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OBJECTIVE: The purpose of this study was to explore exercise dependence in bodybuilders, and undertake preliminary validation of a measurement instrument. EXPERIMENTAL DESIGN: A comparative analysis of self-report indices between groups. PARTICIPANTS: Forty-seven bodybuilders, 31 individuals who weight trained for general fitness purposes and 24 weightlifters participated in the study. MEASURES: Each subject completed the following: demographic information, bodybuilding-specific versions of the social identity and exclusivity scales of the Athletic Identity Measurement Scale, the physical strength and body attractiveness subscales of the Physical Self-Perception Profile, a short form of the Marlowe-Crowne Social Desirability Scale, and a 9-item Bodybuilding Dependence Scale. RESULTS: Factor analysis on the BDS revealed 3 subscales (social dependency, training dependency and mastery) which accounted for 68.4% of the variance. Internal consistency was satisfactory for each subscale (Chronbach's alpha = 0.76, 0.75 and 0.78 respectively). The BDS social dependency and PSPP body attractiveness scores of the bodybuilders were higher than those of the weightlifters, whose scores were higher than those of the fitness trainers. The bodybuilders scored higher on both AIMS subscales than the other groups. The bodybuilders and weightlifters scored higher on PSPP physical strength than the fitness trainers. BDS social dependency correlated with both AIMS and both PSPP subscales, and BDS training dependency correlated with AIMS exclusivity. All three BDS subscales correlated with training frequency. Discriminant analysis found the combination of AIMS social identity, BDS social dependency and years training experience enabled correct classification of 92% of the respondents. CONCLUSIONS: These results support the construct and concurrent validity of the BDS social dependency subscale, but do not wholly support the validity of the other two subscales. [ABSTRACT FROM AUTHOR]

After antigen stimulation, naïve T cells display reproducible population-level responses, which arise from individual T cells pursuing specific differentiation trajectories. However, cell-intrinsic predeterminants controlling these single-cell decisions remain enigmatic. We found that the subcellular architectures of naïve CD8 T cells, defined by the presence (T Ø ) or absence (T O ) of nuclear envelope invaginations, changed with maturation, activation, and differentiation. Upon T cell receptor (TCR) stimulation, naïve T Ø cells displayed increased expression of the early-response gene Nr4a1 , dependent upon heightened calcium entry. Subsequently, in vitro differentiation revealed that T Ø cells generated effector-like cells more so compared with T O cells, which proliferated less and preferentially adopted a memory-precursor phenotype. These data suggest that cellular architecture may be a predeterminant of naïve CD8 T cell fate.

Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment., (© 2023. Springer Nature Limited.)

Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM., (© 2023. The Author(s).)

Phenotypic plasticity is essential to the immune system, yet the factors that shape it are not fully understood. Here, we comprehensively analyze immune cell phenotypes including morphology across human cohorts by single-round multiplexed immunofluorescence, automated microscopy, and deep learning. Using the uncertainty of convolutional neural networks to cluster the phenotypes of eight distinct immune cell subsets, we find that the resulting maps are influenced by donor age, gender, and blood pressure, revealing distinct polarization and activation-associated phenotypes across immune cell classes. We further associate T cell morphology to transcriptional state based on their joint donor variability and validate an inflammation-associated polarized T cell morphology and an age-associated loss of mitochondria in CD4 + T cells. Together, we show that immune cell phenotypes reflect both molecular and personal health information, opening new perspectives into the deep immune phenotyping of individual people in health and disease.

