Search

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple autoantibody types, some of which are produced by long-lived plasma cells (LLPC). Active SLE generates increased circulating antibody-secreting cells (ASC). Here, we examine the phenotypic, molecular, structural, and functional features of ASC in SLE. Relative to post-vaccination ASC in healthy controls, circulating blood ASC from patients with active SLE are enriched with newly generated mature CD19 - CD138 + ASC, similar to bone marrow LLPC. ASC from patients with SLE displayed morphological features of premature maturation and a transcriptome epigenetically initiated in SLE B cells. ASC from patients with SLE exhibited elevated protein levels of CXCR4, CXCR3 and CD138, along with molecular programs that promote survival. Furthermore, they demonstrate autocrine production of APRIL and IL-10, which contributed to their prolonged in vitro survival. Our work provides insight into the mechanisms of generation, expansion, maturation and survival of SLE ASC., (© 2024. The Author(s).)

Human bone marrow (BM) plasma cells are heterogeneous, ranging from newly arrived antibody-secreting cells (ASCs) to long-lived plasma cells (LLPCs). We provide single-cell transcriptional resolution of 17,347 BM ASCs from five healthy adults. Fifteen clusters are identified ranging from newly minted ASCs (cluster 1) expressing MKI67 and high major histocompatibility complex (MHC) class II that progress to late clusters 5-8 through intermediate clusters 2-4. Additional ASC clusters include the following: immunoglobulin (Ig) M predominant (likely of extra-follicular origin), interferon responsive, and high mitochondrial activity. Late ASCs are distinguished by G2M checkpoints, mammalian target of rapamycin (mTOR) signaling, distinct metabolic pathways, CD38 expression, utilization of tumor necrosis factor (TNF)-receptor superfamily members, and two distinct maturation pathways involving TNF signaling through nuclear factor κB (NF-κB). This study provides a single-cell atlas and molecular roadmap of LLPC maturation trajectories essential in the BM microniche. Altogether, understanding BM ASC heterogeneity in health and disease enables development of new strategies to enhance protective ASCs and to deplete pathogenic ones., Competing Interests: Declaration of interests F.E.L. is the founder of Micro-Bplex, Inc., serves on the scientific board of Be Biopharma, and is a recipient of grants from the BMGF and Genentech, Inc. I.S. has consulted for GSK, Pfizer, Kayverna, Johnson & Johnson, Celgene, Bristol Myer Squibb, and Visterra. F.E.L, D.C.N., and I.S. are inventors of the issued patents: 9/21/21 US 11,124766 B2 PCT/US2016/036650 and 9/21/21 US 11, 125757 B2 for the PC survival media., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin (Ig) E is central to the pathogenesis of allergic conditions, including allergic fungal rhinosinusitis. However, little is known about IgE antibody secreting cells (ASCs). We performed single-cell RNA sequencing from cluster of differentiation (CD)19 + and CD19 - ASCs of nasal polyps from patients with allergic fungal rhinosinusitis (n = 3). Nasal polyps were highly enriched in CD19 + ASCs. Class-switched IgG and IgA ASCs were dominant (95.8%), whereas IgE ASCs were rare (2%) and found only in the CD19 + compartment. Through Ig gene repertoire analysis, IgE ASCs shared clones with IgD - CD27 - "double-negative" B cells, IgD + CD27 + unswitched memory B cells, and IgD - CD27 + switched memory B cells, suggesting ontogeny from both IgD + and memory B cells. Transcriptionally, mucosal IgE ASCs upregulate pathways related to antigen presentation, chemotaxis, B cell receptor stimulation, and survival compared with non-IgE ASCs. Additionally, IgE ASCs have a higher expression of genes encoding lysosomal-associated protein transmembrane 5 (LAPTM5) and CD23, as well as upregulation of CD74 (receptor for macrophage inhibitory factor), store-operated Calcium entry-associated regulatory factor (SARAF), and B cell activating factor receptor (BAFFR), which resemble an early minted ASC phenotype. Overall, these findings reinforce the paradigm that human ex vivo mucosal IgE ASCs have a more immature plasma cell phenotype than other class-switched mucosal ASCs and suggest unique functional roles for mucosal IgE ASCs in concert with Ig secretion., (Copyright © 2023. Published by Elsevier Inc.)

