Biology subjects

Cummings, M.

Publications and source records attributed to Cummings, M..

5 recordsLinked to original sources

bioRxiv2024

Predictive biomarkers of breast ductal carcinoma in situ may underestimate the risk of recurrence due to de novo ipsilateral breast carcinoma development

Development of ipsilateral breast carcinoma following diagnosis of breast ductal carcinoma in situ (DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not be the case and it is important to know how often recurrences are new tumours. Ipsilateral primary-recurrence pairs (n=78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n=54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced by a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare recurrent and non-recurrent disease. We found that 7% of DCIS recurrences were non-clonal by whole exome sequencing, indicative of a new breast carcinoma. Lower resolution methods detected a higher non-clonality rate (29%). Comparing primary DCIS with their recurrences found that evolution of DCIS to invasive disease was associated with increased ploidy and copy number events. TP53 mutations were enriched in DCIS with clonal recurrence compared with non-recurrent DCIS. Our results verify that de novo "recurrent tumours" of independent origin occur in patients who may be at high risk.

cancer biology↗

bioRxiv2022

Recurrent evolution of small body size and loss of the sword ornament in Northern Swordtail fish

Across the tree of life, species have repeatedly evolved similar phenotypes. While well-studied for ecological traits, there is also evidence for convergent evolution of sexually selected traits. Swordtail fish (Xiphophorus) are a classic model system for studying sexual selection, and female Xiphophorus exhibit strong mate preferences for large male body size and a range of sexually dimorphic ornaments. However, sexually selected traits have been lost multiple times in the genus. Phylogenetic relationships between species in this group have historically been controversial, likely as a result of prevalent gene flow, resulting in uncertainty over the number of losses of ornamentation and large body size. Here, we use whole-genome sequencing approaches to re-examine phylogenetic relationships within a Xiphophorus clade that varies in the presence and absence of sexually selected traits. Using wild-caught individuals, we determine the phylogenetic placement of a small, unornamented species, X. continens, confirming an additional loss of ornamentation and large body size in the clade. With these revised phylogenetic relationships, we analyze evidence for coevolution between body size and other sexually selected traits using a phylogenetically independent contrasts approach. These results provide insights into the evolutionary pressures driving the recurrent loss of suites of sexually selected traits.

evolutionary biology↗

bioRxiv2021

Estimates of persistent inward currents are reduced in upper limb motor units of older adults

Aging is a natural process that causes alterations in the neuromuscular system, which contribute to weakness and reduced quality of life. Reduced firing rates of individual motor units (MUs) likely contribute to weakness, but the mechanisms underlying reduced firing rates are not clear. Persistent inward currents (PICs) are crucial for the initiation, gain control, and maintenance of motoneuron firing, and are directly proportional to the level of monoaminergic input. Since the concentration of monoamines (i.e. serotonin and norepinephrine) are reduced with age, we sought to determine if estimates of PICs are reduced in older (>60 years old) compared to younger adults (<35 years old). We decomposed MU spike trains from high-density surface electromyography over the biceps brachii and triceps brachii during isometric ramp contractions to 20% of maximum. Estimates of PICs (i.e. {Delta}F) were computed using the paired MU analysis technique. Regardless of the muscle, peak firing rates of older adults were reduced by ~1.6 pulses per second (pps) (P = 0.0292), and {Delta}F was reduced by ~1.9 pps (P < 0.0001), compared to younger adults. We further found that age predicted {Delta}F in older adults (P = 0.0261), resulting in a reduction of ~1pps per decade, but there was no relationship in younger adults (P = 0.9637). These findings suggest that PICs are reduced in older adults, and, further, age is a significant predictor of estimates of PICs in older adults. Reduced PIC magnitude represents one plausible mechanism for reduced firing rates and weakness in older individuals. KEY POINTSO_LIPersistent inward currents play an important role in the neural control of human movement and are influenced by neuromodulation via monoamines originating in the brainstem. C_LIO_LIDuring aging, motor unit firing rates are reduced, and there is deterioration of brainstem nuclei, which may reduce persistent inward currents in alpha motoneurons. C_LIO_LIHere we show that estimates of persistent inward currents ({Delta}F) of both elbow flexor and extensor motor units are reduced in older adults. C_LIO_LIEstimates of persistent inward currents have a negative relationship with age in the older adults, but not young. C_LIO_LIThis novel mechanism may play a role in alteration motor firing rates that occurs with aging, which may have consequences for motor control. C_LI