Purpose: Most chimeric antigen receptor (CAR) T-cell strategies against glioblastoma have demonstrated only modest therapeutic activity and are based on persistent gene modification strategies that have limited transgene capacity, long manufacturing processes, and the risk for uncontrollable off-tumor toxicities. mRNA-based T-cell modifications are an emerging safe, rapid, and cost-effective alternative to overcome these challenges, but are underexplored against glioblastoma., Experimental Design: We generated mouse and human mRNA-based multifunctional T cells coexpressing a multitargeting CAR based on the natural killer group 2D (NKG2D) receptor and the proinflammatory cytokines IL12 and IFNα2 and assessed their antiglioma activity in vitro and in vivo., Results: Compared with T cells that either expressed the CAR or cytokines alone, multifunctional CAR T cells demonstrated increased antiglioma activity in vitro and in vivo in three orthotopic immunocompetent mouse glioma models without signs of toxicity. Mechanistically, the coexpression of IL12 and IFNα2 in addition to the CAR promoted a proinflammatory tumor microenvironment and reduced T-cell exhaustion as demonstrated by ex vivo immune phenotyping, cytokine profiling, and RNA sequencing. The translational potential was demonstrated by image-based single-cell analyses of mRNA-modified T cells in patient glioblastoma samples with a complex cellular microenvironment. This revealed strong antiglioma activity of human mRNA-based multifunctional NKG2D CAR T cells coexpressing IL12 and IFNα2 whereas T cells that expressed either the CAR or cytokines alone did not demonstrate comparable antiglioma activity., Conclusions: These data provide a robust rationale for future clinical studies with mRNA-based multifunctional CAR T cells to treat malignant brain tumors., (©2022 American Association for Cancer Research.)

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently affects 36 million people worldwide with no effective treatment available. Development of AD follows a distinctive pattern in the brain and is poorly modelled in animals. Therefore, it is vital to widen the spatial scope of the study of AD and prioritise the study of human brains. Here we show that functionally distinct human brain regions display varying and region-specific changes in protein expression. These changes provide insights into the progression of disease, novel AD-related pathways, the presence of a gradient of protein expression change from less to more affected regions and a possibly protective protein expression profile in the cerebellum. This spatial proteomics analysis provides a framework which can underpin current research and open new avenues to enhance molecular understanding of AD pathophysiology, provide new targets for intervention and broaden the conceptual frameworks for future AD research., Competing Interests: The authors declare no competing interests.

Background and Aims: Extensive research has shown that male bodybuilders are at high risk for exercise dependence, but few studies have measured these variables in female bodybuilders. Prior research has postulated that muscular dysmorphia was more prevalent in men than women, but several qualitative studies of female bodybuilders have indicated that female bodybuilders show the same body image concerns. Only one study has compared female bodybuilders with control recreational female lifters on eating behaviors, body image, shape pre-occupation, body dissatisfaction, and steroid use. The purpose of this study was to compare exercise dependence and muscle dysmorphia measures between groups of female weight lifters., Methods: Seventy-four female lifters were classified into three lifting types (26 expert bodybuilders, 10 or more competitions; 29 novice bodybuilders, 3 or less competitions; and 19 fitness lifters, at least 6 months prior lifting) who each completed a demographic questionnaire, the Exercise Dependence Scale (EDS), the Drive for Thinness scale (DFT) of the Eating Disorder Inventory-2, the Bodybuilding Dependence Scale (BDS), and the Muscle Dysmorphia Inventory (MDI)., Results: Female bodybuilders scored higher than fitness lifters for EDS Total, BDS Training and Social Dependence, and on Supplement Use, Dietary Behavior, Exercise Dependence, and Size Symmetry scales of the MDI., Discussion and Conclusions: Female bodybuilders seem to be more at risk for exercise dependence and muscle dysmorphia symptoms than female recreational weight lifters.

Based on electromyographic (EMG) studies, an anterior (in front of the face) wide grip with a pronated forearm has been recommended as the optimal lat pull-down (LPD) variation for strengthening the latissimus dorsi (LD) (Signorile, JF, Zink, A, and Szwed, S. J Strength Cond Res 16: 539-546, 2002; Wills, R, Signorile, J, Perry, A, Tremblay, L, and Kwiatkowski, K. Med Sci Sports Exerc 26: S20, 1994). However, it is not clear whether this finding was because of grip width or forearm orientation. This study aimed to resolve this issue by comparing wide-pronated, wide-supinated, narrow-pronated, and narrow-supinated grips of an anterior LPD. Twelve healthy men performed the 4 grip variations using an experimentally determined load of 70% of 1 repetition maximum. Two trials of 5 repetitions were analyzed for each grip type. Participants maintained a cadence of 2-second concentric and 2-second eccentric phases. The grip widths were normalized for each individual by using a wide grip that corresponded to their carrying width and a narrow grip that matched their biacromial diameter. Surface EMG of the LD, middle trapezius (MT), and biceps brachii (BB) was recorded, and the root mean square of the EMG was normalized, using a maximum isometric voluntary contraction. Repeated-measures analysis of variance for each muscle revealed that a pronated grip elicited greater LD activity than a supinated grip (p < 0.05), but had no influence of grip type on the MT and BB muscles. Based on these findings, an anterior LPD with pronated grip is recommended for maximally activating the LD, irrespective of the grip width (carrying width or biacromial diameter).