Seasonal influenza vaccination elicits hemagglutinin (HA)-specific memory B (Bmem) cells, and although multiple Bmem cell populations have been characterized, considerable heterogeneity exists. We found that HA-specific human Bmem cells differed in the expression of surface marker FcRL5 and transcriptional factor T-bet. FcRL5 + T-bet + Bmem cells were transcriptionally similar to effector-like memory cells, while T-bet neg FcRL5 neg Bmem cells exhibited stem-like central memory properties. FcRL5 + Bmem cells did not express plasma-cell-commitment factors but did express transcriptional, epigenetic, metabolic, and functional programs that poised these cells for antibody production. Accordingly, HA + T-bet + Bmem cells at day 7 post-vaccination expressed intracellular immunoglobulin, and tonsil-derived FcRL5 + Bmem cells differentiated more rapidly into antibody-secreting cells (ASCs) in vitro. The T-bet + Bmem cell response positively correlated with long-lived humoral immunity, and clonotypes from T-bet + Bmem cells were represented in the secondary ASC response to repeat vaccination, suggesting that this effector-like population predicts influenza vaccine durability and recall potential., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Evolutionarily conserved, "natural" (n)IgM is broadly reactive to both self and foreign antigens. Its selective deficiency leads to increases in autoimmune diseases and infections. In mice, nIgM is secreted independent of microbial exposure to bone marrow (BM) and spleen B-1 cell-derived plasma cells (B-1PC), generating the majority of nIgM, or by B-1 cells that remain non-terminally differentiated (B-1sec). Thus, it has been assumed that the nIgM repertoire is broadly reflective of the repertoire of body cavity B-1 cells. Studies here reveal, however, that B-1PC generate a distinct, oligoclonal nIgM repertoire, characterized by short CDR3 variable immunoglobulin heavy chain regions, 7-8 amino acids in length, some public, many arising from convergent rearrangements, while specificities previously associated with nIgM were generated by a population of IgM-secreting B-1 (B-1sec). BM, but not spleen B-1PC, or B-1sec also required the presence of TCRαβ CD4 T cells for their development from fetal precursors. Together, the studies identify important previously unknown characteristics of the nIgM pool., (© 2023 Smith et al.)

Human bone marrow (BM) plasma cells are heterogeneous, ranging from newly arrived antibody-secreting cells (ASC) to long-lived plasma cells (LLPC). We provide single cell transcriptional resolution of 17,347 BM ASC from 5 healthy adults. Fifteen clusters were identified ranging from newly minted ASC (cluster 1) expressing MKI67 and high MHC Class II that progressed to late clusters 5-8 through intermediate clusters 2-4. Additional clusters included early and late IgM-predominant ASC of likely extra-follicular origin; IFN-responsive; and high mitochondrial activity ASC. Late ASCs were distinguished by differences in G2M checkpoints, MTOR signaling, distinct metabolic pathways, CD38 expression, and utilization of TNF-receptor superfamily members. They mature through two distinct paths differentiated by the degree of TNF signaling through NFKB. This study provides the first single cell resolution atlas and molecular roadmap of LLPC maturation, thereby providing insight into differentiation trajectories and molecular regulation of these essential processes in the human BM microniche. This information enables investigation of the origin of protective and pathogenic antibodies in multiple diseases and development of new strategies targeted to the enhancement or depletion of the corresponding ASC. One Sentence Summary: The single cell transcriptomic atlas of human bone marrow plasma cell heterogeneity shows maturation of class-switched early and late subsets, specific IgM and Interferon-driven clusters, and unique heterogeneity of the late subsets which encompass the long-lived plasma cells.

The emergence, survival, growth and maintenance of autoreactive (AR) B-cell clones, the hallmark of humoral autoimmunity, leave their footprints in B-cell receptor repertoires. Collecting IgH sequences related to polyreactive (PR) ones from adaptive immune receptor repertoire (AIRR) datasets make the reconstruction and analysis of PR/AR B-cell lineages possible. We developed a computational approach, named ImmChainTracer, to extract members and to visualize clonal relationships of such B-cell lineages. Our approach was successfully applied on the IgH repertoires of patients suffering from monogenic hypomorphic RAG1 and 2 deficiency (pRD) or polygenic systemic lupus erythematosus (SLE) autoimmune diseases to identify relatives of AR IgH sequences and to track their fate in AIRRs. Signs of clonal expansion, affinity maturation and class-switching events in PR/AR and non-PR/AR B-cell lineages were revealed. An extension of our method towards B-cell expansion caused by any trigger (e.g., infection, vaccination or antibody development) may provide deeper insight into antigen specific B-lymphogenesis.

Severe SARS-CoV-2 infection 1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic 2-5 . More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential 6-10 , although their origins and resolution have remained unclear 11 . Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity 12,13 , as a dominant feature of severe and critical COVID-19 (refs. 14-18 ). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10-15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae., (© 2022. The Author(s).)