physiology↗

bioRxiv2019

Sensitivity of the paired motor unit analysis for estimation of motoneuron excitability to commonly used constraints and filters

The nervous system has a tremendous ability to modify motoneuron excitability according to task demands through neuromodulatory synaptic input to motoneurons. Neuromodulatory inputs adjust the response of the motoneuron to excitatory and inhibitory ionotropic input and can facilitate the induction of persistent inward currents (PICs). PICs amplify and prolong the motoneuron response to synaptic inputs, and PIC impairment may play a major role in motor deficits observed in pathological conditions. Noninvasive estimation of the magnitude of neuromodulatory input and persistent inward currents in human motoneurons is achieved through a paired motor unit analysis ({Delta}F) that quantifies hysteresis in the firing rates at motor unit recruitment and derecruitment. While the {Delta}F technique is commonly used for estimating motoneuron excitability, computational parameters used for the technique vary across studies. In the present study, we assessed the sensitivity of the {Delta}F technique to several criteria commonly used in selecting motor unit pairs for analysis, as well as to methods used for smoothing the instantaneous motor unit firing rates. Using HD-sEMG and motor unit decomposition we obtained 5,409 motor unit pairs from the triceps brachii of ten healthy individuals during submaximal triangle contractions. The mean (SD) {Delta}F was 4.9 (1.08) pps, consistent with previous work using intramuscular recordings. There was an exponential plateau relationship between {Delta}F and the recruitment time difference between the motor unit pairs, with the plateau occurring at approximately 1 s. There was an exponential decay relationship between {Delta}F and the derecruitment time difference between the motor unit pairs, with the decay stabilizing at approximately 1.5 s. We found that reducing or removing the minimum threshold for the correlation of the rate-rate slope for the two units did not affect {Delta}F values or variance. Additionally, we found that removing motor unit pairs in which the control unit was saturated had no significant effect on {Delta}F. Smoothing filter selection had no substantial effect on {Delta}F values and {Delta}F variance; however, the length and type of smoothing filter affected the minimum recruitment and derecruitment time differences. Our results facilitate interpretation of findings from studies that implement the {Delta}F approach but use different computational parameters.

neuroscience↗

bioRxiv2017

Adaptive plasticity generates microclines in threespine stickleback male nuptial color

Adaptive phenotypic divergence is typically studied across relatively broad spatial scales (continents, archipelagos, river basins) because at these scales we expect environmental differences to be strong, and the homogenizing effect of gene flow to be weak. However, phenotypic plasticity and phenotype-dependent habitat choice are additional mechanisms that could also drive adaptation across spatially variable environments. We present evidence for apparently adaptive phenotypic variation across surprisingly small spatial scales (<2 vertical meters) in the threespine stickleback. We find that male breeding coloration varies as a function of the lakes optical-depth gradient, and these small-scale clines ( microclines) appear to be an adaptive response to ambient light gradients, as male color changes predictably in the opposite direction ( countergradient) to ambient light spectral shifts. Using visual models and field enclosure experiments, we show that these microclines result from phenotypic plasticity that maintains male conspicuousness. Our results show that adaptive phenotypic clines can exist across small spatial scales, because phenotypic plasticity rapidly generates repeatable trait-environment correlations despite the overwhelming opportunity for gene flow. Furthermore, these results provide strong evidence that phenotypic plasticity in nuptial coloration is an important mechanism for adjusting the conspicuousness of a visual signal to conspecifics.

evolutionary biology↗