Differences in the morphology of spinal V2a neurons reflect their recruitment order during swimming in larval zebrafish

Networks of neurons in spinal cord generate locomotion. However, little is known about potential differences in network architecture that underlie the production of varying speeds of movement. In larval zebrafish, as swimming speed increases, Chx10‐positive V2a excitatory premotor interneurons are activated from ventral to dorsal in a topographic pattern that parallels axial motoneuron recruitment. Here, we examined whether differences in the morphology and synaptic output of V2a neurons reflect their recruitment order during swimming. To do so, we used in vivo single‐cell labeling approaches to quantify the dorsoventral distribution of V2a axonal projections and synapses. Two different classes of V2a neurons are described, cells with ascending and descending axons and cells that are only descending. Among the purely descending V2a cells, more dorsal cells project longer distances than ventral ones. Proximally, all V2a neurons have axonal distributions that suggest potential connections to cells at and below their own soma positions. At more distal locations, V2a axons project dorsally, which creates a cumulative intersegmental bias to dorsally located spinal neurons. Assessments of the synapse distribution of V2a cells, reported by synaptophysin expression, support the morphological observations and also demonstrate that dorsal V2a cells have higher synapse densities proximally. Our results suggest that V2a cells with more potential output to spinal neurons are systematically engaged during increases in swimming frequency. The findings help explain patterns of axial motoneuron recruitment and set up clear predictions for future physiological studies examining the nature of spinal excitatory network connectivity as it relates to movement intensity. J. Comp. Neurol. 522:1232–1248, 2014. © 2013 Wiley Periodicals, Inc.     

Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden

Trimethlyamine-N-oxide (TMAO) was recently identified as a promoter of atherosclerosis. Patients with CKD exhibit accelerated development of atherosclerosis; however, no studies have explored the relationship between TMAO and atherosclerosis formation in this group. This study measured serum concentrations and urinary excretion of TMAO in a CKD cohort (n=104), identified the effect of renal transplant on serum TMAO concentration in a subset of these patients (n=6), and explored the cross-sectional relationship between serum TMAO and coronary atherosclerosis burden in a separate CKD cohort (n=220) undergoing coronary angiography. Additional exploratory analyses examined the relationship between baseline serum TMAO and long-term survival after coronary angiography. Serum TMAO concentrations demonstrated a strong inverse association with eGFR (r²=0.31, P<0.001). TMAO concentrations were markedly higher in patients receiving dialysis (median [interquartile range], 94.4 μM [54.8–133.0 μM] for dialysis-dependent patients versus 3.3 μM [3.1–6.0 μM] for healthy controls; P<0.001); whereas renal transplantation resulted in substantial reductions in TMAO concentrations (median [min–max] 71.2 μM [29.2–189.7 μM] pretransplant versus 11.4 μM [8.9–20.2 μM] post-transplant; P=0.03). TMAO concentration was an independent predictor for coronary atherosclerosis burden (P=0.02) and predicted long-term mortality independent of traditional cardiac risk factors (hazard ratio, 1.26 per 10 μM increment in TMAO concentration; 95% confidence interval, 1.13 to 1.40; P<0.001). In conclusion, serum TMAO concentrations substantially increase with decrements in kidney function, and this effect is reversed by renal transplantation. Increased TMAO concentrations correlate with coronary atherosclerosis burden and may associate with long-term mortality in patients with CKD undergoing coronary angiography.     

Administration time estimates for Wechsler Intelligence Scale for Children-IV subtests, composites, and short forms

The administration times for Wechsler Intelligence Scale for Children-IV (WISC-IV) subtests, indexes, and the Full Scale IQ were recorded for 57 school children. Also determined were administration times for eight short forms and the General Ability Index (GAI). All eight short forms reduced testing time by >50%, but the GAI required approximately 56 minutes. The time to administer the 10 core subtests that yield the Full Scale IQ and index scores averaged 72 minutes (range = 42 to 100), but 31% of the administrations required 80 minutes or longer. These results indicate that administration times are quite variable and that D. Wechsler's (2003) guideline of 65 to 80 minutes can be misleading for certain settings and for specific examinees. The present research found administration time to be positively correlated with examinee age, grade placement, and Full Scale IQ. In addition, the extent of examiner experience is known to be positively related to administration speed. In the present research, as in many settings, the examiners were competent, but not highly experienced.     

Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1–0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1–2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.     

Freezing and Thawing Resistance of Fine Recycled Concrete Aggregate (FRCA) Mixtures Designed with Distinct Techniques

The pressure to use sustainable materials and adopt practices reducing the carbon footprint of the construction industry has risen. Such materials include recycled concrete aggregates (RCA) made from waste concrete. However, concrete made with RCA often presents poor fresh and hardened properties along with a decrease in its durability performance, especially when using its fine fraction (i.e., FRCA). Most studies involving FRCA use direct replacement methods (DRM) to proportion concrete although other techniques are available such as the Equivalent Volume (EV) and Particle Packing Models (PPMs); yet their impact on the durability performance, especially its performance against freezing and thawing (F/T), remains unknown. This work, therefore, appraises the F/T resistance of FRCA mixtures proportioned through various mix proportioning techniques (i.e., DRM, EV and PPMs), produced with distinct crushing processes (i.e., crusher’s fines vs. finely ground). The results show that the mix design technique has a significant influence on the FRCA mixture’s F/T resistance where PPM-proportioned mixtures demonstrate the best overall performance, exceeding the specified requirements while DRM-proportioned mixtures failed F/T resistance requirements. Moreover, the crushing process plays an important role in the recycled mixtures’ cracking behavior under F/T cycles, where less processing leads to fewer cracks while remaining the most sustainable option overall.