patients with stable rMR ≤ 1+ grades within 12 months showed significantly higher survival rates compared to patients with rMR ≤ 1+ at discharge and rMR ≥ 2+ at 12-month follow-up or rMR ≥ 2+ at discharge and 12-month follow-up (P = 0.029). CONCLUSIONS: Patients with optimal and durable rMR ≤ 1+ at discharge and 12-month follow-up showed better outcome compared to patients with rMR 2+ and rMR ≥ 3+. Treatment success and durability characterized by rMR ≤ 1+ at discharge and 12 months seem to be important factors for long-term outcomes, which has to be further confirmed by prospective randomized trials.

Modest alterations in patterns of motor neuron dendrite morphology in the Fmr1 knockout mouse model for fragile X.

Fragile X, an inheritable form of mental retardation, is caused by the inactivation of a gene on the X chromosome, FMR1 which codes for an RNA binding protein, fragile X mental retardation protein. Loss of this protein is associated with reduced complexities of neuronal dendrites and alterations in spine morphology in a number of cortical brain regions, and these deficits may underlie the cognitive impairment observed in fragile X patients. Among the many symptoms of fragile X are altered motor functions, although the neuronal basis for these remains unclear. In this study we investigated whether knockout of Fmr1 in the mouse model of fragile X altered dendrite morphology in developing spinal cord motor neurons. We find that Fmr1 knockout leads to modest alterations in the distribution of dendritic arbor across the span of the motor neuron dendritic tree in 2- and 4-week-old mice, compared to wild-type controls, consistent with slower rates of extension and abnormal pruning of intermediate dendritic segments. These studies suggest that some motor deficits in fragile X patients may be due to abnormal maturation of dendritic patterning within spinal motor neurons, and suggest that strategies aimed at preventing motor impairment in fragile X patients may be targeted at motor functions during early development.

Body mass index, disordered eating behavior, and acquisition of health information: examining ethnicity and weight-related issues in a college population.

OBJECTIVE AND PARTICIPANTS: To investigate ethnic differences related to weight, the authors assessed body mass index, dysfunctional eating, receipt of health information, and perceived obstacles to healthy lifestyles of 210 ethnically diverse college women. METHODS: The authors used the Eating Attitudes Test to assess dieting, food preoccupation, and bulimic behaviors. RESULTS: The authors found no ethnic differences in body mass index or disordered eating, but African Americans were more likely than were European Americans and Latina Americans to receive nutrition information from professionals and less likely than European Americans to perceive time as an obstacle. Overall, receipt of health information from a professional was related to fewer disordered eating behaviors; however, the specific eating behavior that was reduced varied by ethnicity. CONCLUSIONS: Health professionals should reconsider traditional assumptions of disordered eating behavior as a European American problem and consider cultural appropriateness in the development of effective health programs.

Gender-Based Differences and Barriers in Skin Protection Behaviors in Melanoma Survivors.

Purpose. Skin protection behaviors and environmental exposure play a crucial role in the development and subsequent management of melanoma. This study investigates gender-based differences in skin protection behaviors after melanoma treatment. Methods. Patients diagnosed and surgically treated for cutaneous melanomas over the last six years in a geographically high risk area were surveyed over telephone using a standardized script. Results. Of 150 survey results obtained, there were 82 males and 68 females. Overall, 87% of participants reported skin self-examination for abnormal markings more often and 94% reported wearing skin protective clothing more often, with females being more than males. Females limited outdoor activity more often than males, 79% to 54%, p < 0.05. When outside, females sought shade more often than males, 75% to 56%, p < 0.05. However, males wore a wide brim hat more often than females, 52% to 28%, p < 0.05. Interestingly, 60% of participants reported wearing SPF 30 sunscreen less often, p < 0.05. Conclusion. Larger percentage of females adopted behavioral changes to prevent future melanoma. Those living in high risk areas and with outdoor occupations need particular attention to skin care. Population based screening should be adopted to deal with this rising public health crisis.

Transcatheter Mitral Valve Repair in Surgical High-Risk Patients: Gender-Specific Acute and Long-Term Outcomes.

BACKGROUND: Analyses emphasizing gender-related differences in acute and long-term outcomes following MitraClip therapy for significant mitral regurgitation (MR) are rare. METHODS: 592 consecutive patients (75 ± 8.7 years, 362 men, 230 women) underwent clinical and echocardiographic follow-up for a median of 2.13 (0.99-4.02) years. RESULTS: Significantly higher prevalence of cardiovascular comorbidities, renal failure, and adverse echocardiographic parameters in men resulted in longer device time (p = 0.007) and higher numbers of implanted clips (p = 0.0075), with equal procedural success (p = 1.0). Rehospitalization for heart failure did not differ (p[logrank] = 0.288) while survival was higher in women (p[logrank] = 0.0317). Logarithmic increase of NT-proBNP was a common independent predictor of death. Hypercholesterolemia and peripheral artery disease were predictors of death only in men while ischemic and dilative cardiomyopathy (CM) and age were predictors in women. Independent predictors of rehospitalization for heart failure were severely reduced ejection fraction and success in men while both ischemic and dilative CM, logistic EuroSCORE, and MR severity were predictive in women. CONCLUSIONS: Higher numbers of implanted clips and longer device time are likely related to more comorbidities in men. Procedural success and acute and mid-term clinical outcomes were equal. Superior survival for women in long-term analysis is presumably attributable to a comparatively better preprocedural health.

Inflammasome activation and inhibition in primary murine bone marrow-derived cells, and assays for IL-1α, IL-1ß, and caspase-1.

Through its ability to control the proteolytic maturation and secretion of interleukin-1 family cytokines, the inflammasome occupies a central role in the activation of inflammation and also influences the shaping of adaptive immunity. Since it affects a multitude of different immune responses from autoinflammatory diseases to host defense, vaccine efficacy, and even cancer, it has become of interest to many researchers. Here, we describe a straightforward method for inflammasome assays in primary murine bone marrow--derived myeloid cells. The protocol encompasses cell handling, inflammasome activation and inhibition, as well as the detection of IL-1ß, caspase-1, and IL-1α by ELISA and Western blot.