Dynamic Trait Distribution as a Source for Shifts in Interaction Strength and Population Density.

AbstractIntraspecific trait variation has been increasingly recognized as an important factor in determining species interactions and diversity. Eco-evolutionary models have studied the distribution of trait values within a population that changes over the generations as a result of selection and heritability. Nonheritable traits that can change within the lifetime, such as behavior, can cause trait-mediated indirect effects, often studied by modeling the dynamics of a homogeneous trait. Complementary to these approaches, we study the distribution of traits within a population and its dynamics on short timescales due to ecological processes. We consider several mechanisms by which the trait distribution can shift dynamically: phenotypic plasticity within each individual, differential growth among individuals, and preferential consumption by the predator. Through a simple predator-prey model that explicitly tracks the trait distribution within the prey, we identify the density and trait effects from the predator. We show that the dynamic shift of the trait distribution can lead to the modification of interaction strength between species and result in otherwise unexpected consequences. A particular example is the emergent promotion of the prey by the predator, where the introduction of the predator causes the prey population to increase rather than decrease.

Chimeric Antigen Receptor (CAR)-T Cell Therapy for Non-Hodgkin's Lymphoma.

This review focuses on the use of chimeric antigen receptor (CAR)-T cell therapy to treat non-Hodgkin's lymphoma (NHL), a classification of heterogeneous malignant neoplasms of the lymphoid tissue. Despite various conventional and multidrug chemotherapies, the poor prognosis for NHL patients remains and has prompted the utilization of groundbreaking personalized therapies such as CAR-T cells. CAR-T cells are T cells engineered to express a CAR that enables T cells to specifically lyse tumor cells with extracellular expression of a tumor antigen of choice. A CAR is composed of an extracellular antibody fragment or target protein binding domain that is conjugated to activating intracellular signaling motifs common to T cells. In general, CAR-T cell therapies for NHL are designed to recognize cellular markers ubiquitously expressed on B cells such as CD19+, CD20+, and CD22+. Clinical trials using CAR-T cells such as ZUMA-7 and TRANSFORM demonstrated promising results compared to standard of care and ultimately led to FDA approval for the treatment of relapsed/refractory NHL. Despite the success of CAR-T therapy for NHL, challenges include adverse side effects as well as extrinsic and intrinsic mechanisms of tumor resistance that lead to suboptimal outcomes. Overall, CAR-T cell therapies have improved clinical outcomes in NHL patients and generated optimism around their future applications.

Acclimating Nursing Students After the Pandemic: "It's ASNAP!"

BACKGROUND: This article describes the development of a comprehensive pilot program, "It's ASNAP!" (Acclimating Nursing Students After the Pandemic). The program incorporated the academic, social, and emotional well-being of undergraduate nursing students returning to campus after the coronavirus disease 2019 (COVID-19) pandemic. METHOD: A purposeful sample of 488 students was recruited to participate via an anonymous survey on the academic, social, and emotional aspects of acclimating back to campus life. RESULTS: A total of 121 undergraduate nursing students responded to the survey. The majority of students reported study groups (79%) and de-stressing events (86%) were the most helpful as they acclimated back to campus. Compared with the emotional and social areas of support, the academic area of support was of highest interest to the students. CONCLUSION: The "It's ASNAP!" program has been acculturated into the school of nursing to support students via study halls, tutoring, and social activities, as well as resilient threads and listening sessions during finals week. [J Nurs Educ. 2023;62(9):516-518.].

NK cells from COVID-19 positive patients exhibit enhanced cytotoxic activity upon NKG2A and KIR2DL1 blockade.

SARS CoV-2 has caused a global pandemic leading to significant morbidity and mortality. There is a need to elucidate and further understand the implications of COVID-19 disease on the immune system to develop improved therapeutic strategies. In particular, Natural Killer (NK) cells play an essential role in mediating the innate immune response against viral infections. To better understand the role of innate immunity in COVID-19, we characterized the phenotype of circulating NK cells from 74 COVID-19 patients and 25 controls. Through evaluating the protein expression of activating and inhibitory NK cell surface molecules using dimension reduction analysis and clustering, we identified 4 specific clusters of NK cells specific to disease state (COVID-19 positive or COVID-19 negative) and characterized COVID-19 positive NK cells as: NGK2A+KIR2DL1+NKG2C-. Utilizing blocking antibodies specific for receptors NKG2A and KIR2DL1, we found that both NKG2A and KIR2DL1 blockade markedly enhances the ability of NK cells from COVID-19 positive patients to lyse SARS-Cov-2 infected cells. Overall, this study reveals new insights into NK cell phenotypes during SARS-CoV-2 infection and suggests a therapeutic approach worthy of further investigation to enhance NK cell-mediated responses against the virus.

