HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects.

Major depressive disorder (MDD) is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to respond adequately to existing treatments, and new pharmacologic targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate excitability in neurons, and blocking HCN channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN-channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN-channel trafficking and its relationship with antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN-channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN-channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b-HCN interaction bidirectionally influences channel trafficking and antidepressant-like behavior. Overall, our work suggests that small-molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of MDD.

Energetic Coupling between Ligand Binding and Dimerization in Escherichia coli Phosphoglycerate Mutase.

Energetic coupling of two molecular events in a protein molecule is ubiquitous in biochemical reactions mediated by proteins, such as catalysis and signal transduction. Here, we investigate energetic coupling between ligand binding and folding of a dimer using a model system that shows three-state equilibrium unfolding of an exceptional quality. The homodimeric Escherichia coli cofactor-dependent phosphoglycerate mutase (dPGM) was found to be stabilized by ATP in a proteome-wide screen, although dPGM does not require or utilize ATP for enzymatic function. We investigated the effect of ATP on the thermodynamic stability of dPGM using equilibrium unfolding. We found that, in the absence of ATP, dPGM populates a partially unfolded, monomeric intermediate during equilibrium unfolding. However, addition of 1.0 mM ATP drastically reduces the population of the intermediate by selectively stabilizing the native dimer. Using a computational ligand docking method, we predicted ATP binds to the active site of the enzyme using the triphosphate group. By performing equilibrium unfolding and isothermal titration calorimetry with active-site variants of dPGM, we confirmed that active-site residues are involved in ATP binding. Our findings show that ATP promotes dimerization of the protein by binding to the active site, which is distal from the dimer interface. This cooperativity suggests an energetic coupling between the active site and the dimer interface. We also propose a structural link to explain how ligand binding to the active site is energetically coupled with dimerization.

Conotoxin Prediction: New Features to Increase Prediction Accuracy.

Conotoxins are toxic, disulfide-bond-rich peptides from cone snail venom that target a wide range of receptors and ion channels with multiple pathophysiological effects. Conotoxins have extraordinary potential for medical therapeutics that include cancer, microbial infections, epilepsy, autoimmune diseases, neurological conditions, and cardiovascular disorders. Despite the potential for these compounds in novel therapeutic treatment development, the process of identifying and characterizing the toxicities of conotoxins is difficult, costly, and time-consuming. This challenge requires a series of diverse, complex, and labor-intensive biological, toxicological, and analytical techniques for effective characterization. While recent attempts, using machine learning based solely on primary amino acid sequences to predict biological toxins (e.g., conotoxins and animal venoms), have improved toxin identification, these methods are limited due to peptide conformational flexibility and the high frequency of cysteines present in toxin sequences. This results in an enumerable set of disulfide-bridged foldamers with different conformations of the same primary amino acid sequence that affect function and toxicity levels. Consequently, a given peptide may be toxic when its cysteine residues form a particular disulfide-bond pattern, while alternative bonding patterns (isoforms) or its reduced form (free cysteines with no disulfide bridges) may have little or no toxicological effects. Similarly, the same disulfide-bond pattern may be possible for other peptide sequences and result in different conformations that all exhibit varying toxicities to the same receptor or to different receptors. We present here new features, when combined with primary sequence features to train machine learning algorithms to predict conotoxins, that significantly increase prediction accuracy.

Understanding the rehabilitation psychology specialty career pathway.

OBJECTIVE: Little is known about how psychologists choose their specialty practice area, and rehabilitation psychology is no exception. Specialization and specialty certification in professional psychology have been controversial topics impacting the field during the training sequence and across the span of professional careers (Drum & Blom, 2001; Robiner & Fossum, 2017). The American Board of Rehabilitation Psychology (ABRP) has been providing specialty certification since 1995 and rehabilitation psychology was recognized as a unique specialty in 2015 by the APA's Council for the Recognition of Specialties and Proficiencies in Professional Psychology (CRSPPP). There are limited established training programs and minimal information about the specialty in undergraduate course materials. The current survey is intended to provide information about how people are introduced to the field of rehabilitation psychology, specialty identification, and to identify opportunities for improvement. METHOD: A survey of members of APA Division 22 and ABRP specialists was conducted to collect information about their exposure to and involvement in rehabilitation psychology. RESULTS: Results from 174 respondents suggest that personal relationships are the current key means of recruitment and confirms that rehabilitation psychology has limited presence in undergraduate training. Most professionals come to identify with rehabilitation psychology after training in clinical neuropsychology and health psychology. CONCLUSIONS: These preliminary results suggest that the current generalist training sequence does not provide sufficient exposure to, or preparation for the field of rehabilitation psychology. Recruitment opportunities should emphasize student leadership network activities and the identification of early and midcareer practitioners unaware of the rehabilitation specialty. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Bringing the social back in: a critique of the biomedicalization of dementia.