Use of adaptive immune receptor repertoire sequencing (AIRR-seq) has become widespread, providing new insights into the immune system with potential broad clinical and diagnostic applications. However, like many high-throughput technologies, it comes with several problems, and the AIRR Community was established to understand and help solve them. We, the AIRR Community's Biological Resources Working Group, have surveyed scientists about the need for standards and controls in generating and annotating AIRR-seq data. Here, we review the current status of AIRR-seq, provide the results of our survey, and based on them, offer recommendations for developing AIRR-seq standards and controls, including future work., Competing Interests: JT, AE, PB, CT, DB, CS, JS, AP, ML, EM No competing interests declared, EL is consulting or is an advisor for Roche Diagnostics Corporation, Enpicom, The Antibody Society, The American Autoimmune Related Diseases Association and IEDB. AF works for Takara Bio USA, but has no ownership or stock in the company, MB During the writing of the manuscript, Magnolia Bostick was employed by Takara Bio USA, but has no ownership or stock in the company., (© 2021, Trück et al.)

IgG antibodies play a role in malaria immunity, but whether and how IgM protects from malaria and the biology of Plasmodium falciparum (Pf)-specific IgM B cells is unclear. In a Mali cohort spanning infants to adults, we conducted longitudinal analyses of Pf- and influenza-specific B cells. We found that Pf-specific memory B cells (MBCs) are disproportionally IgM+ and only gradually shift to IgG+ with age, in contrast to influenza-specific MBCs that are predominantly IgG+ from infancy to adulthood. B cell receptor analysis showed Pf-specific IgM MBCs are somatically hypermutated at levels comparable to influenza-specific IgG B cells. During acute malaria, Pf-specific IgM B cells expand and upregulate activation/costimulatory markers. Finally, plasma IgM was comparable to IgG in inhibiting Pf growth and enhancing phagocytosis of Pf by monocytes in vitro. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in children, expand and activate during malaria, and produce IgM that inhibits Pf through neutralization and opsonic phagocytosis., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Hopp et al.)

Background: B cell affinity maturation enables B cells to generate high-affinity antibodies. This process involves somatic hypermutation of B cell immunoglobulin receptor (BCR) genes and selection by their ability to bind antigens. Lineage trees are used to describe this microevolution of B cell immunoglobulin genes. In a lineage tree, each node is one BCR sequence that mutated from the germinal center and each directed edge represents a single base mutation, insertion or deletion. In BCR sequencing data, the observed data only contains a subset of BCR sequences in this microevolution process. Therefore, reconstructing the lineage tree from experimental data requires algorithms to build the tree based on partially observed tree nodes., Results: We developed a new algorithm named Grow Lineages along Minimum Spanning Tree (GLaMST), which efficiently reconstruct the lineage tree given observed BCR sequences that correspond to a subset of the tree nodes. Through comparison using simulated and real data, GLaMST outperforms existing algorithms in simulations with high rates of mutation, insertion and deletion, and generates lineage trees with smaller size and closer to ground truth according to tree features that highly correlated with selection pressure., Conclusions: GLaMST outperforms state-of-art in reconstruction of the BCR lineage tree in both efficiency and accuracy. Integrating it into existing BCR sequencing analysis frameworks can significant improve lineage tree reconstruction aspect of the analysis.

Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5 - CD11c + cells (DN2) representing pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Despite the availability and utilization of the physiology textbooks authored by Albrecht von Haller during the 18th century that heralded the modern age of physiology, not all physicians or physiologists were satisfied with its presentation, contents, or application to medicine. Initial reasons were fundamental disagreements between the "mechanists," represented by Boerhaave, Robinson, and von Haller, and the "vitalists," represented by the faculty and graduates of the Montpellier School of Medicine in France, notably, Bordeu and Barthez. Subsequently, objections originated from Europe, United Kingdom, and the United States in publications that focused not only on the teaching of physiology to medical and secondary students, but on the specific applications of the content of physiology to medicine, health, hygiene, pathology, and chronic diseases. At the turn of the 20th century, texts began to appear with applied physiology in their titles and in 1926, physician Samson Wright published a textbook entitled Applied Physiology that was intended for both medical students and the medical profession. Eleven years later, physicians Best and Taylor published The Physiological Basis of Medical Practice: A University of Toronto Texbook in Applied Physiology Although both sets of authors defined the connection between applied physiology and physiology, they failed to define the areas of physiology that were included within applied physiology. This was accomplished by the American Physiological Society (APS) Publications Committee in 1948 with the publication of the Journal of Appplied Physiology, that stated the word "applied" would broadly denote human physiology whereas the terms stress and environment would broadly include work, exercise, plus industrial, climatic and social factors. NIH established a study section (SS) devoted to applied physiology in 1964 which remained active until 2001 when it became amalgamated into other SSs. Before the end of the 20th century when departments were changing their titles to reflect a stronger science orientation, many established laboratories and offered degree programs devoted to Applied Physiology. We concluded that Applied Physiology has been an important contributor to the discipline of physiology while becoming an integral component of APS., (Copyright © 2016 the American Physiological Society.)