Heterogeneity of interaction strengths and its consequences on ecological systems.

Ecosystems are formed by networks of species and their interactions. Traditional models of such interactions assume a constant interaction strength between a given pair of species. However, there is often significant trait variation among individual organisms even within the same species, causing heterogeneity in their interaction strengths with other species. The consequences of such heterogeneous interactions for the ecosystem have not been studied systematically. As a theoretical exploration, we analyze a simple ecosystem with trophic interactions between two predators and a shared prey, which would exhibit competitive exclusion in models with homogeneous interactions. We consider several scenarios where individuals of the prey species differentiate into subpopulations with different interaction strengths. We show that in all these cases, whether the heterogeneity is inherent, reversible, or adaptive, the ecosystem can stabilize at a new equilibrium where all three species coexist. Moreover, the prey population that has heterogeneous interactions with its predators reaches a higher density than it would without heterogeneity, and can even reach a higher density in the presence of two predators than with just one. Our results suggest that heterogeneity may be a naturally selected feature of ecological interactions that have important consequences for the stability and diversity of ecosystems.

Excess Growth Hormone Alters the Male Mouse Gut Microbiome in an Age-dependent Manner.

The gut microbiome has an important role in host development, metabolism, growth, and aging. Recent research points toward potential crosstalk between the gut microbiota and the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Our laboratory previously showed that GH excess and deficiency are associated with an altered gut microbial composition in adult mice. Yet, no study to date has examined the influence of GH on the gut microbiome over time. Our study thus tracked the effect of excess GH action on the longitudinal changes in the gut microbial profile (ie, abundance, diversity/maturity, predictive metabolic function, and short-chain fatty acid [SCFA] levels) of bovine GH (bGH) transgenic mice at age 3, 6, and 12 months compared to littermate controls in the context of metabolism, intestinal phenotype, and premature aging. The bGH mice displayed age-dependent changes in microbial abundance, richness, and evenness. Microbial maturity was significantly explained by genotype and age. Moreover, several bacteria (ie, Lactobacillus, Lachnospiraceae, Bifidobacterium, and Faecalibaculum), predictive metabolic pathways (such as SCFA, vitamin B12, folate, menaquinol, peptidoglycan, and heme B biosynthesis), and SCFA levels (acetate, butyrate, lactate, and propionate) were consistently altered across all 3 time points, differentiating the longitudinal bGH microbiome from controls. Of note, the bGH mice also had significantly impaired intestinal fat absorption with increased fecal output. Collectively, these findings suggest that excess GH alters the gut microbiome in an age-dependent manner with distinct longitudinal microbial and predicted metabolic pathway signatures.

Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma.

Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB-based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL. SIGNIFICANCE: This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone. This article is highlighted in the In This Issue feature, p. 1825.

Adolescent Relationship Abuse, Gender Equitable Attitudes, Condom and Contraception Use Self-Efficacy Among Adolescent Girls.

