Notes

Study the particular ideas and techniques regarding ecological movement ensure charge list below distinct occasion scales.
Acute myeloid leukemia (AML) has a poor prognosis under the current standard of care. In recent years, venetoclax, a BCL-2 inhibitor, was approved to treat patients, ineligible for intensive induction chemotherapy. Complete remission rates with venetoclax-based therapies are, however, hampered by minimal residual disease (MRD) in a proportion of patients, leading to relapse. MRD is due to leukemic stem cells retained in bone marrow protective environments; activation of the CXCL12/CXCR4 pathway was shown to be relevant to this process. An important role is also played by cell adhesion molecules such as CD44, which has been shown to be crucial for AML development. Here we show that CD44 is involved in CXCL12 promotion of resistance to venetoclax-induced apoptosis in human AML cell lines and AML patient samples which could be abrogated by CD44 knockdown, knockout or blocking with an anti-CD44 antibody. Split-Venus biomolecular fluorescence complementation showed that CD44 and CXCR4 physically associate at the cell membrane upon CXCL12 induction. In the venetoclax-resistant OCI-AML3 cell line, CXCL12 promoted an increase in the proportion of cells expressing high levels of embryonic-stem-cell core transcription factors (ESC-TFs Sox2, Oct4, Nanog), abrogated by CD44 knockdown. This ESC-TF-expressing subpopulation which could be selected by venetoclax treatment, exhibited a basally-enhanced resistance to apoptosis, and expressed higher levels of CD44. Finally, we developed a novel AML xenograft model in zebrafish, showing that CD44 knockout sensitizes OCI-AML3 cells to venetoclax treatment in vivo. Our study shows that CD44 is a potential molecular target to sensitize AML cells to venetoclax-based therapies.
Blood pressure variability (BPV) is associated with adverse events (AE) independently of hypertension. It has been suggested that calcium channel blockers (CCB) may reduce BPV, and thus be particularly valuable in hypertensives with high BPV. We sought to investigate how CCB affect BPV progression and whether long- term adverse effects of BPV differ after CCB treatment than after treatment with other anti-hypertensives.

We retrospectively analyzed 25,268 US veterans who had been followed for three years without hypertensive therapy, started on a single class of anti-hypertensive agents (thiazides, calcium channel blockers, ACE inhibitors, or beta blockers), treated for six years, and then followed for three additional years. BPV was calculated as standard deviation of systolic or diastolic blood pressures from at least 10 measurements over each three-year period. A combined AE endpoint included hospitalization, coronary artery bypass grafting, carotid endarterectomy, angioplasty, amputation, arteriovenous fistula creation, and mortality was assessed in years 9-12.

Post medication high BPV and beta blocker or thiazide use were associated with increased AE risk. Medication type also affected mean post medication BPV. The effects of medications except for beta blockers on AE and mortality was independent of the patient BPV.