Researchers have hypothesized differences in exercise dependence and drive for muscularity between bodybuilders and power lifters, while others have not found the predicted differences. This study assessed 146 weight lifters (bodybuilders, n=59; power lifters, n=47; fitness lifters, n=40) on the Exercise Dependence Scale, Bodybuilding Dependence Scale, and the Drive for Muscularity Scale. Results showed that bodybuilders and power lifters were significantly higher than fitness lifters on EDS Total, 7 EDS scales, and the 3 BDS scales. In contrast, power lifters were found to be significantly higher on DMS Total and DMS Behavior scales than bodybuilders. The regression results suggest that exercise dependence may be directly related to the drive for muscularity., (2010 Elsevier Ltd. All rights reserved.)

Objective: Recent studies using multidimensional measures have shown that men (Exercise Dependence Scale; EDS-R) are more exercise-dependent than women, whereas others have found that women (Exercise Dependence Questionnaire; EDQ) are more exercise-dependent than men. This study investigated whether there may be sex differences in exercise dependence or whether the questionnaires may be measuring different dimensions of exercise dependence., Design: Regular exercisers voluntarily completed the EDS-R, EDQ and Drive for Thinness (DFT) subscale before or after a workout., Setting: A local health club in the eastern USA., Participants: Male (n = 102) and female (n = 102) exercisers completed the three questionnaires, but 11 participants (1 man, 10 women) were excluded from further analysis because scores indicated possible secondary exercise dependence (eating disorder)., Primary Outcome Measures: Eight subscales of the EDQ, seven subscales of the EDS, the DFT subscale, and several demographic variables served as dependent measures., Results: A multivariate analysis of variance (MANOVA) on the EDS-R showed that men were significantly higher than women on the Withdrawal, Continuance, Tolerance, Lack of Control, Time, and Intention Effect subscales. Another MANOVA on the EDQ indicated that women scored significantly higher than did men on the Interference, Positive Rewards, Withdrawal, and Social Reasons subscales. Statistical analysis using t tests revealed that men had significantly higher total EDS-R scores than women, but women had significantly higher EDQ and DFT scores., Conclusion: These results suggest that both questionnaires measure different aspects of exercise dependence that favour either gender. It remains for further research to determine whether these instruments are equally viable for measurement of ED in both men and women.

This study considered relationships between the intensity and directional aspects of competitive state anxiety as measured by the modified Competitive Sport Anxiety Inventory-2(D) (Jones & Swain, 1992) in a sample of 12 experienced male golfers. Anxiety and performance scores from identical putting tasks performed under three different anxiety-manipulated competitive conditions were used to assess both the predictions of Multidimensional Anxiety Theory (MAT; Martens et al., 1990) and the relative value of intensity and direction in explaining performance variance. A within-subjects regression analysis of the intra-individual data showed partial support for the three MAT hypotheses. Cognitive anxiety intensity demonstrated a negative linear relationship with performance, somatic anxiety intensity showed a curvilinear relationship with performance, and self-confidence intensity revealed a positive linear relation. Cognitive directional anxiety illustrated a positive linear relationship with putting performance. Multiple regression analyses indicated that direction (42% of variance) was a better predictor of performance than intensity (22%).