Antibody responses to viral infections are sustained for decades by long-lived plasma cells (LLPCs). However, LLPCs have yet to be characterized in humans. Here we used CD19, CD38, and CD138 to identify four PC subsets in human bone marrow (BM). We found that the CD19(-)CD38(hi)CD138(+) subset was morphologically distinct, differentially expressed PC-associated genes, and exclusively contained PCs specific for viral antigens to which the subjects had not been exposed for more than 40 years. Protein sequences of measles- and mumps-specific circulating antibodies were encoded for by CD19(-)CD38(hi)CD138(+) PCs in the BM. Finally, we found that CD19(-)CD38(hi)CD138(+) PCs had a distinct RNA transcriptome signature and human immunoglobulin heavy chain (VH) repertoire that was relatively uncoupled from other BM PC subsets and probably represents the B cell response's "historical record" of antigenic exposure. Thus, our studies define human LLPCs and provide a mechanism for the life-long maintenance of anti-viral antibodies in the serum., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Protective antibodies in Plasmodium falciparum malaria are only acquired after years of repeated infections. Chronic malaria exposure is associated with a large increase in atypical memory B cells (MBCs) that resemble B cells expanded in a variety of persistent viral infections. Understanding the function of atypical MBCs and their relationship to classical MBCs will be critical to developing effective vaccines for malaria and other chronic infections. We show that VH gene repertoires and somatic hypermutation rates of atypical and classical MBCs are indistinguishable indicating a common developmental history. Atypical MBCs express an array of inhibitory receptors and B cell receptor (BCR) signaling is stunted in atypical MBCs resulting in impaired B cell responses including proliferation, cytokine production and antibody secretion. Thus, in response to chronic malaria exposure, atypical MBCs appear to differentiate from classical MBCs becoming refractory to BCR-mediated activation and potentially interfering with the acquisition of malaria immunity.

This invited autobiographical article pertains to 52 years as an exercise physiologist of which 16 years were devoted to being an active emeriti. Although the career pathway was circuitous in nature, once resolved, it included preparation of future exercise physiologists; reducing the health hazards associated with the "making of weight" by scholastic wrestlers; using animals (rats and dogs) as the model system with a myriad of experimental procedure for obtaining insights and understandings of various exercise training mechanism in one-G environments, and in simulated μG environments. From the results, we have concluded that (a) inactivity, as represented by immobilization, is the most undesirable physiological state an animal should experience and (b) movement, as represented by training, will have an intrinsic adaptive influence on select biological tissues that, in some situations, can be independent of autonomic and hormonal influences.

In 2007, the American College of Sports Medicine, with endorsement from the American Medical Association and the Office of the Surgeon General, launched a global initiative to mobilize physicians, healthcare professionals and providers, and educators to promote exercise in their practice or activities to prevent, reduce, manage, or treat diseases that impact health and the quality of life in humans. Emerging from this initiative, termed Exercise Is Medicine, has been an extensively documented position stand by the American College of Sports Medicine that recommended healthy adults perform 150 min of moderate dynamic exercise per week. The purpose of this article is to demonstrate the foundation for this global initiative and its exercise prescription for health and disease prevention has roots that began in antiquity more than two millennia ago. Individuals and concepts to remember are that Susruta of India was the first “recorded” physician to prescribe moderate daily exercise, Hippocrates of Greece was the first “recorded” physician to provide a written exercise prescription for a patient suffering from consumption, and the global influence of Galen from Rome combined with his recommendation on the use of exercise for patients in the management of disease prevailed until the 16th century. Historically intertwined with these concepts was exercise being advocated by select physicians to minimize the health problems associated with obesity, diabetes, and inactivity.

Society members whose research publication during the past 125 yr had an important impact on the discipline of physiology were featured at the American Physiological Society (APS)'s 125th Anniversary symposium. The daunting and challenging task of identifying and selecting significant publications was assumed by the Steering Committee of the History of Physiology Interest Group, who requested recommendations and rationales from all Sections, select Interest Groups, and active senior APS members. The request resulted in recommendations and rationales from nine Sections, one Interest Group, and 28 senior members, identifying 38 publications and 43 members for recognition purposes. The publication recommendations included 5 individuals (Cournand, Erlanger, Gasser, Hubel, and Wiesel) whose research significantly contributed to their selection for the Nobel Prize in Medicine or Physiology, 4 individuals who received multiple recommendations [i.e., Cannon (3), Curran (2), Fenn (3), and Hamilton (2)], and 11 members who had been APS Presidents. Of the recommended articles, 33% were from the American Journal of Physiology, with the earliest being published in 1898 (Cannon) and the latest in 2007 (Sigmund). For the brief oral presentations, the History of Physiology Steering Committee selected the first choices of the Sections or Interest Group, whereas rationales and representation of the membership were used for the presentations by senior members.

