Hunger and aversion: drives that influence food intake of hospitalized geriatric patients

BACKGROUND: Diminished appetite occurs frequently with aging and is considered an important clinical symptom of malnutrition, a condition associated with negative clinical outcome, decreased quality of life, and increased health care costs in hospitalized geriatric patients. Yet, in this population, research is scant on hunger and aversion, the two underlying drives that shape appetite, or on their influence on food intake. This study aimed (a) to examine their interrelationship and respective contribution to food intake; (b) to determine how each relate to other health-related contemporaneous subjective states preceding the meal (good physical health, positive mood, pain); and (c) to explore clinical variables as moderators of the drives-intake relationships to identify population segments for which these relationships are the strongest. METHODS: 32 patients (21 women, 11 men; age range, 65-92 years) were observed during repeated meals in a geriatric rehabilitation unit (for a total of 1477 meals). Perceived hunger, aversion, and contemporaneous subjective states were reported before each meal. Protein and energy consumption was calculated from plate leftovers. Clinical measures were obtained from participants' medical charts. RESULTS: The hunger-aversion relationship had a low inverse correlation (p =.001), with each uniquely contributing to protein intake (positive and negative effects, respectively; all p <.05). Hunger was positively associated with the perception of physical health and with mood (all p =.001). Aversion was associated with pain (p =.001). Furthermore, aversion-intake relationships were influenced by moderators, whereas hunger-intake relationships remained constant. CONCLUSIONS: From a clinical perspective, these results suggest that nutritional interventions aimed at bolstering hunger and curbing aversion may be necessary to ensure optimal food intake. Subgroups of patients who would particularly benefit from these interventions are suggested.     

Mode of interaction of TRIP13 AAA-ATPase with the Mad2-binding protein p31comet and with mitotic checkpoint complexes

The AAA-ATPase thyroid hormone receptor interacting protein 13 (TRIP13), jointly with the Mad2-binding protein p31^comet, promotes the inactivation of the mitotic (spindle assembly) checkpoint by disassembling the mitotic checkpoint complex (MCC). This checkpoint system ensures the accuracy of chromosome segregation by delaying anaphase until correct bipolar attachment of chromatids to the mitotic spindle is achieved. MCC inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets for degradation securin, an inhibitor of anaphase initiation. MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3, in association with the APC/C activator Cdc20. The assembly of MCC in active checkpoint is initiated by the conversion of Mad2 from an open (O-Mad2) to a closed (C-Mad2) conformation, which then binds tightly to Cdc20. Conversely, the disassembly of MCC that takes place when the checkpoint is turned off involves the conversion of C-Mad2 back to O-Mad2. Previously, we found that the latter process is mediated by TRIP13 together with p31^comet, but the mode of their interaction remained unknown. Here, we report that the oligomeric form of TRIP13 binds both p31^comet and MCC. Furthermore, p31^comet and checkpoint complexes mutually promote the binding of each other to oligomeric TRIP13. We propose that p31^comet bound to C-Mad2–containing checkpoint complex is the substrate for the ATPase and that the substrate-binding site of TRIP13 is composed of subsites specific for p31^comet and C-Mad2–containing complex. The simultaneous occupancy of both subsites is required for high-affinity binding to TRIP13.Thyroid hormone receptor interacting protein 13 (TRIP13 ) is an AAA-ATPase that is required for the inactivation of the mitotic (spindle assembly) checkpoint (1, 2). This checkpoint system delays anaphase until correct bipolar attachment of sister chromatids to the mitotic spindle is achieved and thus ensures accuracy of chromosome segregation in mitosis (3–5). When the mitotic checkpoint system is on, it inhibits the action of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets for degradation specific cell cycle regulatory proteins, such as securin, an inhibitor of anaphase initiation (6). APC/C is inhibited by the mitotic checkpoint complex (MCC), which is composed of the checkpoint proteins Mad2, BubR1, and Bub3, in association with the APC/C activator Cdc20. The active checkpoint converts Mad2 from an open (O-Mad2) to a closed (C-Mad2) conformation, and the latter associates with Cdc20 in a very tight complex. It is thought that the C-Mad2–Cdc20 (MC) subcomplex associates with BubR1-Bub3 to form the MCC (4, 5).In studying the mechanisms of the disassembly of MCC, we found that ATP hydrolysis is required for this process (7). ATP was also required for the action of p31^comet, a Mad2-binding protein involved in the exit from the mitotic checkpoint (8) and in MCC dissociation (9). Subsequently, we purified a factor that promotes ATP- and p31^comet-dependent release of Mad2 from MC and MCC and identified it as the TRIP13 ATPase (1). The role of TRIP13 in checkpoint inactivation was corroborated by in vivo results of other investigators indicating that TRIP13 knockdown delays metaphase–anaphase transition (2). We proposed that the energy of ATP hydrolysis is used by the TRIP13 ATPase to promote conformational transition of C-Mad2 to O-Mad2, thus leading to its release from MCC or MC (1). The action of TRIP13 to convert C-Mad2 to O-Mad2 was recently demonstrated by direct methods (10).The question arose concerning what is the role of p31^comet in the action of the TRIP13 ATPase. Because it had been suggested by a proteomic data-mining study that TRIP13 interacts with p31^comet (11) and because p31^comet specifically binds to the closed conformation of Mad2 (12), it seemed reasonable to assume that p31^comet serves as an adaptor protein that targets the TRIP13 AAA-ATPase to C-Mad2–containing checkpoint complexes. However, in our previous experiments on immunodepletion of TRIP13 or p31^comet from checkpoint extracts, using antibodies directed against either protein, we could not detect coimmunodepletion of either protein with its presumed partner (1). The present investigation was initiated to solve this problem and to gain insight into the role of p31^comet in TRIP13 action. We find that p31^comet and checkpoint complexes mutually stimulate the binding of each other to the oligomeric form of the TRIP13 ATPase. We propose that p31^comet bound to C-Mad2–containing checkpoint complex is the substrate for the ATPase and that the substrate-binding site of TRIP13 is composed of subsites specific for p31^comet and the C-Mad2 moiety of the checkpoint complex. The simultaneous binding of p31^comet and C-Mad2 to these subsites is required for their high-affinity interaction with TRIP13.     

