How to be an effective ally.

Inclusivity in biomedical research provides many positive attributes, including increased productivity, higher creativity, and improved wellness for all. While marginalized individuals work tirelessly to achieve equity and inclusion, this task should not be left solely to those most affected by exclusionary tactics. These individuals and the organizations with whom they are affiliated would benefit from the support of an ally. An ally is defined as a person or organization that actively supports the rights of a marginalized group without being a member of it. Allies have a unique opportunity to play a pivotal role in promoting fairness, equity, and inclusion, and thus serve as positive change agents within an organizational setting. We summarize here the importance of being an effective and dynamic ally and offer guidance on how to achieve that goal.

Exercise to Prevent Accelerated Vascular Aging in People Living With HIV.

Given advances in antiretroviral therapy, the mortality rate for HIV infection has dropped considerably over recent decades. However, people living with HIV (PLWH) experience longer life spans coupled with persistent immune activation despite viral suppression and potential toxicity from long-term antiretroviral therapy use. Consequently, PLWH face a cardiovascular disease (CVD) risk more than twice that of the general population, making it the leading cause of death among this group. Here, we briefly review the epidemiology of CVD in PLWH highlighting disparities at the intersections of sex and gender, age, race/ethnicity, and the contributions of social determinants of health and psychosocial stress to increased CVD risk among individuals with marginalized identities. We then overview the pathophysiology of HIV and discuss the primary factors implicated as contributors to CVD risk among PLWH on antiretroviral therapy. Subsequently, we highlight the functional evidence of premature vascular dysfunction as an early pathophysiological determinant of CVD risk among PLWH, discuss several mechanisms underlying premature vascular dysfunction in PLWH, and synthesize current research on the pathophysiological mechanisms underlying accelerated vascular aging in PLWH, focusing on immune activation, chronic inflammation, and oxidative stress. We consider understudied aspects such as HIV-related changes to the gut microbiome and psychosocial stress, which may serve as mechanisms through which exercise can abrogate accelerated vascular aging. Emphasizing the significance of exercise, we review various modalities and their impacts on vascular health, proposing a holistic approach to managing CVD risks in PLWH. The discussion extends to critical future study areas related to vascular aging, CVD, and the efficacy of exercise interventions, with a call for more inclusive research that considers the diversity of the PLWH population.

Establishing the short course in transferable skills training program.

While PhD programs prepare graduate students to perform biomedical research, a defined systematic training program for transferable skills is generally lacking. When provided, this training is often informal, unstructured, or inconsistent. Therefore, there is a need to provide critical skills in marketing, relationship building, project management, and budgeting to prepare trainees to navigate into a productive, engaging, and rewarding biomedical research career. To address this gap in training, the School of Graduate Studies at Meharry Medical College has developed the SHort Course In transFerable skills Training (SHIFT) Program, a 1-year professional development program accessible to graduate students in the United States who are enrolled in graduate biomedical research related programs. The SHIFT Program has been launched to equip trainees with skills essential for success in all biomedical science careers. PhD students will be taught the primary constituents of career management through the use of four training modules. In Module I, students complete self-assessments and are assigned to a small peer-mentoring team with mentors. Module II consists of a 5-day workshop that encompasses instruction on the transferable skills identified as essential for career success. Module III entails monthly interactive discussions over a 6-month period involving case study review and mentor-guided discussions to further reinforce skills learned. In Module IV, students compile the information learned from Modules I-III to develop an Individual Development Plan that incorporates 3-5 specific, measurable, attainable, relevant, and time-based career goals. Collectively, the SHIFT Program will allow participants to train, practice, and refresh skills, empowering them to navigate career transitions and obtain success in the career of their choice.

Guidelines on antibody use in physiology research.

Antibodies are one of the most used reagents in scientific laboratories and are critical components for a multitude of experiments in physiology research. Over the past decade, concerns about many biological methods, including those that use antibodies, have arisen as several laboratories were unable to reproduce the scientific data obtained in other laboratories. The lack of reproducibility could be largely attributed to inadequate reporting of detailed methods, no or limited verification by authors, and the production and use of unvalidated antibodies. The goal of this guideline article is to review best practices concerning commonly used techniques involving antibodies, including immunoblotting, immunohistochemistry, and flow cytometry. Awareness and integration of best practices will increase the rigor and reproducibility of these techniques and elevate the quality of physiology research.

Guidelines on the use of sex and gender in cardiovascular research.

