ORGAN SPECIFIC VASCULAR RESPONSE TO FIBROSIS AFFECTS BREAST CANCER METASTATIC ORGANOTROPISM

The solid tumor microenvironment, pre-metastatic niche, and fibrotic environment are known to have significant biochemical and biomechanical similarities to the fibrotic environment. All have significantly increased levels of factors such as TGFβ, HIF1α, TNFα, PDGF, VEGF, FGF, interleukins and other growth factors that are known to be pro-tumorigenic. Clinical and basic science research has shown that fibrosis presents an environment that favors tumor growth, such as hepatocellular carcinoma being commonly preceded by liver cirrhosis, or bleomycin induced lung fibrosis enhancing pulmonary metastasis in mouse models of breast cancer. In addition to the evidence indicating that fibrosis enhances primary tumor growth and metastasis it is also well characterized that primary tumor metastasis has specific organotropism, for example breast cancer commonly spreads to the lungs, brain, bone, liver and lymph nodes. However, whether non-organtropic fibrosis can redirect metastasis to the damaged organ has not been investigated. To elucidate the fibrotic effect on tumor organotropism we induced fibrosis in the organotropic lungs and in the non-organotropic kidney of two mouse models of breast cancer, the 4T1 murine cancer cell line model and the genetic MMTV-Pymt model, both of which are known to metastasize. Using histopathology, microarrays, gene expression by polymerase chain reaction, ELISA, chemokine array, and in vitro experiments we demonstrate that despite the pro-tumorigenic environment, kidney fibrosis does not redirect metastasis to the non-organotropic damaged organ. However, mice with kidney fibrosis had increased metastasis to their lungs. Furthermore, we found that kidney fibrosis increases the circulating levels of the pro-angiogenic factor Angiopoietin 2 that increased vascular permeability of the lungs, but not the kidneys. In fact, while fibrotic lungs showed decreased expression of endothelial tight gap junction protein Claudin-5, the fibrotic kidneys had an elevated expression of Claudin-5. Our findings suggest that despite the similarities between fibrosis, the tumor microenvironment and the pre-metastatic niche, that while it can enhance tropic metastatic disease, it cannot redirect organotropism indicating that other factors must be involved in directing organotropism. Here we report that tumor organotropism may be a result of organ specific vascular responses to excess circulating factors and increased fibrotic factors. These findings indicate that organotropism is directly related to and as a result of organ specific vascular alterations

Motor simulation without motor expertise: enhanced corticospinal excitability in visually experienced dance spectators

The human “mirror-system” is suggested to play a crucial role in action observation and execution, and is characterized by activity in the premotor and parietal cortices during the passive observation of movements. The previous motor experience of the observer has been shown to enhance the activity in this network. Yet visual experience could also have a determinant influence when watching more complex actions, as in dance performances. Here we tested the impact visual experience has on motor simulation when watching dance, by measuring changes in corticospinal excitability. We also tested the effects of empathic abilities. To fully match the participants' long-term visual experience with the present experimental setting, we used three live solo dance performances: ballet, Indian dance, and non-dance. Participants were either frequent dance spectators of ballet or Indian dance, or “novices” who never watched dance. None of the spectators had been physically trained in these dance styles. Transcranial magnetic stimulation was used to measure corticospinal excitability by means of motor-evoked potentials (MEPs) in both the hand and the arm, because the hand is specifically used in Indian dance and the arm is frequently engaged in ballet dance movements. We observed that frequent ballet spectators showed larger MEP amplitudes in the arm muscles when watching ballet compared to when they watched other performances. We also found that the higher Indian dance spectators scored on the fantasy subscale of the Interpersonal Reactivity Index, the larger their MEPs were in the arms when watching Indian dance. Our results show that even without physical training, corticospinal excitability can be enhanced as a function of either visual experience or the tendency to imaginatively transpose oneself into fictional characters. We suggest that spectators covertly simulate the movements for which they have acquired visual experience, and that empathic abilities heighten motor resonance during dance observation

More than a feeling: A unified view of stress measurement for population science.