Emergence of system roles in normative neurodevelopment

Adult human cognition is supported by systems of brain regions, or modules, that are functionally coherent at rest and collectively activated by distinct task requirements. However, an understanding of how the formation of these modules supports evolving cognitive capabilities has not been delineated. Here, we quantify the formation of network modules in a sample of 780 youth (aged 8–22 y) who were studied as part of the Philadelphia Neurodevelopmental Cohort. We demonstrate that the brain’s functional network organization changes in youth through a process of modular evolution that is governed by the specific cognitive roles of each system, as defined by the balance of within- vs. between-module connectivity. Moreover, individual variability in these roles is correlated with cognitive performance. Collectively, these results suggest that dynamic maturation of network modules in youth may be a critical driver for the development of cognition.The human brain is composed of large-scale functional networks that are coherent at rest, forming identifiable modules that support specific cognitive functions (1–3). These modules include well-known subsystems, such as the default-mode, visual, motor, auditory, attention, salience, and cognitive control systems. Prior research has shown that this modular structure evolves considerably during development in youth (4, 5) and across the life span (6, 7). Network modularity, a measure of the segregation between modules, is high during young adulthood and decreases across the latter life span (6, 7). Other features of network reorganization accompany development (8), including a growing preference for interactions between hubs and nonhubs (9), and between regions separated by large physical distances (10).Although prior research has explored such changes in gross network features, it remains unknown how the relationships between specific types of cognitive systems evolve during adolescent development. Ongoing developmental changes in connectivity between cognitive systems are suggested by known differences in how these systems are organized in the adult brain: Primary motor and sensory systems display a high degree of segregation with limited connections to other modules, whereas higher order cognitive systems have more between-module connectivity (1). Moreover, the disparate connectivity profiles of such systems may be critical for optimal cognitive functioning (11). Differentiation of specific network modules may thus support the burgeoning cognitive, emotional, and motor capabilities seen during adolescence (12). Furthermore, abnormalities in functional network organization are a ubiquitous finding in major neuropsychiatric conditions (11), which are increasingly considered disorders of neurodevelopment (13). Thus, a quantitative characterization of the modular maturation of functional networks in youth is critical to understanding the development of both normal and abnormal brain function.Here, we tested the hypothesis that the brain’s functional network organization changes in youth through a process of modular evolution that is governed by the specific cognitive roles of each system. Specifically, we predicted that the development of the functional organization of the brain is driven, in part, by changes in the balance of within- vs. between-module (henceforth “system”) connectivity. To address this hypothesis, we quantify the formation of putative functional network systems (1) in a sample of 780 youth (aged 8–22 y) who were studied as part of the Philadelphia Neurodevelopmental Cohort. Critically, we adapt a previously defined approach to role determinations used in other complex systems, such as airline transportation networks and the Internet (14). This approach allows network systems roles to be defined based on their position in a 2D plane mapped out by their within- and between-system connectivity. In this framework, modules with high between-system connectivity are designated connector systems, whereas modules with low between-system connectivity are provincial systems. Similarly, modules with high within-system connectivity are cohesive systems, whereas modules with low within-system connectivity are incohesive systems. Using this approach, we define intuitive network roles for network modules in the early life span and delineate changes in these roles over development.As described below, our results demonstrate that network modules, initially less disparately sized and highly integrated, become increasingly differentiated in a manner that matches the organization of the adult brain. Moreover, we observe that the within- vs. between-network connectivity profile of each network module falls into one of four categories that correspond to their functional role in the brain: Roles are defined as functional hub (connectors) vs. nonhub (provincial) systems and as functionally cohesive vs. incohesive systems. Finally, we find that individual variability in the between-network connectivity of the sensorimotor and default mode networks is correlated with cognitive performance. Collectively, these results suggest that dynamic maturation of network modules in youth may be a critical driver for the development of cognition and provides an important context for understanding psychopathology.     

Heel height affects lower extremity frontal plane joint moments during walking

Wearing high heels alters walking kinematics and kinetics and can create potentially adverse effects on the body. Our purpose was to determine how heel height affects frontal plane joint moments at the hip, knee, and ankle, with a specific focus on the knee moment due to its importance in joint loading and knee osteoarthritis. 15 women completed overground walking using three different heel heights (1, 5, and 9 cm) for fixed speed (1.3 ms(-1)) and preferred speed conditions while kinematic and force platform data were collected concurrently. For both fixed and preferred speeds, peak internal knee abduction moment increased systematically as heel height increased (fixed: 0.46, 0.48, 0.55 N m kg(-1); preferred: 0.47, 0.49, 0.53 N m kg(-1)). Heel height effects on net frontal plane moments of the hip and ankle were similar to those for the knee; peak joint moments increased as heel height increased. The higher peak internal knee abduction moment with increasing heel height suggests greater medial loading at the knee. Kinetic changes at the ankle with increasing heel height may also contribute to larger medial loads at the knee. Overall, wearing high heels, particularly those with higher heel heights, may put individuals at greater risk for joint degeneration and developing medial compartment knee osteoarthritis.