Mesodermal FGF and BMP govern the sequential stages of zebrafish thyroid specification.

Thyroid tissue, the site of de novo thyroid hormone biosynthesis, is derived from ventral pharyngeal endoderm and defects in morphogenesis are a predominant cause of congenital thyroid diseases. The first molecularly recognizable step of thyroid development is the specification of thyroid precursors in anterior foregut endoderm. Recent studies have identified crucial roles of FGF and BMP signaling in thyroid specification, but the interplay between signaling cues and thyroid transcription factors remained elusive. By analyzing Pax2a and Nkx2.4b expression dynamics in relation to endodermal FGF and BMP signaling activities in zebrafish embryos, we identified a Pax2a-expressing thyroid progenitor population that shows enhanced FGF signaling but lacks Nkx2.4b expression and BMP signaling. Concurrent with upregulated BMP signaling, a subpopulation of these progenitors subsequently differentiates into lineage-committed thyroid precursors co-expressing Pax2a and Nkx2.4b. Timed manipulation of FGF/BMP activities suggests a model in which FGF signaling primarily regulates Pax2a expression, whereas BMP signaling regulates both Pax2a and Nkx2.4b expression. Our observation of similar expression dynamics of Pax8 and Nkx2-1 in mouse embryos suggests that this refined model of thyroid cell specification is evolutionarily conserved in mammals.

Effects of Therapeutic Intervention on Spatiotemporal Gait Parameters in Adults With Neurologic Disorder: Systematic Review and Meta-analysis.

OBJECTIVE: This systematic review and meta-analysis aimed to review and quantify the changes in gait parameters after therapeutic intervention in adults with neurologic disorders. DATA SOURCES: A keyword search was performed in 4 databases: PubMed, CINAHL, Scopus, and Web of Science (01/2000-12/2021). We performed the search algorithm including all possible combinations of keywords. Full-text articles were examined further using forward/backward search methods. STUDY SELECTION: Studies were thoroughly screened using the following inclusion criteria: Study design: randomized controlled trial; adults ≥55 years old with a neurologic disorder; therapeutic intervention; spatiotemporal gait characteristics; and language: English. DATA EXTRACTION: A standardized data extraction form was used to collect the following methodological outcome variables from each of the included studies: author, year, population, age, sample size, and spatiotemporal gait parameters such as cadence, step length, step width, or double limb support. A meta-analysis was performed among trials presenting with similar characteristics, including study population and outcome measure. If heterogeneity was >50%, a random plot analysis was used; otherwise, a fixed plot analysis was done. DATA SYNTHESIS: We included 25 out of 34 studies in our meta-analysis that examined gait in adults with neurologic disorders. All analyses used effect sizes and standard error and a P<.05(denoted by *) threshold was considered statistically significant. Overall, we found that sensory (SS) and electrical stimulation (ES) had the most significant effect on step length (SS: z=5.44*, ES: z=2.42*) and gait speed (SS: z=6.19*, ES: z=7.38*) in adults with Parkinson disease (PD). Although balance or physical activity interventions were not found to be effective in modifying step length in adults with PD, they showed a significant effect on gait speed. Further, physical activity had the most significant effect on cadence in adults with PD (z=2.84*) relative to sensory stimulation effect on cadence (z=2.59*). For stroke, conventional physical therapy had the most significant effect on step length (z=3.12*) and cadence (z=3.57*). CONCLUSION: Sensory stimulation such as auditory and somatosensory stimulation while walking had the most significant effect on step length in adults with PD. We also found that conventional physical therapy did improve spatial gait parameters relative to other physical activity interventions in adults with PD and stroke.

Phenotypic expression and clinical outcomes in a South Asian PRKAG2 cardiomyopathy cohort.

The PRKAG2 syndrome is a rare autosomal dominant phenocopy of sarcomeric hypertrophic cardiomyopathy (HCM), characterized by ventricular pre-excitation, progressive conduction system disease and left ventricular hypertrophy. This study describes the phenotype, genotype and clinical outcomes of a South-Asian PRKAG2 cardiomyopathy cohort over a 7-year period. Clinical, electrocardiographic, echocardiographic, and cardiac MRI data from 22 individuals with PRKAG2 variants (68% men; mean age 39.5 ± 18.1 years), identified at our HCM centre were studied prospectively. At initial evaluation, all of the patients were in NYHA functional class I or II. The maximum left ventricular wall thickness was 22.9 ± 8.7 mm and left ventricular ejection fraction was 53.4 ± 6.6%. Left ventricular hypertrophy was present in 19 individuals (86%) at baseline. 17 patients had an WPW pattern (77%). After a mean follow-up period of 7 years, 2 patients had undergone accessory pathway ablation, 8 patients (36%) underwent permanent pacemaker implantation (atrio-ventricular blocks-5; sinus node disease-2), 3 patients developed atrial fibrillation, 11 patients (50%) developed progressive worsening in NYHA functional class, and 6 patients (27%) experienced sudden cardiac death or equivalent. PRKAG2 cardiomyopathy must be considered in patients with HCM and progressive conduction system disease.

Single-cell transcriptome analysis reveals thyrocyte diversity in the zebrafish thyroid gland.

The thyroid gland regulates growth and metabolism via production of thyroid hormone in follicles composed of thyrocytes. So far, thyrocytes have been assumed to be a homogenous population. To uncover heterogeneity in the thyrocyte population and molecularly characterize the non-thyrocyte cells surrounding the follicle, we developed a single-cell transcriptome atlas of the region containing the zebrafish thyroid gland. The 6249-cell atlas includes profiles of thyrocytes, blood vessels, lymphatic vessels, immune cells, and fibroblasts. Further, the thyrocytes show expression heterogeneity, including bimodal expression of the transcription factor pax2a. To validate thyrocyte heterogeneity, we generated a CRISPR/Cas9-based pax2a knock-in line that monitors pax2a expression in the thyrocytes. A population of pax2a-low mature thyrocytes interspersed in individual follicles can be distinguished. We corroborate heterogeneity within the thyrocyte population using RNA sequencing of pax2a-high and pax2a-low thyrocytes, which demonstrates 20% differential expression in transcriptome between the two subpopulations. Our results identify and validate transcriptional differences within the presumed homogenous thyrocyte population.