The possible deleterious effects of thiazides should be considered within the context of the study population, who were mostly male and received only a single class of hypertensives. While CCB may ameliorate BPV over time, this study does not support choosing CCB over other agents specifically to lessen BPV-associated risk.
The possible deleterious effects of thiazides should be considered within the context of the study population, who were mostly male and received only a single class of hypertensives. While CCB may ameliorate BPV over time, this study does not support choosing CCB over other agents specifically to lessen BPV-associated risk.Whereas remarkable advances have uncovered mechanisms that drive nervous system assembly, the processes responsible for the lifelong maintenance of nervous system architecture remain poorly understood. Subsequent to its establishment during embryogenesis, neuronal architecture is maintained throughout life in the face of the animal's growth, maturation processes, the addition of new neurons, body movements, and aging. The C. elegans protein SAX-7, homologous to the vertebrate L1 protein family of neural adhesion molecules, is required for maintaining the organization of neuronal ganglia and fascicles after their successful initial embryonic development. To dissect the function of sax-7 in neuronal maintenance, we generated a null allele and sax-7S-isoform-specific alleles. We find that the null sax-7(qv30) is, in some contexts, more severe than previously described mutant alleles, and that the loss of sax-7S largely phenocopies the null, consistent with sax-7S being the key isoform in neuronal maintenance. Using a sfGFPSAX-7S knock-in, we observe sax-7S to be predominantly expressed across the nervous system, from embryogenesis to adulthood. Yet, its role in maintaining neuronal organization is ensured by post-developmentally acting SAX-7S, as larval transgenic sax-7S(+) expression alone is sufficient to profoundly rescue the null mutants' neuronal maintenance defects. Moreover, the majority of the protein SAX-7 appears to be cleaved, and we show that these cleaved SAX-7S fragments together, not individually, can fully support neuronal maintenance. These findings contribute to our understanding of the role of the conserved protein SAX-7/L1CAM in long-term neuronal maintenance, and may help decipher processes that go awry in some neurodegenerative conditions.The ability to allocate neural resources to task-relevant stimuli, while inhibiting distracting information in the surrounding environment (i.e., selective attention) is critical for high-level cognitive function, and declines in this ability have been linked to functional deficits in later life. Studies of age-related declines in selective attention have focused on frontal circuitry, with almost no work evaluating the contribution of motor cortical dynamics to successful task performance. Herein, we examined 69 healthy adults (23-72 years old) who completed a flanker task during magnetoencephalography (MEG). MEG data were imaged in the time-frequency domain using a beamformer to evaluate the contribution of motor cortical dynamics to age-related increases in behavioral interference effects. Our results showed that gamma oscillations in the contralateral motor cortex (M1) were a robust predictor of reaction time, regardless of interference level. Additionally, we observed condition-wise differences in gamma-by-age interactions, such that in younger adults, increases in M1 gamma power were predictive of faster reaction times during incongruent trials, while older adults did not receive this same behavioral benefit. Importantly, these data indicate that M1 gamma oscillations are differentially predictive of behavior in the presence, but not absence of visual interference, resulting in exhausted compensatory strategies with age.Two shape matching experiments examined the effects of viewing distance and object size on observers' judgments of 3D metric shape under binocular viewing. Unlike previous studies on this topic, the stimuli were specifically designed to satisfy the minimal conditions for computing veridical shape from symmetry. Concretely, the stimuli were complex, mirror-symmetric polyhedra whose symmetry planes were oriented at an angle of 45o relative to the line of sight in a shape-matching task. Although it is mathematically possible to accurately compute the 3D shapes of these stimuli using relatively simple algorithms, the results indicated that human observers are unable to do so. Indeed, the apparent shapes of the objects were systematically expanded or compressed in depth as a function of viewing distance, in exactly the same way as has been reported for simpler stimuli that do not satisfy the minimal conditions for an accurate computational analysis. For objects presented at near distances, we also obtained statistically significant effects of object size on observers' shape judgments.Temporal attention, the allocation of attention to a moment in time, improves perception. Here, we examined the computational mechanism by which temporal attention improves perception, under a divisive normalization framework. Under this framework, attention can improve perception of a target signal in three ways stimulus enhancement (increasing gain across all sensory channels), signal enhancement (selectively increasing gain in channels that encode the target stimulus), or external noise exclusion (reducing the gain in channels that encode irrelevant features). These mechanisms make diverging predictions when a target is embedded in varying levels of noise stimulus enhancement improves performance only when noise is low, signal enhancement improves performance at all noise intensities, and external noise exclusion improves performance only when noise is high. To date, temporal attention studies have used noise-free displays. Therefore, it is unclear whether temporal attention acts via stimulus enhancement (amplifying both target features and noise) or signal enhancement (selectively amplifying target features) because both mechanisms predict improved performance in the absence of noise. To tease these mechanisms apart, we manipulated temporal attention using an auditory cue while parametrically varying external noise in a fine-orientation discrimination task. Temporal attention improved perceptual thresholds across all noise levels. Formal model comparisons revealed that this cuing effect was best accounted for by a combination of signal enhancement and stimulus enhancement, suggesting that temporal attention improves perceptual performance, in part, by selectively increasing gain for target features.Eye blinks are influenced by external sensory and internal cognitive factors, as mainly shown in the visual domain. In previous studies, these factors corresponded to the time period of task-relevant sensory information and were often linked to a motor response. Our aim was to dissociate the influence of overall sensory input duration, task-relevant information duration, and the motor response to further understand how the temporal modulation of blinks compares among sensory modalities. Using a visual and an auditory temporal judgment task, we found that blinks were suppressed during stimulus presentation in both domains and that the overall input length had a significant positive relationship with the length of this suppression (i.e., with the latency of the first blink after stimulus onset). Importantly, excluding the influence of the overall sensory input duration we could show that the duration of task-relevant input had an additional influence on blink latency in the visual and the auditory domain. Our findings further suggest that this influence was not based on sensory input but on top-down processes. We could exclude task difficulty and the timing of the motor response as driving factors in the blink modulation. Our results suggest a sensory domain-independent modulation of blink latencies, introduced by changes in the length of the task-relevant, attended period. Therefore, not only do blinks mark the timing of sensory input or the preparation of the motor output, but they can also act as precise indicators of periods of cognitive processing.
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