Stress can influence health throughout the lifespan, yet there is little agreement about what types and aspects of stress matter most for human health and disease. This is in part because "stress" is not a monolithic concept but rather, an emergent process that involves interactions between individual and environmental factors, historical and current events, allostatic states, and psychological and physiological reactivity. Many of these processes alone have been labeled as "stress." Stress science would be further advanced if researchers adopted a common conceptual model that incorporates epidemiological, affective, and psychophysiological perspectives, with more precise language for describing stress measures. We articulate an integrative working model, highlighting how stressor exposures across the life course influence habitual responding and stress reactivity, and how health behaviors interact with stress. We offer a Stress Typology articulating timescales for stress measurement - acute, event-based, daily, and chronic - and more precise language for dimensions of stress measurement

Estimates of persistent inward current in human motor neurons during postural sway

Persistent inward current (PIC) is a membrane property critical for increasing gain of motor neuron output. In humans, most estimates of PIC are made from plantarflexor or dorsiflexor motor units with the participant in a seated position with the knee flexed. This seated and static posture neglects the task-dependent nature of the monoaminergic drive that modulates PIC activation. Seated estimates may drastically underestimate the amount of PIC that occurs in human motor neurons during functional movement. The current study estimated PIC using the conventional paired motor unit technique which uses the difference between reference unit firing frequency at test unit recruitment and reference unit firing frequency at test unit de-recruitment (∆F) during triangular-shaped, isometric ramps in plantarflexion force as an estimate of PIC. Estimates of PIC were also made during standing anterior postural sway, a postural task that elicits a ramped increase and decrease in soleus motor unit activation similar to the conventional seated ramp contractions. For each motor unit pair, ∆F estimates of PIC made during conventional isometric ramps in the seated posture were compared to those made during standing postural sway. Baseline reciprocal inhibition (RI) was also measured in each posture using the post-stimulus time histogram (PSTH) technique. Hyperpolarizing input has been shown to have a reciprocal relationship with PIC in seated posture and RI was measured to examine if the same reciprocal relationship holds true during functional PIC estimation. It was hypothesized that an increase in ∆F would be seen during standing compared to sitting due to greater neuromodulatory input. We found that ∆F estimates during standing postural sway were equal (2.44 ± 1.17, p=0.44) to those in seated PIC estimates (2.73± 1.20) using the same motor unit pair. Reciprocal inhibition was significantly lower when measured in a standing posture (0.0031 ± 0.0251,

The time course of muscle sympathetic and cardiovascular responses to physical and mental stressors in males and females

Elevated blood pressure (BP) responses to stressors in young people have been associated with greater risk of hypertension later in life. The aim of this project was to determine what drives BP responses to stress in healthy young males and females. The time course of muscle sympathetic nerve activity (MSNA), BP and heart rate (HR) responses to mental stressors (Stroop colour-word test and mental arithmetic) and physical stressors (cold pressor test (CPT), static handgrip exercise, and post-exercise ischemia) were recorded in 21 healthy young males and in 19 healthy young females. Individuals who experienced a rise in MSNA during stress were classified as positive responders, and those who experienced a fall in MSNA during stress were classified as negative responders. In Study 1 it was hypothesised that negative responders to mental stress experience a more rapid rise in BP at the onset of the task than positive responders. It was also hypothesised that parallel increases in BP and MSNA occur during physical stressors and these are consistent between participants. The results indicate that that negative responders to mental stress exhibit a more rapid rise in diastolic pressure at the onset of the stressor (1.3 ± 0.5 mmHg/s), suggesting a baroreflex-mediated suppression of MSNA. In positive responders there is a more sluggish rise in BP during mental stress (0.4 ± 0.1 mmHg/s), which appears to be MSNA-driven. The physical stressors elicited large and consistent increases in BP and MSNA amongst participants. In Study 2, the effects of sex on the early BP response to stress were examined in both positive and negative responders. The peak changes, time of peak, and rate of changes in BP were compared between males and females and between positive and negative responders. Consistent with the findings in the males, the female negative responders experienced a greater rate of rise in diastolic BP (1.1 ± 0.6 mmHg/s) compared to the positive responders (0.2 ± 0.1 mmHg/s). Cardiovascular and sympathetic responses to stressors were generally consistent between males and females. However, changes in total MSNA during mental arithmetic were greater in males and changes in HR during handgrip were also greater in males (P<0.05). In contrast, changes in MSNA burst amplitude during Stroop test were greater in females than in males (P<0.05). In Study 3 the effects of the menstrual cycle on cardiovascular and sympathetic responses to stressors were assessed in young, healthy females. It was concluded that the CPT, but not other stressors, elicits greater sympathetic responses during the low-hormone phase (9±2 bursts/min) compared with the high-hormone phase (5±3; P=0.014), but was not associated with larger elevations in BP. In summary, the work described in this thesis has uncovered novel information on the underlying physiological mechanisms responsible for the differences between responders and non-responders to mental stressors, and has also uncovered sex-based differences and the effects of female hormones on sympathetic responsiveness to stressors

