The motivational role of the ventral striatum and amygdala in learning from gains and losses.

The ventral striatum (VS) and amygdala are two structures often implicated as essential structures for learning. The literature addressing the contribution of these areas to learning, however, is not entirely consistent. We propose that these inconsistencies are due to learning environments and the effect they have on motivation. To differentiate aspects of learning from environmental factors that affect motivation, we ran a series of experiments with varying task factors. We compared monkeys (Macaca mulatta) with VS lesions, amygdala lesions, and unoperated controls on reinforcement learning (RL) tasks that involve learning from both gains and losses as well as from deterministic and stochastic schedules of reinforcement. We found that for all three groups, performance varied by experiment. All three groups modulated their behavior in the same directions, to varying degrees, across the three experiments. This behavioral modulation is why we find deficits in some experiments, but not others. The amount of effort animals exhibited differed depending on the learning environment. Our results suggest that the VS is important for the amount of effort animals will give in rich deterministic and relatively leaner stochastic learning enivornments. We also showed that monkeys with amygdala lesions can learn stimulus-based RL in stochastic environments and environments with loss and conditioned reinforcers. These results show that learning environments shape motivation and that the VS is essential for distinct aspects of motivated behavior. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Hierarchical Reinforcement Learning, Sequential Behavior, and the Dorsal Frontostriatal System.

To effectively behave within ever-changing environments, biological agents must learn and act at varying hierarchical levels such that a complex task may be broken down into more tractable subtasks. Hierarchical reinforcement learning (HRL) is a computational framework that provides an understanding of this process by combining sequential actions into one temporally extended unit called an option. However, there are still open questions within the HRL framework, including how options are formed and how HRL mechanisms might be realized within the brain. In this review, we propose that the existing human motor sequence literature can aid in understanding both of these questions. We give specific emphasis to visuomotor sequence learning tasks such as the discrete sequence production task and the M × N (M steps × N sets) task to understand how hierarchical learning and behavior manifest across sequential action tasks as well as how the dorsal cortical-subcortical circuitry could support this kind of behavior. This review highlights how motor chunks within a motor sequence can function as HRL options. Furthermore, we aim to merge findings from motor sequence literature with reinforcement learning perspectives to inform experimental design in each respective subfield.

A liposome/gelatin methacrylate nanocomposite hydrogel system for delivery of stromal cell-derived factor-1α and stimulation of cell migration.

Chronic, non-healing skin and soft tissue wounds are susceptible to infection, difficult to treat clinically, and can severely reduce a patient's quality of life. A key aspect of this issue is the impaired recruitment of mesenchymal stem cells (MSCs), which secrete regenerative cytokines and modulate the phenotypes of other effector cells that promote healing. We have engineered a therapeutic delivery system that can controllably release the pro-healing chemokine stromal cell derived factor-1α (SDF-1α) to induce the migration of MSCs. In order to protect the protein cargo from hydrolytic degradation and control its release, we have loaded SDF-1α in anionic liposomes (lipoSDF) and embedded them in gelatin methacrylate (GelMA) to form a nanocomposite hydrogel. In this study, we quantify the release of SDF-1α from our hydrogel system and measure the induced migration of MSCs in vitro via a transwell assay. Lastly, we evaluate the ability of this system to activate intracellular signaling in MSCs by using Western blots to probe for the phosphorylation of key proteins in the mTOR pathway. To our knowledge, this is the first study to report the delivery of liposomal SDF-1α using a nanocomposite approach. The results of this study expand on our current understanding of factors that can be modified to affect MSC behavior and phenotype. Furthermore, our findings contribute to the development of new hydrogel-based therapeutic delivery strategies for clinical wound healing applications. STATEMENT OF SIGNIFICANCE: Chronic, non-healing wounds promote an inflammatory environment that inhibits the migration of mesenchymal stem cells (MSCs), which secrete pro-healing and regenerative cytokines. The goal of this project is to apply principles of tissue engineering to achieve controllable release of the pro-healing chemokine SDF-1α to modulate the intracellular signaling and migratory behavior of MSCs. In this work, we introduce a nanocomposite strategy to tailor the release of SDF-1α using a liposome/gelatin methacrylate hydrogel approach. We are the first group to report the delivery of liposomal SDF-1α using this strategy. Our findings aim to further elucidate the role of MSCs in directing wound healing and guide the development of immunomodulatory and therapeutic delivery strategies for clinical wound healing applications.

