Hyperpolarized carbon 13 MRI: clinical applications and future directions in oncology

Hyperpolarized carbon 13 MRI (13C MRI) is a novel imaging approach that can noninvasively probe tissue metabolism in both normal and pathologic tissues. The process of hyperpolarization increases the signal acquired by several orders of magnitude, allowing injected 13C-labeled molecules and their downstream metabolites to be imaged in vivo, thus providing real-time information on kinetics. To date, the most important reaction studied with hyperpolarized 13C MRI is exchange of the hyperpolarized 13C signal from injected [1-13C]pyruvate with the resident tissue lactate pool. Recent preclinical and human studies have shown the role of several biologic factors such as the lactate dehydrogenase enzyme, pyruvate transporter expression, and tissue hypoxia in generating the MRI signal from this reaction. Potential clinical applications of hyperpolarized 13C MRI in oncology include using metabolism to stratify tumors by grade, selecting therapeutic pathways based on tumor metabolic profiles, and detecting early treatment response through the imaging of shifts in metabolism that precede tumor structural changes. This review summarizes the foundations of hyperpolarized 13C MRI, presents key findings from human cancer studies, and explores the future clinical directions of the technique in oncology

An empirical approach to assessing pediatric residents\u27 attitudes, knowledge, and skills in primary care behavioral health

This paper describes an empirical approach to assessing pediatric residents\u27 attitudes, knowledge and skills in primary care behavioral health. Outcomes from that assessment approach are presented from two pediatric residency training programs in the northeastern United States. Thirty-six pediatric residents completed attitudes, knowledge and skills surveys. The survey was developed to align with the American Academy of Pediatrics’ Policy Statement in 2009 citing aspirational competencies for pediatricians in primary care behavioral health. This alignment addressed both learner variables (attitudes, knowledge, and skills) as well as clinical presentations (ADHD, anxiety, depression, and suicide) highlighted in the policy statement. The survey specifically inquired about self-reported confidence and comfort in managing behavioral health concerns using evidence-based practice parameters (attitudes and knowledge) and their measured ability to deliver evidence-based care in response to clinical vignettes (skills). Findings largely revealed no statistically significant differences in attitudes, knowledge or skills between interns and upper-level residents. Training programs can use the approach described in this paper and the assessment instrument with some possible modifications to monitor annual progress and evaluate any changes in didactic and clinical training

As a Pediatrician, I Don’t Know the Second, Third, or Fourth Thing to Do: A Qualitative Study of Pediatric Residents’ Training and Experiences in Behavioral Health

Despite a mandated 1-month rotation in developmental-behavioral pediatrics (DBP), pediatric residents report inadequate training in behavioral health care. As a first step in much needed curriculum development in this area, this study sought to assess learner experiences regarding the management of behavioral health problems during residency. Four focus groups were conducted for residents in years 1-3 of training in 2 residency programs in a northeastern state. Transcripts were analyzed and coded by researchers through qualitative classical content analysis. The exploratory analysis revealed 9 key themes: time requirements, rapport building, resources and referrals for behavioral health, psychiatric medications, diagnosis vs. treatment, working with families, the importance of behavioral health, fears of working with a pediatric population, and training issues. These qualitative data further identify gaps in the behavioral health training of pediatric residents and may inform future innovations in training curricula

Ozanimod to treat relapsing forms of multiple sclerosis: A comprehensive review of disease, drug efficacy and side effects

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators

Ozanimod to treat relapsing forms of multiple sclerosis: A comprehensive review of disease, drug efficacy and side effects

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing–remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Protective management of trees against debarking by deer negatively impacts bryophyte diversity