In 2005, the American Physiological Society (APS) initiated the Living History of Physiology Archival Program to recognize senior members who have made significant contributions during their career to the advancement of the discipline and the profession of physiology. Subsequently, the leadership of the APS Section of Environmental and Exercise Physiology selected Prof. Elsworth R. Buskirk of Pennsylvania State University to be profiled in Advances in Physiology Education.

When considering the history of exercise physiology, authors begin with Hippocrates and the "Golden Age" of Greece before mentioning Galen and the contributions from Rome. However, this approach has omitted the information from the ancient civilizations of India which flourished before and during the emergence of Mycenaen cultures. Specifically ignored have been 1) the tridosa doctrine (humoral theory), which as early as 1500 B.C., emphasized that disease occurred because of a displacement of one or more of the three humors, with health being achieved when the humors were in equilibrium and 2) the perspective of Susruta (Sushruta) who was a 600 B.C. physician who included exercise in his prescriptions to prevent and treat diseases. Susruta not only advocated exercise to maintain equilibrium among the humors, notably kapha, he promoted exercise to minimize the consequences of obesity and diabetes. To be effective, exercise had to be daily and moderate in intensity and never excessive or to exceed the half-maximum limit for exhaustion, because disease or even death could ensue. It is concluded that Susruta's concepts pertaining to chronic exercise and to the health benefits of exercise were "remarkably modern" and that future authors on the history of exercise physiology should include contributions from ancient India.

In 2005, the American Physiological Society (APS) initiated the Living History Project to recognize senior members who have made significant contributions during their career to the advancement of the discipline and profession of physiology. During 2007, the APS Section of Environmental and Exercise Physiology selected Prof. G. Edgar Folk, Jr., of the University of Iowa to be profiled in Advances in Physiology Education.

At the first International Congress of Physiologists in Basel, Switzerland, the Italian physiologist Angelo Mosso (1846-1910) discussed his findings on muscular fatigue while demonstrating the functioning of an ergograph (work recorder). One hundred sixteen years later, Mosso's career, scientific accomplishments, and legacy in the study of muscular fatigue were commemorated at the 2005 International Congress of Physiological Sciences. After receiving his degree in Medicine and Surgery from Turin, Italy, in 1870, Mosso was able to study and interact with renowned physiologists as Wilhelm Ludwig, Du Bois-Reymond, Hugo Kronecker, and Etienne Marey. By 1879, he was Professor of Physiology at the University in Turin, where he conducted research pertaining to blood circulation, respiration, physical education, high-altitude physiology, and muscular fatigue. Using tracings from the ergograph (concentric contractions of the flexor muscles of the middle finger that were volitionally or electrically stimulated), he was able to characterize muscle fatigue and to associate its occurrence with central or peripheral influences. He demonstrated that exercise would increase muscular strength and endurance while prolonging the occurrence of fatigue, which he postulated was a chemical process that involved the production of toxic substances such as carbonic acid. The phenomenon of contracture was described, and his collective studies led to the formulation of laws pertaining to exhaustion and to the 1891 publication of La Fatica (Fatigue). Besides La Fatica, Mosso will be remembered as a scientist with a love for physiology, a concern for the social welfare of his countrymen, and as one who sought to integrate physiological, philosophical, and psychological concepts in his experimental studies.