Jointly discussing care plans for real-life patients: The potential of a student-led interprofessional team meeting in undergraduate health professions education.

BACKGROUND: Interprofessional education is promoted as a means of enhancing future collaborative practice in healthcare. We developed a learning activity in which undergraduate medical, nursing and allied healthcare students practice interprofessional collaboration during a student-led interprofessional team meeting. DESIGN AND DELIVERY: During their clinical rotation at a family physician's practice, each medical student visits a frail elderly patient and prepares a care plan for the patient. At a student-led interprofessional team meeting, medical, nursing and allied healthcare students jointly review these care plans. Subsequently, participating students reflect on their interprofessional collaboration during the team meeting, both collectively and individually. Every 4 weeks, six interprofessional team meetings take place. Each team comprises 9-10 students from various healthcare professions, and meets once. To date an average of 360 medical and 360 nursing and allied healthcare students have participated in this course annually. EVALUATION: Students mostly reported positive experiences, including the opportunity to learn with, from and about other healthcare professions in the course of jointly reviewing care plans, and feeling collectively responsible for the care of the patients involved. Additionally, students reported a better understanding of the contextual factors at hand. The variety of patient cases, diversity of participating health professions, and the course material need improvement. CONCLUSION: Students from participating institutions confirmed that attending a student-led interprofessional team meeting had enabled them to learn with, from and about other health professions in an active role. The use of real-life cases and the educational design contributed to the positive outcome of this interprofessional learning activity.

Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency.

Cystathionine beta-synthase (CBS) deficiency is a rare inherited disorder in the methionine catabolic pathway, in which the impaired synthesis of cystathionine leads to accumulation of homocysteine. Patients can present to many different specialists and diagnosis is often delayed. Severely affected patients usually present in childhood with ectopia lentis, learning difficulties and skeletal abnormalities. These patients generally require treatment with a low-methionine diet and/or betaine. In contrast, mildly affected patients are likely to present as adults with thromboembolism and to respond to treatment with pyridoxine. In this article, we present recommendations for the diagnosis and management of CBS deficiency, based on a systematic review of the literature. Unfortunately, the quality of the evidence is poor, as it often is for rare diseases. We strongly recommend measuring the plasma total homocysteine concentrations in any patient whose clinical features suggest the diagnosis. Our recommendations may help to standardise testing for pyridoxine responsiveness. Current evidence suggests that patients are unlikely to develop complications if the plasma total homocysteine concentration is maintained below 120 µmol/L. Nevertheless, we recommend keeping the concentration below 100 µmol/L because levels fluctuate and the complications associated with high levels are so serious.

Defining the phenotype and diagnostic considerations in adults with congenital disorders of N-linked glycosylation.

Congenital disorders of N-glycosylation (CDG) form a rapidly growing group of more than 20 inborn errors of metabolism. Most patients are identified at the pediatric age with multisystem disease. There is no systematic review on the long-term outcome and clinical presentation in adult patients. Here, we review the adult phenotype in 78 CDG patients diagnosed with 18 different forms of N-glycosylation defects. Characteristics include intellectual disability, speech disorder and abnormal gait. After puberty, symptoms might remain non-progressive and patients may lead a socially functional life. Thrombosis and progressive symptoms, such as peripheral neuropathy, scoliosis and visual demise are specifically common in PMM2-CDG. Especially in adult patients, diagnostic glycosylation screening can be mildly abnormal or near-normal, hampering diagnosis. Features of adult CDG patients significantly differ from the pediatric phenotype. Non-syndromal intellectual disability, or congenital malformations in different types of CDG and decreasing sensitivity of screening might be responsible for the CDG cases remaining undiagnosed until adulthood.

