School of Medicine

Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development of novel treatments targeting AQP4 to reduce edema could lessen the neuropathologic sequelae. We hypothesized that inhibiting AQP4 expression by injection of small-interfering RNA (siRNA) targeting AQP4 (siAQP4) after juvenile TBI would decrease edema formation, neuroinflammation, neuronal cell death, and improve neurologic outcomes. The siAQP4 or a RNA-induced silencing complex (RISC)-free control siRNA (siGLO) was injected lateral to the trauma site after controlled cortical impact in postnatal day 17 rats. Magnetic resonance imaging, neurologic testing, and immunohistochemistry were performed to assess outcomes. Pups treated with siAQP4 showed acute (3 days after injury) improvements in motor function and in spatial memory at long term (60 days after injury) compared with siGLO-treated animals. These improvements were associated with decreased edema formation, increased microglial activation, decreased blood-brain barrier disruption, reduced astrogliosis and neuronal cell death. The effectiveness of our treatment paradigm was associated with a 30% decrease in AQP4 expression at the injection site.

tRNA function is based on unique structures that enable mRNA decoding using anticodon trinucleotides. These structures interact with specific aminoacyl-tRNA synthetases and ribosomes using 3D shape and sequence signatures. Beyond translation, tRNAs serve as versatile signaling molecules interacting with other RNAs and proteins. Through evolutionary processes, tRNA fragmentation emerges as not merely random degradation but an act of recreation, generating specific shorter molecules called tRNA-derived small RNAs (tsRNAs). These tsRNAs exploit their linear sequences and newly arranged 3D structures for unexpected biological functions, epitomizing the tRNA "renovatio" (from Latin, meaning renewal, renovation, and rebirth). Emerging methods to uncover full tRNA/tsRNA sequences and modifications, combined with techniques to study RNA structures and to integrate AI-powered predictions, will enable comprehensive investigations of tRNA fragmentation products and new interaction potentials in relation to their biological functions. We anticipate that these directions will herald a new era for understanding biological complexity and advancing pharmaceutical engineering.

Molecular evolution is driven by mutations, which may affect the fitness of an organism and are then subject to natural selection or genetic drift. Analysis of primary protein sequences and tertiary structures has yielded valuable insights into the evolution of protein function, but little is known about the evolution of functional mechanisms, protein dynamics and conformational plasticity essential for activity. We characterized the atomic-level motions across divergent members of the dihydrofolate reductase (DHFR) family. Despite structural similarity, Escherichia coli and human DHFRs use different dynamic mechanisms to perform the same function, and human DHFR cannot complement DHFR-deficient E. coli cells. Identification of the primary-sequence determinants of flexibility in DHFRs from several species allowed us to propose a likely scenario for the evolution of functionally important DHFR dynamics following a pattern of divergent evolution that is tuned by cellular environment.

Children with cerebral palsy (CP) have motor impairments that make it challenging for them to participate in standard physical activity (PA) interventions. There is a need to evaluate adapted PA interventions for this population. Dance can promote coordination, posture, muscle strength, motor learning, and executive functioning. This pilot study evaluated the feasibility and the effects of a new therapeutic ballet intervention specifically designed for children with CP. Methods: Eight children with CP (9-14 y/o; 75% female) participated in a 6-week therapeutic ballet intervention. Outcomes were measured in multiple domains, including body composition (DXA), muscle strength (hand-grip dynamometer), habitual physical activity, gait and selective motor control functions, and executive functioning. Follow-up assessments of habitual physical activity, gait, and executive functioning were completed 4 to 5 weeks post-intervention. Results: Five of the eight participants were overfat or obese based on DXA percentage of body fat. All participants were below the 50th percentile for their age and gender for bone density. Four participants showed a trend to improve hand-grip strength in one hand only, while one improved in both hands. There were significant improvements in gait across time points (pre, post, and follow-up), specifically in time of ambulation (X _pre = 4.36, X _post = 4.22, X _follow-up = 3.72, d = 0.056, p = 0.02), and in step length (cm) on the right: X _pre = 48.29, X _post = 50.77, X _follow-up = 52.11, d = 0.22, p = 0.027, and left stride: X _pre = 96.29, X _post = 102.20, X _follow-up = 104.20, d = 0.30, p = 0.027, indicating gait changes in bilateral lower extremities. There was improvement in inhibitory control (d = 0.78; 95% Confidence Limit = ±0.71, p < 0.05) with large individual responses primarily among those above the mean at baseline. Conclusions: Therapeutic ballet may prove to be a useful intervention to promote physiological and cognitive functions in children with CP. Results demonstrated feasibility of the physical, physiological, and cognitive assessments and suggested improvements in participants' gait and inhibitory control with large individual responses. Modifications to personalize the intervention may be needed to optimize positive outcomes. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03681171.

Community access to deep (i ~ 25), highly-multiplexed optical and near-infrared multi-object spectroscopy (MOS) on 8-40m telescopes would greatly improve measurements of cosmological parameters from LSST. The largest gain would come from improvements to LSST photometric redshifts, which are employed directly or indirectly for every major LSST cosmological probe; deep spectroscopic datasets will enable reduced uncertainties in the redshifts of individual objects via optimized training. Such spectroscopy will also determine the relationship of galaxy SEDs to their environments, key observables for studies of galaxy evolution. The resulting data will also constrain the impact of blending on photo-z's. Focused spectroscopic campaigns can also improve weak lensing cosmology by constraining the intrinsic alignments between the orientations of galaxies. Galaxy cluster studies can be enhanced by measuring motions of galaxies in and around clusters and by testing photo-z performance in regions of high density. Photometric redshift and intrinsic alignment studies are best-suited to instruments on large-aperture telescopes with wider fields of view (e.g., Subaru/PFS, MSE, or GMT/MANIFEST) but cluster investigations can be pursued with smaller-field instruments (e.g., Gemini/GMOS, Keck/DEIMOS, or TMT/WFOS), so deep MOS work can be distributed amongst a variety of telescopes. However, community access to large amounts of nights for surveys will still be needed to accomplish this work. In two companion white papers we present gains from shallower, wide-area MOS and from single-target imaging and spectroscopy.

OBJECTIVE: To estimate the burden of genital warts (GW)in Mexico. MATERIALS AND METHODS: We estimated the annual incidence of GW based on data reported by specialist physicians. We also assessed GW treatment practices, the average cost of treatment, and the psychosocial burden of GW among patients. RESULTS: The annual incidence of GW in Mexico was estimated to be 547 200 cases. Treatment procedures vary by specialist and patient gender. The estimated annual cost was $195 million USD. The psychosocial impact of GW was slightly greater in males than females. CONCLUSIONS: This is the first evaluation of the burden of GW in Mexico. Our data suggest that GW are common, with significant health-related costs and psychosocial impact.