Synaptic vesicle protein 2 (SV2) is a membrane glycoprotein common to all synaptic and endocrine vesicles. Unlike many proteins involved in synaptic exocytosis, SV2 has no homolog in yeast, indicating that it performs a function unique to secretion in higher eukaryotes. Although the structure and protein interactions of SV2 suggest multiple possible functions, its role in synaptic events remains unknown. To explore the function of SV2 in an in vivo context, we generated mice that do not express the primary SV2 isoform, SV2A, by using targeted gene disruption. Animals homozygous for the SV2A gene disruption appear normal at birth. However, they fail to grow, experience severe seizures, and die within 3 weeks, suggesting multiple neural and endocrine deficits. Electrophysiological studies of spontaneous inhibitory neurotransmission in the CA3 region of the hippocampus revealed that loss of SV2A leads to a reduction in action potential-dependent gamma-aminobutyric acid (GABA)ergic neurotransmission. In contrast, action potential-independent neurotransmission was normal. Analyses of synapse ultrastructure suggest that altered neurotransmission is not caused by changes in synapse density or morphology. These findings demonstrate that SV2A is an essential protein and implicate it in the control of exocytosis.

The purpose of this study was to determine whether the calcium binding protein calbindin-D28k was present within the cortically projecting basal forebrain neurons of various rodent species not previously examined. Double-label immunocytochemistry was performed using antibodies against calbindin-D28k and choline acetyltransferase (ChAT) to detect the presence of the calcium binding protein within the cholinergic basal forebrain neurons of various species (i.e., humans, rats, mice, gerbils, guinea pigs). Antibodies against calbindin-D28k, ChAT, and glutamic acid decarboxylase (GAD) were also used in combination with a cortically injected retrograde tracer (Fluoro-Gold) to determine whether calbindin-D28k immunoreactive (IR) neurons within the basal forebrain projected to the frontoparietal cortex. The nucleus basalis of rats was examined for the presence of calbindin-D27k IR within the GABAergic basal forebrain neurons. All species examined had cholinergic, GABAergic, and calbindinergic neurons within the basal forebrain; however, only the cholinergic neurons within the human nucleus basalis of Meynert were also immunoreactive for calbindin-D28k. Although all rodent species had both cholinergic and GABAergic basal forebrain neurons that contained the Fluoro-Gold dye, none of the calbindin-D28k IR neurons, detected using monoclonal and polyclonal antibodies, were found to contain the retrograde tracer. These results indicate that the cortically projecting cholinergic and GABAergic basal forebrain neurons within these rodent species do not contain calbindin-D28k. Therefore, age- and disease-related loss of nucleus basalis projection neurons may not be mediated by alterations in calbindin-D28k.(ABSTRACT TRUNCATED AT 250 WORDS)

To examine whether manipulating self-efficacy affects strength performance on a bench press, and to see if these situation-specific changes would affect levels of physical self-efficacy, 24 undergraduates untrained in weightlifting were randomly assigned to three groups: 'light', who lifted less weight than they believed; 'heavy', who lifted more weight than they believed; and control, for whom there was no manipulation. Self-efficacy measures were taken before and after the manipulation. Physical self-efficacy was measured using the Physical Self-Efficacy Scale (PSE). 'Light' subjects lifted significantly greater increases in weight than the other subjects. 'Heavy' subjects significantly decreased self-efficacy following the manipulation. Initial self-efficacy was found to be a significant predictor of baseline maximum, while manipulated self-efficacy was significant for performance change. The PSE scores did not change pre- to post-study. The results suggest that self-efficacy is a situation-specific construct which can be manipulated, and which relates to both past performance experience and future performance.

Recent investigations indicate that an iris pigmentation-motor behavior exists, but may be limited to the reaction time component of a motor task. The absence of differences in peripheral nervous conduction (Wolf and Landers, 1978) suggests that a central nervous system mechanism may be operating, possibly dependent on the characteristics of neuromelanin or catecholamine turnover. Experiment 1 tested this notion by fractionating simple reaction time into the premotor and motor components by electromyography. ANOVA revealed that dark-eyed subjects had faster total reaction times and premotor times, but only the premotor time component approached significance (p < 0.07). Experiment 2 fractionated patellar reflex time of light-eyed and dark-eyed subjects into reflex lagency and motor components. There were no eye color differences for any of the reflex time measures. The results of Experiments 1 and 2 support a central nervous system explanation for the iris pigmentation-reaction time phenomenon.