Comparison of the human and canine cytokines IL-1(alpha/beta) and TNF-alpha to orthologous other mammalians.

The cytokines interleukin-1 (IL-1alpha and IL-1beta) and the tumor necrosis factor-alpha (TNF-alpha) both play a major role in the initiation and regulation of inflammation and immunity responses. Polymorphisms within the gene sequences of these cytokines IL-1 and TNF-alpha have been proposed to play an important role in the pathogenesis of certain diseases. Affecting nearly every organ, various diseases, including some cancers, are described to be associated with an increased level of IL-1 and TNF-alpha proteins, for example, solid tumors, hematologic malignancies, malignant histiocytosis, autoimmune disorders, Alzheimer's disease, Parkinson's disease, sepsis, and rheumatoid arthritis. Regarding genetic backgrounds and pathways, numerous canine diseases show close similarities to their human counterparts. As a genetic model, the dog could be used to unravel the genetic mechanisms, for example, in particular the predispositions, the development, and progression of cancer and metabolic diseases. The identity comparison of gene and protein sequences of different species could be used to elucidate the structure and function of the genes and proteins by identifying the evolutionary conserved regions and domains. Herein we analyzed in detail the mRNA and protein structures and identities of the present known mammalian (human, canine, murine, rat, ovine, equine, feline, porcine, and bovine) TNF-alpha, IL-1alpha, and IL-1beta mRNAs and proteins. Additionally, based on the canine genome sequence, we derived in silico the complete mRNA structures of the IL-1alpha and IL-1beta mRNAs.

The long-term effect of multidisciplinary back training: a systematic review.

STUDY DESIGN: Systematic review of randomized controlled trials. OBJECTIVES: To determine the long-term effect of multidisciplinary back training on the work participation of patients with nonspecific chronic low back pain. SUMMARY OF BACKGROUND DATA: Chronic low back pain is influenced by multiple factors. Multidisciplinary back training represents one of the options to take this multiplicity into account. So far, only evidence of the short-term effectiveness of this approach in terms of work participation is available. METHODS: Electronic databases were searched and the references of various articles were screened for relevant publications. Ten studies met the inclusion criteria. All included studies were evaluated for their methodologic quality. RESULTS: Five of the studies had a low methodologic quality. All high-quality studies found a positive effect on at least one of the 4 outcome measures used. Based on our criteria, effectiveness was found for the outcome measures of work participation and quality of life. No effectiveness was found for experienced pain and functional status. The intensity of the intervention seems to have no substantial influence on the effectiveness of the intervention. CONCLUSION: In the long-term, multidisciplinary back training has a positive effect on work participation in patients with nonspecific chronic low back pain.

Cytokine genes single nucleotide polymorphism (SNP) screening analyses in canine malignant histiocytosis.

In humans, malignant histiocytosis is a tumour-like disease characterised by increasing proliferation of macrophages and reinforced degradation of erythrocytes. High progression of this disease leads to an unfavourable prognosis for the patients, most of them children up to the age of three years. Histological and cytological findings have proposed an important role of aberrant expression of cytokines in histiocytosis. Due to the fact that Bernese Mountain Dogs (BMD) show a predisposition for spontaneously developing malignant histiocytosis, these dogs could possibly be used as a genetic model organism to elucidate the mechanisms of human malignant histiocytosis. Canine cytokine cDNA transcripts of TNFalpha, Interleukin-1-alpha (IL-1alpha) and Interleukin-1-beta (IL-1beta) were screened for single nucleotide polymorphisms (SNPs). SNP screening in canine cytokine transcripts for malignant histiocytosis has not been carried out before. Total RNA was isolated from tissue samples from lung, spleen, testis and skin of 17 different dogs (fifteen BMDs, one Collie and one West Highland Terrier). The corresponding cytokine cDNAs were amplified, sequenced and then screened for SNPs. The resulting effects on the protein sequence were analysed. Several BMDs and the West Highland Terrier showed SNPs in the coding sequences which led to missense mutations within the protein sequences of TNFalpha, IL1alpha and IL1beta.