The relationships between the discipline of exercise physiology and the activities of the Harvard Fatigue Laboratory were examined. Even though 5 decades have elapsed since the Laboratory's closure, its existence, leaders, and accomplishments continue to be revered by exercise physiologists. The Laboratory was unique because it was the first research facility of its type and because no single exercise physiology laboratory in the United States since 1947 has been able to attract the stature of the national and international investigators that conducted the interdisciplinary research published by the Laboratory. Despite the inference from its name, the Laboratory's purpose was not to advance the discipline of exercise physiology; rather, it was to advance our understanding and interactions of applied physiology, physiology, and sociology. Consequently, its contributions to the critical mass of exercise physiology literature were limited even though may of the publications were seminal in nature. As documented by the Horvaths, the closure resulted in the establishment of many different research laboratories by former Laboratory staff members and associates (R.E. Johnson at Illinois, Horvath at Santa Barbara, and Dill at Nevada); however, their impact on exercise physiology was delayed because Keys and Robinson had left for Minnesota and Indiana, respectively, well in advance of closing. Unfortunately, the administrative structure and organization of the Laboratory was not conducive to the training of Ph.D candidates with an interest in exercise physiology. Consequently, only two individuals graduated during its existence. Since departments of physiology or biology had limited faculty or interest in preparing students for such a future before and after closure, departments of physical education with specialization graduate programs in exercise physiology assumed this responsibility, which was facilitated by post-World War II funding that supported mass education, graduate training, health related research, and facility development. Today, the majority of the leaders in exercise physiology are the "products" of the specialization movement. Although undergraduates were encouraged to participate in the research activities, the talented faculty of the Laboratory did not offer formal courses in exercise physiology. Thus, the development of an academic discipline in exercise physiology was left to institutions that required a science-oriented curriculum in their undergraduate and graduate degree programs in physical education, exercise science, or kinesiology. The emergence of exercise physiology as a discipline in the United States was enhanced by the publications of the Journal of Applied Physiology in 1948 and by Medicine and Science in Sports in 1969. These were peer-reviewed journals that were interested in publishing research studies on exercise topics. Two other reasons contributed to its development. The first was the creation of an Applied Physiology Study Section at the National Institute of Health in 1964, whose purpose was to evaluate grant proposals in subject matter area intrinsic to exercise physiology, while the second reason was the formation of the American College of Sports Medicine in 1954. ACSM was an important for the establishment of the discipline because it had an organizational structure that encouraged exercise physiologists to join, provided opportunities for members to present at regional and national meetings, and would publish their findings. Although the American Physiological Society had been established more than a 100 years ago, only a limited number of its members were interested and active in exercise physiology at the time of the Laboratory's closure or at the beginning of the specialization era (1963). However, in 1977, APS created a membership section that included exercise physiology in its title. Currently, both APS and ACSM are effectively representing the professional interests of exercise ph

We examined skeletal and cardiac muscle responses of mature (8 mo) and old (23 mo) male Fischer 344 rats to 14 days of hindlimb suspension. Hexokinase (HK) and citrate synthase (CS) activities and GLUT-4 glucose transporter protein level, which are coregulated in many instances of altered neuromuscular activity, were analyzed in soleus (Sol), plantaris (PI), tibialis anterior (TA), extensor digitorum longus (EDL), and left ventricle. Protein content was significantly (P < 0.05) lower in all four hindlimb muscles after suspension compared with controls in both mature (21-44%) and old (17-43%) rats. Old rats exhibited significantly lower CS activities than mature rats for the Sol, Pl, and TA. HK activities were significantly lower in the old rats for the Pl (19%) and TA (33%), and GLUT-4 levels were lower in the old rats for the TA (38%) and EDL (24%) compared with the mature rats. Old age was also associated with a decrease in CS activity (12%) and an increase in HK activity (14%) in cardiac muscle. CS activities were lower in the Sol (20%) and EDL (18%) muscles from mature suspended rats and in the Sol (25%), Pl (27%), and EDL (25%) muscles from old suspended rats compared with corresponding controls. However, suspension was associated with significantly higher HK activities for all four hindlimb muscles examined, in both old (16-57%) and mature (10-43%) rats, and higher GLUT-4 concentrations in the TA muscles of the old rats (68%) but not the mature rats. These results indicate that old age is associated with decreased CS and HK activities and GLUT-4 protein concentration for several rat hindlimb muscles, and these variables are not coregulated during suspension. Finally, old rat skeletal muscle appears to respond to suspension to a similar or greater degree than mature rat muscle responds.

Post-spaceflight results and findings from humans and rodents after conditions of bed rest or simulated microgravity indicate maximum exercise performance is significantly compromised. However, the chronic administration of dobutamine (a synthetic adrenomimetic) to humans in relevant experiments improves exercise performance by mechanisms that prevent the decline in peak O2 consumption (VO2peak) and reduce the concentration of lactic acid measured in the blood. Although dobutamine restores maximum VO2 values in animals participating in simulated microgravity studies, it is unknown whether injections of this alpha 1-, beta 1-, and beta 2-adrenoceptor agonist in rats will enhance exercise performance. To investigate this, adult male rats were assigned to three experimental groups: caged control receiving saline; head-down, tail-suspended (HDS) receiving saline (HDS-S); and an HDS group receiving dobutamine hydrochloride injections (1.8 mg/kg twice daily per rat). Treadmill tests were performed before suspension, at 14 days, and after 21 days. VO2peak, run time, and the rate of rise in colonic temperature (heating index) were evaluated after 14 days, whereas at 21 days, hemodynamic responses (heart rate, systolic blood pressure, and double product) were determined during submaximal exercise with blood pH, blood gases, and lactic acid concentration values obtained during maximal exercise. In contrast to the results for the HDS-S rats, dobutamine administration did restore VO2peak and "normalized" lactic acid concentrations during maximal exercise. However, daily injections were unable to enhance exercise performance aspects associated with treadmill run time, the mechanical efficiency of running, the heating index, or the retention of muscle and body mass. These simulated microgravity findings suggest that dobutamine's potential value as a countermeasure for postflight maximal performance or for egress emergencies is limited and that other countermeasures must be considered.

