Clonal cytopenia of undetermined significance (CCUS) with dysplasia is enriched for MDS-type molecular findings compared to CCUS without dysplasia.

OBJECTIVES: Although morphologic dysplasia is not typically considered a feature of CCUS, we have consistently observed low-level bone marrow (BM) dysplasia among CCUS patients. We sought to determine whether sub-diagnostic BM dysplasia in CCUS patients is associated with other clinico-pathologic findings of myelodysplastic syndrome (MDS). METHODS: We identified 49 CCUS patients, 25 with sub-diagnostic dysplasia (CCUS-D), and 24 having no dysplasia (CCUS-ND). We compared the clinical, histologic, and laboratory findings of CCUS-D and CCUS-ND patients to 49 MDS patients, including blood cell counts, BM morphology, flow cytometry, cytogenetics, and results of next-generation sequencing. RESULTS: No statistically significant differences were observed between CCUS-D and CCUS-ND patients in the degree of cytopenias, BM cellularity, myeloid-to-erythroid ratio, or the presence of flow cytometric abnormalities. However, compared to CCUS-ND, CCUS-D patients exhibited increased mutations in myeloid malignancy-associated genes, including non-TET2/DNMT3A/ASXL1 variants, spliceosome (SF3B1, SRSF2, ZRSR2, or U2AF1) variants, and IDH2/RUNX1/CBL variants. CCUS-D patients were also enriched for higher variant allele frequencies and co-mutation of TET2/DNMT3A/ASXL1 with other genes. CONCLUSIONS: CCUS-D patients exhibit a molecular (but not clinical) profile more similar to MDS patients than CCUS-ND, suggesting CCUS-D may represent a more immediate precursor to MDS and may warrant closer clinical follow-up.

Simultaneity and Temporal Order Judgments Exhibit Distinct Reaction Times and Training Effects.

A considerable body of sensory research has addressed the rules governing simultaneity judgments (SJs) and temporal order judgments (TOJs). In principle, neural events that register stimulus-arrival-time differences at an early sensory stage could set the limit on SJs and TOJs alike. Alternatively, distinct limits on SJs and TOJs could arise from task-specific neural events occurring after the stimulus-driven stage. To distinguish between these possibilities, we developed a novel reaction-time (RT) measure and tested it in a perceptual-learning procedure. The stimuli comprised dual-stream Rapid Serial Visual Presentation (RSVP) displays. Participants judged either the simultaneity or temporal order of red-letter and black-number targets presented in opposite lateral hemifield streams of black-letter distractors. Despite identical visual stimulation across-tasks, the SJ and TOJ tasks generated distinct RT patterns. SJs exhibited significantly faster RTs to synchronized targets than to subtly asynchronized targets; TOJs exhibited the opposite RT pattern. These task-specific RT patterns cannot be attributed to the early, stimulus-driven stage and instead match what one would predict if the limits on SJs and TOJs arose from task-specific decision spaces. That is, synchronized targets generate strong evidence for simultaneity, which hastens SJ RTs. By contrast, synchronized targets provide no information about temporal order, which slows TOJ RTs. Subtly asynchronizing the targets reverses this information pattern, and the corresponding RT patterns. In addition to investigating RT patterns, we also investigated training-transfer between the tasks. Training to improve SJ precision failed to improve TOJ precision, and vice versa, despite identical visual stimulation across tasks. This, too, argues against early, stimulus-driven limits on SJs and TOJs. Taken together, the present study offers novel evidence that distinct rules set the limits on SJs and TOJs.

Olfactory tubercle stimulation alters odor preference behavior and recruits forebrain reward and motivational centers.

Rodents show robust behavioral responses to odors, including strong preferences or aversions for certain odors. The neural mechanisms underlying the effects of odors on these behaviors in animals are not well understood. Here, we provide an initial proof-of-concept study into the role of the olfactory tubercle (OT), a structure with known anatomical connectivity with both brain reward and olfactory structures, in regulating odor-motivated behaviors. We implanted c57bl/6 male mice with an ipsilateral bipolar electrode into the OT to administer electric current and thereby yield gross activation of the OT. We confirmed that electrical stimulation of the OT was rewarding, with mice frequently self-administering stimulation on a fixed ratio schedule. In a separate experiment, mice were presented with either fox urine or peanut odors in a three-chamber preference test. In absence of OT stimulation, significant preference for the peanut odor chamber was observed which was abolished in the presence of OT stimulation. Perhaps providing a foundation for this modulation in behavior, we found that OT stimulation significantly increased the number of c-Fos positive neurons in not only the OT, but also in forebrain structures essential to motivated behaviors, including the nucleus accumbens and lateral septum. The present results support the notion that the OT is integral to the display of motivated behavior and possesses the capacity to modulate odor hedonics either by directly altering odor processing or perhaps by indirect actions on brain reward and motivation structures.