In cardiovascular research, sex and gender have not typically been considered in research design and reporting until recently. This has resulted in clinical research findings from which not only all women, but also gender-diverse individuals have been excluded. The resulting dearth of data has led to a lack of sex- and gender-specific clinical guidelines and raises serious questions about evidence-based care. Basic research has also excluded considerations of sex. Including sex and/or gender as research variables not only has the potential to improve the health of society overall now, but it also provides a foundation of knowledge on which to build future advances. The goal of this guidelines article is to provide advice on best practices to include sex and gender considerations in study design, as well as data collection, analysis, and interpretation to optimally establish rigor and reproducibility needed to inform clinical decision-making and improve outcomes. In cardiovascular physiology, incorporating sex and gender is a necessary component when optimally designing and executing research plans. The guidelines serve as the first guidance on how to include sex and gender in cardiovascular research. We provide here a beginning path toward achieving this goal and improve the ability of the research community to interpret results through a sex and gender lens to enable comparison across studies and laboratories, resulting in better health for all.

Sex as a biological variable for cardiovascular physiology.

There have been ongoing efforts by federal agencies and scientific communities since the early 1990s to incorporate sex and/or gender in all aspects of cardiovascular research. Scientific journals provide a critical function as change agents to influence transformation by encouraging submissions for topic areas, and by setting standards and expectations for articles submitted to the journal. As part of ongoing efforts to advance sex and gender in cardiovascular physiology research, the American Journal of Physiology-Heart and Circulatory Physiology recently launched a call for papers on Considering Sex as a Biological Variable. This call was an overwhelming success, resulting in 78 articles published in this collection. This review summarizes the major themes of the collection, including Sex as a Biological Variable Within: Endothelial Cell and Vascular Physiology, Cardiovascular Immunity and Inflammation, Metabolism and Mitochondrial Energy, Extracellular Matrix Turnover and Fibrosis, Neurohormonal Signaling, and Cardiovascular Clinical and Epidemiology Assessments. Several articles also focused on establishing rigor and reproducibility of key physiological measurements involved in cardiovascular health and disease, as well as recommendations and considerations for study design. Combined, these articles summarize our current understanding of sex and gender influences on cardiovascular physiology and pathophysiology and provide insight into future directions needed to further expand our knowledge.

How to be a GREAT mentor.

Formal training in how to mentor is not generally available to students, postdoctoral fellows, or junior faculty. We provide here a framework to develop as a mentor, using the GREAT model. This includes giving opportunities and opening doors; reaching out to help students identify their strengths and reach their goals; encouraging them by serving as a positive example; advising each mentee as an individual; and training them for independent thinking. In this personal view, we expand on each of these steps to illustrate how to develop a personalized mentoring style of your own. By combining these approaches, you as a mentor can work with your mentees to develop an effective and productive mentoring relationship.NEW & NOTEWORTHY We provide here a framework to develop as a mentor, using the GREAT model. This includes giving opportunities and opening doors; reaching out to help students identify their strengths and reach their goals; encouraging them by serving as a positive example; advising each mentee as an individual; and training them for independent thinking.

Skin wound healing as a mirror to cardiac wound healing.

NEW FINDINGS: What is the topic of this review? Wound healing is a general response of the body to injury and can be divided into three phases: inflammation, inflammation resolution and repair. In this review, we compare the wound-healing response of the skin after an injury and the wound-healing response of the heart after a myocardial infarction. What advances does it highlight? We highlight differences and similarities between skin and cardiac wound healing and summarize how skin can be used to provide information about the heart. ABSTRACT: Wound healing is a general response of the body to injury. All organs share in common three response elements to wound healing: inflammation to prevent infection and stimulate the removal of dead cells, active anti-inflammatory signalling to turn off the inflammatory response, and a repair phase characterized by extracellular matrix scar formation. The extent of scar formed depends on the ability of endogenous cells that populate each organ to regenerate. The skin has keratinocytes that have regenerative capacity, and in general, wounds are fully re-epithelialized. Heart, in contrast, has cardiac myocytes that have little to no regenerative capacity, and necrotic myocytes are entirely replaced by scars. Despite differences in tissue regeneration, the skin and heart share many wound-healing properties that can be exploited to predict the cardiac response to pathology. We summarize in this review article our current understanding of how the response of the skin to a wounding event can inform us about the ability of the myocardium to respond to a myocardial infarction.

The cardiac wound healing response to myocardial infarction.

Myocardial infarction (MI) is defined as evidence of myocardial necrosis consistent with prolonged ischemia. In response to MI, the myocardium undergoes a series of wound healing events that initiate inflammation and shift to anti-inflammation before transitioning to tissue repair that culminates in scar formation to replace the region of the necrotic myocardium. The overall response to MI is determined by two major steps, the first of which is the secretion of proteases by infiltrating leukocytes to breakdown extracellular matrix (ECM) components, a necessary step to remove necrotic cardiomyocytes. The second step is the generation of new ECM that comprises the scar; and this step is governed by the cardiac fibroblasts as the major source of new ECM synthesis. The leukocyte component resides in the middle of the two-step process, contributing to both sides as the leukocytes transition from pro-inflammatory to anti-inflammatory and reparative cell phenotypes. The balance between the two steps determines the final quantity and quality of scar formed, which in turn contributes to chronic outcomes following MI, including the progression to heart failure. This review will summarize our current knowledge regarding the cardiac wound healing response to MI, primarily focused on experimental models of MI in mice. This article is categorized under: Cardiovascular Diseases > Molecular and Cellular Physiology Immune System Diseases > Molecular and Cellular Physiology.