According to the international Olympic Committee, it is the responsibility of the sports medicine profession to care for the health and welfare of Olympic athletes, treat and prevent injuries, conduct medical examinations, evaluate performance capacity, provide nutritional advice, prescribe and supervise training programs, and to monitor substance use. Implicit in these functions is to assist Olympic athletes in achieving the objectives of the Olympic Motto (Citius, Altius, Fortius), which is to become faster, higher, and stronger. During the past Olympiads, athletic performance has increased, as indicated by times for the men's marathon (-28%) or by the distance covered in the women's javelin throw (+80%). However, the fulfillment of these responsibilities was a slow and protracted process, as demonstrated by the facts that medical examinations were not required until 1920, that 28 years elapsed before an official team physician was appointed, and that women had to wait until 1984 before sanction was given to compete in the marathon race. Doping was not defined until 1964, and monitoring of substance abuse did not materialize until after 1972. Although individuals have prepared for athletic competition since the ancient Olympics, the scientific foundations for various training prescriptions were not firmly established until the 1960s and 1970s. It was speculated that performance records will continue to improve in the next century because more scientific sports medicine information would be available and because such information would be better disseminated to athletes.

Two prominent theories to explain the physiological effects of microgravity relate to the cascade of changes associated with the cephalic shifts of fluids and the absence of tissue deformation forces. One-g experiments for humans used bed rest and the head-down tilt (HDT) method, while animal experiments have been conducted using the tail-suspended, head-down, and hindlimbs non-weightbearing model. Because of the success of the HDT approach with rats to simulate the gravitational effects on the musculoskeletal system exhibited by humans, the same model has been used to study the effects of gravity on the cardiopulmonary systems of humans and other vertebrates. Results to date indicate the model is effective in producing comparable changes associated with blood volume, erythropoiesis, cardiac mass, baroreceptor responsiveness, carbohydrate metabolism, post-flight VO2max, and post-flight cardiac output during exercise. Inherent with these results is the potential of the model to be useful in investigating responsible mechanisms. The suspension model has promise in understanding the capillary blood PO2 changes in space as well as the arterial PO2 changes in subjects participating in a HDT experiment. However, whether the model can provide insights on the up-or-down regulation of adrenoreceptors remains to be determined, and many investigators believe the HDT approach should not be followed to study gravitational influences on pulmonary function in either humans or animals. It was concluded that the tail-suspended animal model had sufficient merit to study in-flight and post-flight human physiological responses and mechanisms.

Since 1961, there have been more than 165 flights involving several hundred individuals who have remained in a space environment from 15 min to more than a year. In addition, plans exist for humans to explore, colonize, and remain in microgravity for 1000 d or more. This symposium will address the current state of knowledge in select aspects associated with the cardiovascular, fluid and electrolytes, musculoskeletal, and the neuroendocrine and immune systems. The authors will focus on responses, mechanisms, and the appropriate countermeasures to minimize or prevent the physiological and biochemical consequences of a microgravity environment. Since exercise is frequently cited as a generic countermeasure, this topic will be covered in greater detail. Models for simulated microgravity conditions will be discussed in subsequent manuscripts, as will future directions for ground-based research.

We investigated the effects of purified histone H4 on glucose transport activity in rat soleus and flexor digitorum brevis muscles. Histone H4, at concentrations up to 11.8 microM, increased 2-deoxyglucose (2-DG) uptake in a dose-dependent fashion. However, at concentrations higher than 11.8 microM, H4 caused a decrease in 2-DG uptake from the maximum, suggesting a secondary inhibitory action of this compound. The maximal effect of H4 on 2-DG uptake was not additive to the maximal effect of insulin. Moreover, 2-DG uptake in the presence of both H4 and insulin was significantly lower than the 2-DG uptake in the presence of insulin alone. The maximal effect of H4 on stimulation of 2-DG uptake was neither additive nor inhibitory to the maximal effects of the intracellularly acting insulin mimetics sodium vanadate or H2O2. It was, on the other hand, additive to the maximal effects of muscle contractions. Also, in contrast with the effects of H4 on insulin-stimulated 2-DG uptake, H4 did not inhibit insulin-like growth factor-I (IGF-I)-stimulated 2-DG uptake, as the maximal effects of H4 and IGF-I were additive. Scatchard analysis of the binding of 125I-insulin in the absence or presence of histone H4 revealed that H4 increased the specific binding of insulin without affecting receptor affinity. These data suggest that H4 interacts with the insulin, rather than the hypoxia/contraction, pathway for activation of glucose transport in muscle tissue, and that H4 acts either directly or indirectly to increase the number of insulin receptors at the surface of the muscle cell. This interaction does not appear to occur with the similar, although distinct, IGF-I receptor. These studies may provide additional insight into the complex signal-transduction systems of insulin action.