Introduction: Experiencing adolescent relationship abuse (ARA) negatively impacts sexual health and influences risk behaviors of adolescent girls. ARA may be associated with more inequitable gender attitudes among girls, a potentially modifiable factor in violence prevention. This study examines the association among gender equitable attitudes, experiences of ARA, and sexual behaviors among girls participating in Sisterhood 2.0, a community-based violence prevention program implemented in low resource neighborhoods. Methods: Data were from baseline surveys collected for Sisterhood 2.0 implemented in Pittsburgh, PA. Participant demographics, gender equitable attitudes, self-efficacy to use condoms with partners, and self-efficacy to select appropriate contraception were assessed. A latent class analysis (LCA) estimated probability of responses to nine indicators, including sexual behavior self-efficacy and violence. Multigroup LCA by grade (9-12) was also estimated and analyses were performed with SAS V9.4. Results: Female-identified adolescents ages 13-19 (n = 246) were primarily Black (75%) and evenly distributed across grade in school. Sixty-five percent reported emotional relationship abuse and 31% reported physical abuse within the previous nine months. A three-class solution was best fitting for the LCA. Experiences of violence were related to less equitable gender attitudes, being sexually active, and lower condom and contraception self-efficacy. Younger participants who were sexual minorities with less educated heads of household had more experiences with ARA and less equitable gender attitudes. Discussion: Gender equitable attitudes were lower in adolescent girls with greater experiences of ARA and worse condom and contraception self-efficacy. Integrating discussions about healthy sexual relationships and gender equity may be salient factors in violence prevention.

Chemical screening identifies novel small molecule activators of natural killer cell cytotoxicity against cancer cells.

Natural killer (NK) cells are cytotoxic lymphocytes that play a major role in the innate immune system. NK cells exhibit potent cytotoxic activity against cancer cells and virally infected cells without antigen priming. These unique cytotoxic properties make NK cells a promising therapeutic against cancer. Limitations of NK cell therapy include deficiencies in high clinical efficacy often due to a need for a high NK cell to target cell ratio to achieve effective killing. In order to address the suboptimal efficacy of current adoptive NK cell therapy, a high throughput screen (HTS) was designed and performed to identify drug-like compounds that increase NK cytotoxic activity against tumor cells without affecting the normal cells. This screen was performed in a 384-well plate format utilizing an expanded primary NK cell product and ovarian cancer cells as a target cell (TC) line. Of the 8000 diverse small molecules screened, 16 hits were identified (0.2% hit rate) based on both a robust Z (RZ) score < -3 and a greater than 10% increase in NK cell killing. A validation screen had a confirmation rate of 70%. Select compounds were further validated and characterized by additional cytotoxicity assays including activity against multiple blood cancer and solid tumor cell lines, with no effect on primary human T cells. This work demonstrates that high-throughput screening can be reliably used to identify compounds that increase NK tumoricidal activity in vitro that can be further investigated and translated for potential clinical application. Précis: Our work led to the identification of promising compound that potently increases NK cell-mediated killing of a variety of different cancer cells, but no impact on the killing of normal cells. This compound demonstrates the utility of this assay.

Single cell RNA sequencing of AML initiating cells reveals RNA-based evolution during disease progression.

The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC's) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML progression have focused on genetic changes at the DNA mutation level mostly in bulk AML cells and demonstrated the existence of DNA clonal evolution. Here we identified in LICs that the phenomenon of RNA clonal evolution occurs during AML progression. Despite the presence of vast transcriptional heterogeneity at the single cell level, pathway analysis identified common signaling networks involving metabolism, apoptosis and chemokine signaling that evolved during AML progression and become a signature of relapse samples. A subset of this gene signature was validated at the protein level in LICs by flow cytometry from an independent AML cohort and functional studies were performed to demonstrate co-targeting BCL2 and CXCR4 signaling may help overcome therapeutic challenges with AML heterogeneity. It is hoped this work will facilitate a greater understanding of AML relapse leading to improved prognostic biomarkers and therapeutic strategies to target LIC's.

Safety and Tolerability of Burst-Cycling Deep Brain Stimulation for Freezing of Gait in Parkinson's Disease.

Background: Freezing of gait (FOG) is a common symptom in Parkinson's disease (PD) and can be difficult to treat with dopaminergic medications or with deep brain stimulation (DBS). Novel stimulation paradigms have been proposed to address suboptimal responses to conventional DBS programming methods. Burst-cycling deep brain stimulation (BCDBS) delivers current in various frequencies of bursts (e.g., 4, 10, or 15 Hz), while maintaining an intra-burst frequency identical to conventional DBS. Objective: To evaluate the safety and tolerability of BCDBS in PD patients with FOG. Methods: Ten PD subjects with STN or GPi DBS and complaints of FOG were recruited for this single center, single blinded within-subject crossover study. For each subject, we compared 4, 10, and 15 Hz BCDBS to conventional DBS during the PD medication-OFF state. Results: There were no serious adverse events with BCDBS. It was feasible and straightforward to program BCDBS in the clinic setting. The benefit was comparable to conventional DBS in measures of FOG, functional mobility and in PD motor symptoms. BCDBS had lower battery consumption when compared to conventional DBS. Conclusions: BCDBS was feasible, safe and well tolerated and it has potential to be a viable future DBS programming strategy.