Piglet cardiopulmonary bypass induces intestinal dysbiosis and barrier dysfunction associated with systemic inflammation.

The intestinal microbiome is essential to human health and homeostasis, and is implicated in the pathophysiology of disease, including congenital heart disease and cardiac surgery. Improving the microbiome and reducing inflammatory metabolites may reduce systemic inflammation following cardiac surgery with cardiopulmonary bypass (CPB) to expedite recovery post-operatively. Limited research exists in this area and identifying animal models that can replicate changes in the human intestinal microbiome after CPB is necessary. We used a piglet model of CPB with two groups, CPB (n=5) and a control group with mechanical ventilation (n=7), to evaluate changes to the microbiome, intestinal barrier dysfunction and intestinal metabolites with inflammation after CPB. We identified significant changes to the microbiome, barrier dysfunction, intestinal short-chain fatty acids and eicosanoids, and elevated cytokines in the CPB/deep hypothermic circulatory arrest group compared to the control group at just 4 h after intervention. This piglet model of CPB replicates known human changes to intestinal flora and metabolite profiles, and can be used to evaluate gut interventions aimed at reducing downstream inflammation after cardiac surgery with CPB.

Intercellular model predicts mechanisms of inflammation-fibrosis coupling after myocardial infarction.

After myocardial infarction (MI), cardiac cells work together to regulate wound healing of the infarct. The pathological response to MI yields cardiac remodelling comprising inflammatory and fibrosis phases, and the interplay of cellular dynamics that underlies these phases has not been elucidated. This study developed a computational model to identify cytokine and cellular dynamics post-MI to predict mechanisms driving post-MI inflammation, resolution of inflammation, and scar formation. Additionally, this study evaluated the interdependence between inflammation and fibrosis. Our model bypassed limitations of in vivo approaches in achieving cellular specificity and performing specific perturbations such as global knockouts of chemical factors. The model predicted that inflammation is a graded response to initial infarct size that is amplified by a positive feedback loop between neutrophils and interleukin 1ß (IL-1ß). Resolution of inflammation was driven by degradation of IL-1ß, matrix metalloproteinase 9, and transforming growth factor ß (TGF-ß), as well as apoptosis of neutrophils. Inflammation regulated TGFß secretion directly through immune cell recruitment and indirectly through upregulation of macrophage phagocytosis. Lastly, we found that mature collagen deposition was an ultrasensitive switch in response to inflammation, which was amplified primarily by cardiac fibroblast proliferation. These findings describe the relationship between inflammation and fibrosis and highlight how the two responses work together post-MI. This model revealed that post-MI inflammation and fibrosis are dynamically coupled, which provides rationale for designing novel anti-inflammatory, pro-resolving or anti-fibrotic therapies that may improve the response to MI. KEY POINTS: Inflammation and matrix remodelling are two processes involved in wound healing after a heart attack. Cardiac cells work together to facilitate these processes; this is done by secreting cytokines that then regulate the cells themselves or other cells surrounding them. This study developed a computational model of the dynamics of cardiac cells and cytokines to predict mechanisms through which inflammation and matrix remodelling is regulated. We show the roles of various cytokines and signalling motifs in driving inflammation, resolution of inflammation and fibrosis. The novel concept of inflammation-fibrosis coupling, based on the model prediction that inflammation and fibrosis are dynamically coupled, provides rationale for future studies and for designing therapeutics to improve the response after a heart attack.

Harnessing the Plasma Proteome to Mirror Current and Predict Future Cardiac Remodeling After Myocardial Infarction.

To identify plasma proteins that mirror current and predict future remodeling after myocardial infarction (MI), we retrospectively interrogated plasma proteomes of day (D)0 control (n = 16) and D3 MI (n = 15) from C57BL/6 J mice (20 ± 1 months). A total of 165 unique proteins were correlated with cardiac physiology variables. We prospectively tested the hypothesis that candidates identified retrospectively would predict cardiac physiology at an extended timepoint (D7 MI) in a second cohort of mice (n = 4 ± 1 months). We also examined human plasma from healthy controls (n = 18) and patients 48 h after presentation for MI (n = 41). Retrospectively, we identified 5 strong reflectors of remodeling (all r ≥ 0.60 and p < 0.05). Prospectively, ApoA1, IgA, IL-17E, and TIMP-1 mirrored current and predicted future remodeling. In humans, cytokine-cytokine receptor signaling was the top enriched KEGG pathway for all candidates. In summary, we identified plasma proteins that serve as useful prognostic indicators of adverse remodeling and progression to heart failure.