To study the influences of 16 wk of endurance training on the reflex regulation of resting blood pressure, nontrained (NT) and trained (T) female hypertensive rats (SHR) were subjected to conditions of lower body negative pressure (LBNP). Measurements of muscle cytochrome oxidase activity and run time to exhaustion indicated that the animals were endurance trained. The rats (NT = 6, T = 7) were tranquilized with 300-600 micrograms.kg-1 diazepam (IV) before heart rates and blood pressures were measured over a range of 2.5-10.0 mm Hg of negative pressure. When subjected to conditions of LBNP, the reflex tachycardia of the T group was greater than the NT at the lower (-2.5 and -5.0 mm Hg) negative pressures. Although arterial pressure declines were similar in both groups, the T group experienced significantly less of a decline in central venous pressure than the NT animals. When chlorisondamine was used as a ganglionic blocker (2.5 mg.kg-1, IV), the fall in CVP at 10 mm Hg negative pressure was greater for the NT group while the fall in the initial systemic arterial pressure was more for the T group. From these results we concluded that training had altered the interaction between cardiopulmonary and arterial baroreflexes in these hypertensive rats and a nonneural component had been altered such as cardiac function.

This study determined the validity of previously published or newly derived equations to predict fat-free body mass (FFB) in high school wrestlers from the midwestern United States. Five laboratories participated in the data-pooling study (total sample of 860 subjects). Measures included body composition by underwater weighing and anthropometric measurements of body mass, stature, and selected circumferences, diameters, and skinfolds. Cross-validation of selected equations to predict FFB revealed the lowest levels of error from the equations of Lohman, Thorland et al., Katch and McArdle, and Behnke and Wilmore. Modification of the constants in these equations or generation of new equations did not substantially reduce prediction error. Overall, total error for these top equations ranged from 2.44 to 2.59 kg. However, based on observed trends, this error was of lower magnitude with the younger and lighter subjects and of higher magnitude with the older and heavier subjects. We conclude that these equations could be used singularly or collectively to determine FFB, and a minimal weight could then be derived and assigned to a scholastic wrestler.

The purpose of this study was to determine if the arterial baroreceptor reflexes modulate the sympathocirculatory responses to acute heat stress. To address this, arterial pressure, heart rate, mesenteric and renal blood flow velocity (Doppler flow probes), arterial plasma norepinephrine, and colonic temperature were measured before and during whole body heating (42 degrees C ambient temperature) in groups of conscious, unrestrained rats with (sham) or without (sinoaortic deafferentation) intact arterial baroreceptor reflexes. Heating was stopped when a colonic temperature of 41 degrees C was attained. Baseline levels of arterial pressure were similar in the two groups, whereas heart rate was elevated in deafferented versus sham-operated rats (p less than 0.01). The increases above baseline for both arterial pressure (73 +/- 4 vs. 27 +/- 2 mm Hg) and heart rate (127 +/- 10 vs. 33 +/- 5 beats/min) were threefold to fourfold greater at the end of heating in the deafferented versus the sham group (p less than 0.01). Declines in mesenteric and renal blood flow were similar in the two groups during heating; however, deafferented rats had greater increases in both mesenteric and renal vascular resistance (p less than 0.05). Plasma norepinephrine was elevated at baseline in deafferented versus sham rats and increased in both groups during heating (p less than 0.01). The magnitude of the increase in plasma norepinephrine from baseline to 41 degrees C was fivefold greater in the deafferented versus the sham rats (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Previous research by Tcheng and Tipton developed two prediction equations appropriate for the estimation of minimal weight for high school wrestlers. The purpose of this investigation was to cross-validate these equations using densitometric estimates of minimal weight. Skeletal dimension measurements and hydrostatic weighing were completed on 220 Iowa high school wrestlers at various times in and out of season. High concurrent validity (r = 0.93) and small residual errors (less than 0.33 kg) were observed when compared to densitometric estimates. Regression weights were of similar magnitude to those from the previous study. Two new prediction models were tested. Model II enhanced the multiple R over previous equations to 0.962 and decreased the SEE by 25% (0.55 kg). The equation was: Minimal Weight (lbs) = 0.49 x Current Weight (lbs) + 1.65 x Height (inches) + 1.81 x Chest Diameter (cm) + 6.70 x Right Wrist Diameter (cm) + 1.35 x Chest Depth (cm) - 156.56. It was concluded that the Tcheng-Tipton equations or the new models could be used as valid indicators of a minimal weight for scholastic wrestlers.