Emergent, linked traits of fluctuation feedback systems.

A variety of nonequilibrium systems display intermittent switching between semistable macroscopic behaviors. We identify a certain type of indeterminacy, with episodes of patterned behavior irregularly punctuated by transitions. It appears that the long-lived patterns are, not coincidentally, also low-fluctuation states. We describe these linked traits with a small set of examples.

An assessment of sense of belonging in higher education among student service members/veterans.

BACKGROUND: The health, well-being, and integration of student service members/veterans (SSM/Vs) into higher education has become a growing focal point for college health practitioners and researchers. Methods: Secondary data analysis of "Campus Climate and Culture" module of the Healthy Minds Study (HMS), which included 8211 students. Analyses examined whether military status was associated with sense of belonging. Results: The relationship between military-affiliation and sense of belonging (low versus high) was statistically significant [χ2 (2, 8211) = 10.855, p < 0.01], such that 42% of SSM/V reported low sense of belonging compared to their Reservist (33%) and civilian (28%) counterparts. Even after controlling for age, sex, year in school, and grade point average, SSM/V status (OR = 0.16, Wald = 6.17; p < 0.05), was negatively associated with sense of belonging. Conclusions: Results highlight a need for strategic college health initiatives to foster institutional inclusion and cohort building among SSM/V in higher education.

Automated Manufacture of Autologous CD19 CAR-T Cells for Treatment of Non-hodgkin Lymphoma.

Chimeric antigen receptor T cells (CAR-T cell) targeting CD19 are effective against several subtypes of CD19-expressing hematologic malignancies. Centralized manufacturing has allowed rapid expansion of this cellular therapy, but it may be associated with treatment delays due to the required logistics. We hypothesized that point of care manufacturing of CAR-T cells on the automated CliniMACS Prodigy® device allows reproducible and fast delivery of cells for the treatment of patients with non-Hodgkin lymphoma. Here we describe cell manufacturing results and characterize the phenotype and effector function of CAR-T cells used in a phase I/II study. We utilized a lentiviral vector delivering a second-generation CD19 CAR construct with 4-1BB costimulatory domain and TNFRSF19 transmembrane domain. Our data highlight the successful generation of CAR-T cells at numbers sufficient for all patients treated, a shortened duration of production from 12 to 8 days followed by fresh infusion into patients, and the detection of CAR-T cells in patient circulation up to 1-year post-infusion.

An Online Behavioral Health Intervention Promoting Mental Health, Manhood, and Social Support for Young Black Men: The YBMen Project.

Conventional definitions of mental health, manhood, and social support create barriers to accessing behavioral health care for Black men ages 18 to 30. Targeted behavioral health interventions sensitive to culture, social norms, and gender that circumvent these barriers are desperately needed to improve access and integrated care for this group. This article reports mixed methods findings from the 2017 iteration of the Young Black Men, Masculinities, and Mental Health (YBMen) project, a social media-based, psychoeducational program that promotes mental health, progressive definitions of manhood, and sustainable social support for Black men. Young Black men (n = 350) across two universities in the Midwest completed baseline surveys on their mental health, definitions of manhood, and social support. Forty of the men participated in the YBMen intervention and at postintervention reported experiencing fewer depressive symptoms on the Patient Health Questionnaire (PHQ-9, Z = -2.05, p < .01) and the Gotland Male Depression Scale (GMDS; Z = -1.76, p < .05). There were also changes on the Conformity to Masculine Norms Inventory (CMNI) for Self-Reliance (Z = -0.34, p = .26) and Heterosexual Self-Presentation (Z = -0.18, p = .59), though these changes were not statistically significant. A qualitative review of postintervention interviews revealed participants' appreciation of the YBMen project and its influence on their mental health, manhood, and social support. Programmatic efforts that support the behavioral health, positive development, and social relationships of Black men translate into positive families, communities, and experiences as they live, learn, love, and work over the life course.