When wildlife populations become too large, they impact other flora and fauna within the ecosystems that they inhabit. For example, the recent rise in population numbers of sika deer in Japan has led to the stripping of bark from tree overstories in forested areas. This has led to protective management actions, such as wrapping the trunks of trees in wire mesh. The present study investigates the impact of this management action on epiphytic diversity at Mt. Ohdaigahara, which is one of the hotspots for bryophyte diversity in Japan. The correlation between the diversity of epiphytic bryophytes and environmental variables was examined, including the presence/absence of wire mesh protection. A generalized linear model showed that species richness and bryophyte cover was significantly correlated with both tree diameter (at 1.5 m height) and tree density (P < 0.01), but negatively correlated with wire mesh protection. Inductively coupled plasma-mass spectrometry analysis showed a significant 3- to 6-fold higher concentration of zinc in bryophytes occupying tree bark under wire mesh protection than for those without wire mesh. Hence, the high sensitivity of bryophytes to zinc accumulation, as a result of toxicity caused by galvanized iron mesh, has led to the loss of species richness and bryophyte cover on tree trunks. Furthermore, other heavy metals found in wire mesh may also contribute to the negative effect on bryophytes. Therefore, to establish best practices for biodiversity conservation that include bryophytes, materials that are free of heavy metals should be preferentially used for tree protection

The linked units of 5S rDNA and U1 snDNA of razor shells (Mollusca: Bivalvia: Pharidae)

[Abstract] The linkage between 5S ribosomal DNA and other multigene families has been detected in many eukaryote lineages, but whether it provides any selective advantage remains unclear. In this work, we report the occurrence of linked units of 5S ribosomal DNA (5S rDNA) and U1 small nuclear DNA (U1 snDNA) in 10 razor shell species (Mollusca: Bivalvia: Pharidae) from four different genera. We obtained several clones containing partial or complete repeats of both multigene families in which both types of genes displayed the same orientation. We provide a comprehensive collection of razor shell 5S rDNA clones, both with linked and nonlinked organisation, and the first bivalve U1 snDNA sequences. We predicted the secondary structures and characterised the upstream and downstream conserved elements, including a region at −25 nucleotides from both 5S rDNA and U1 snDNA transcription start sites. The analysis of 5S rDNA showed that some nontranscribed spacers (NTSs) are more closely related to NTSs from other species (and genera) than to NTSs from the species they were retrieved from, suggesting birth-and-death evolution and ancestral polymorphism. Nucleotide conservation within the functional regions suggests the involvement of purifying selection, unequal crossing-overs and gene conversions. Taking into account this and other studies, we discuss the possible mechanisms by which both multigene families could have become linked in the Pharidae lineage. The reason why 5S rDNA is often found linked to other multigene families seems to be the result of stochastic processes within genomes in which its high copy number is determinan

Pep1, a Secreted Effector Protein of Ustilago maydis, Is Required for Successful Invasion of Plant Cells

The basidiomycete Ustilago maydis causes smut disease in maize. Colonization of the host plant is initiated by direct penetration of cuticle and cell wall of maize epidermis cells. The invading hyphae are surrounded by the plant plasma membrane and proliferate within the plant tissue. We identified a novel secreted protein, termed Pep1, that is essential for penetration. Disruption mutants of pep1 are not affected in saprophytic growth and develop normal infection structures. However, Δpep1 mutants arrest during penetration of the epidermal cell and elicit a strong plant defense response. Using Affymetrix maize arrays, we identified 116 plant genes which are differentially regulated in Δpep1 compared to wild type infections. Most of these genes are related to plant defense. By in vivo immunolocalization, live-cell imaging and plasmolysis approaches, we detected Pep1 in the apoplastic space as well as its accumulation at sites of cell-to-cell passages. Site-directed mutagenesis identified two of the four cysteine residues in Pep1 as essential for function, suggesting that the formation of disulfide bridges is crucial for proper protein folding. The barley covered smut fungus Ustilago hordei contains an ortholog of pep1 which is needed for penetration of barley and which is able to complement the U. maydis Δpep1 mutant. Based on these results, we conclude that Pep1 has a conserved function essential for establishing compatibility that is not restricted to the U. maydis / maize interaction