This paper presents the argument that social gerontologists have adopted a biomedical model of senile dementia, neglecting social factors involved in the definition and interpretation of brain disease and in the experience of dementing illness. This biomedical model is critiqued, including the definition of pathology, the attribution of behavioral changes to disease stages, and the legitimation of medical control over persons with dementing illnesses.

Day care for persons with dementia: the impact of the physical environment on staff stress and quality of care.

This study considers the impact of the physical environment on work-related stress and quality of care in a day care center that integrates demented people and other frail elderly persons. The researcher examined positive and negative differences before and after the program moved to a new, improved facility. Implications for facility design and other program characteristics are discussed.

Use of rat models to mimic alterations in iron homeostasis during human alcohol abuse and cirrhosis.

With alcoholism, there are marked disturbances in iron homeostasis that are linked to alterations in serum transferrin and ferritin concentrations. This study identifies rat models of alcohol abuse that closely mimic these disturbances. Male rats were placed in one of the following three protocols: (1) pair-feeding of liquid diets for 1-8 weeks; (2) agar-block feeding for 8 weeks; or (3) generation of cirrhosis with CCl(4). Serum samples were analyzed for ferritin, transferrin, and iron levels, and the transferrin iron saturation and ferritin/transferrin ratios were calculated. Liver iron concentrations were also determined. Serum transferrin levels were elevated in animals fed alcohol for 8 weeks in pair-feeding and agar-block feeding protocols, but reduced in rats with cirrhosis. Serum ferritin concentration was reduced in rats fed ethanol in the liquid diet, but increased in rats consuming ethanol in agar blocks, in rats pair-fed the liquid control diet, and in rats with cirrhosis. This finding was mirrored by liver nonheme iron concentrations in all experimental groups, but not in the corresponding control groups. Serum iron levels were significantly elevated only in rats fed the liquid control diet. There was a progressive decrease in transferrin iron saturation and ferritin/transferrin ratios for animals fed ethanol in the liquid diet, but not when ethanol was ingested from agar blocks. The development of cirrhosis resulted in elevated liver iron concentrations and doubled ferritin/transferrin ratios. It is concluded that these models may be used to study disturbances in iron homeostasis that occur during alcohol abuse and the (subsequent) development of liver disease.

Medical needs at high school football games in milwaukee.

To help clarify the medical needs at high school football games, injury and treatment data were recorded during medical coverage of 67 varsity games. Injury evaluations were performed on 11 1 athletes for 139 injuries. Sixty-four injuries resulted in the athlete not returning to complete the game and 8 injuries resulted in the athlete being unable to return to play for over 1 week. Contusions (26.6%), sprains (21.6%), strains (8.6%), and suspected fractures (8.6%) accounted for most of the injuries. The most common sites of injuries were the knee (14.4%), lower leg (13.7%), and ankle (1 1.5Oh). Icing and taping were the most common treatments provided. The frequency of injuries verifies the importance of qualified medical coverage at high school football games. The nature of most injuries indicates that besides having skills in basic emergency medicine, the medical personnel should be skilled in the management of acute soft tissue injuries.J Orthop Sports Phys Ther 1988;10(5):167-171.

Notation of previous falls in admission record of hospitalized elderly.

To test the hypothesis that a history of falling is underreported by physicians and nurses, we assessed the extent to which previous falls are noted in the admission medical history. A total of 168 community-dwelling and institutionalized elderly adults, > or = 70 years old, were evaluated in the emergency ward of a tertiary care community-based teaching hospital, and admitted to a general medical ward. Physicians' and nurses' emergency ward and admission notes were reviewed for the inclusion of "falls." Within 72 hours of admission, the information provided or omitted in the medical record was confirmed or refuted by face-to-face interview. Follow-up data were gleaned from computer-based records. The sample population consisted of 113 patients, 56% female, with a mean age of 80.7. Seventy-six patients had fallen within the past 10 years: of these, 32 (42%) were Recent Fallers, and 44 (58%) were Multiple Fallers. Review of the medical records revealed that 56 (74%) of the 76 Fallers were not noted to have fallen by the medical staff. Moreover, 15 (47%) of the Recent Fallers and 28 (64%) of the Multiple Fallers were missed. Examination of the nursing notes yielded similar results. In conclusion, elderly patients fall more frequently than recognized. Physicians and/or nurses should include a question regarding falls as part of the routine medical history.

Survival analysis in quality improvement: the Diabetic Kidney Disease Project extrapolation group estimates.

Survival analysis is used in a wide variety of research settings to maximize the information extracted from a group of timed observations. Measures employed in continuous quality improvement (CQI) efforts often involve such observations. Yet to date, survival analysis has not been widely used to guide CQI efforts. This article presents the features of survival analysis that are most applicable to CQI efforts and illustrates the application of these techniques to a quality improvement project focused on diabetic kidney disease. Results are compared with those from a "standard" analysis. The interpretation of results is discussed in the context of constraints typical of CQI efforts. The article concludes with a recommendation for broader application of this valuable analytic methodology.