Growth Hormone Deficiency and Excess Alter the Gut Microbiome in Adult Male Mice.

The gut microbiome has been implicated in host metabolism, endocrinology, and pathophysiology. Furthermore, several studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. Yet, no study to date has examined the specific role of GH on the gut microbiome. Our study thus characterized the adult gut microbial profile and intestinal phenotype in GH gene-disrupted (GH-/-) mice (a model of GH deficiency) and bovine GH transgenic (bGH) mice (a model of chronic, excess GH action) at 6 months of age. Both the GH-/- and bGH mice had altered microbial signatures, in opposing directions at the phylum and genus levels. For example, GH-/- mice had significantly reduced abundance in the Proteobacteria, Campylobacterota, and Actinobacteria phyla, whereas bGH mice exhibited a trending increase in those phyla compared with respective controls. Analysis of maturity of the microbial community demonstrated that lack of GH results in a significantly more immature microbiome while excess GH increases microbial maturity. Several common bacterial genera were shared, although in opposing directions, between the 2 mouse lines (e.g., decreased in GH-/- mice and increased in bGH mice), suggesting an association with GH. Similarly, metabolic pathways like acetate, butyrate, heme B, and folate biosynthesis were predicted to be impacted by GH. This study is the first to characterize the gut microbiome in mouse lines with altered GH action and indicates that GH may play a role in the growth of certain microbiota thus impacting microbial maturation and metabolic function.

Dynamics of tinnitus and coordinated reset therapy.

A clinical study of tinnitus patients found promising results using a noninvasive therapy. We introduce a dynamical model to explore both the onset of tinnitus and the effects of coordinated reset therapy. Our model extends an existing theory of individual outer hair cell dynamics to include their mutual interaction, and considers how sustained activity can inhibit the natural recovery exhibited by normal (healthy) individuals. The model is investigated through numerical simulations and shows behavior broadly similar to that reported in the clinical study.

National college health assessment sampling: Organizational barriers preventing black participation and organizational solutions for appropriate representation.

Objective: This investigation longitudinally examined the participation of Black college students in the American College Health Association?s National College Health Assessment (ACHA-NCHA). Participants: All respondents to ACHA-NCHA from the years 2008, 2011, & 2014 were included in the analysis. Methods: This study compared the descriptive demographic student characteristics from the 2008, 2011, & 2014 ACHA-NCHA data to the National Center for Education Statistics (NCES) college enrollment for the corresponding years. Results: Despite constituting 14.5% of the total enrollment in 4-year universities and colleges from 2005 to 2013, Black students represented about 7% of the ACHA-NCHA respondents. Conclusion: Having a sample lacking valid representation of minorities can further lead to biased and flawed assumptions. Therefore, organizations such as ACHA should make concerted efforts to gather data that is reflective of national enrollment rates.

Association between Foot Care Knowledge and Practices among African Americans with Type 2 Diabetes: An Exploratory Pilot Study.

OBJECTIVES: African Americans bear a disproportionate burden of lower extremity complications associated with a type 2 diabetes diagnosis. We examined the relationship that self-reported foot care knowledge, foot self-care behaviors, and foot self-care management barriers had on a participants' intention to maintain long term foot self-care. METHODS: African Americans were recruited using a convenience and snowball sampling plan, as well as telephone, email and flyers detailing the study. The data from the previously modified foot care knowledge questionnaire was analyzed using SPSS. Descriptive analysis and ANOVAs analyzed basic foot care knowledge, specialized foot care knowledge, and foot self-care. RESULTS: The analysis indicated that a main effect of insurance status, F(2,87) = 4.082, p = .020, was detected, and was the only significant interaction found. CONCLUSION: When comparing the basic and extended foot care education means scores, participants had less extended foot care knowledge than basic foot care knowledge. This study also showed that insurance status had considerable influence on extended foot care knowledge. In an African American population with T2DM, regardless of education and gender, there are considerable differences between how foot care knowledge is translated into actual foot self-care behaviors.