Changes in women’s facial skin color over the ovulatory cycle are not detectable by the human visual system

Human ovulation is not advertised, as it is in several primate species, by conspicuous sexual swellings. However, there is increasing evidence that the attractiveness of women’s body odor, voice, and facial appearance peak during the fertile phase of their ovulatory cycle. Cycle effects on facial attractiveness may be underpinned by changes in facial skin color, but it is not clear if skin color varies cyclically in humans or if any changes are detectable. To test these questions we photographed women daily for at least one cycle. Changes in facial skin redness and luminance were then quantified by mapping the digital images to human long, medium, and shortwave visual receptors. We find cyclic variation in skin redness, but not luminance. Redness decreases rapidly after menstrual onset, increases in the days before ovulation, and remains high through the luteal phase. However, we also show that this variation is unlikely to be detectable by the human visual system. We conclude that changes in skin color are not responsible for the effects of the ovulatory cycle on women’s attractiveness

Conspicuous Coloration May Function To Deter Avian Predators In Appalachian Salamanders

I combined three complementary approaches to explore the potential for aposematic signaling in Plethodon yonahlossee and Ambystoma maculatum. I quantified integument conspicuousness from an avian perspective via reflectance spectrometry and spot size using Adobe Photoshop and the pavo package in R. I conducted a field experiment using clay models of conspicuous P. yonahlossee salamanders and inconspicuous P. montanus to assess predator response to conspicuous prey. I also used a comparative approach to explore whether conspicuous coloration in the genera Plethodon and Ambystoma co-occurs with other traits associated with aposematism (i.e. increased body size

Social interactions, emotion and sleep: a systematic review and research agenda

Sleep and emotion are closely linked, however the effects of sleep on socio-emotional task performance have only recently been investigated. Sleep loss and insomnia have been found to affect emotional reactivity and social functioning, although results, taken together, are somewhat contradictory. Here we review this advancing literature, aiming to 1) systematically review the relevant literature on sleep and socio-emotional functioning, with reference to the extant literature on emotion and social interactions, 2) summarize results and outline ways in which emotion, social interactions, and sleep may interact, and 3) suggest key limitations and future directions for this field. From the reviewed literature, sleep deprivation is associated with diminished emotional expressivity and impaired emotion recognition, and this has particular relevance for social interactions. Sleep deprivation also increases emotional reactivity; results which are most apparent with neuro-imaging studies investigating amygdala activity and its prefrontal regulation. Evidence of emotional dysregulation in insomnia and poor sleep has also been reported. In general, limitations of this literature include how performance measures are linked to self-reports, and how results are linked to socio-emotional functioning. We conclude by suggesting some possible future directions for this field

Tactile Modulation of the Sensory and Cortical Responses Elicited by Focal Cooling in Humans and Mice

Distinct sensory receptors transduce thermal and mechanical energies, but we have unified, coherent thermotactile experiences of the objects we touch. These experiences must emerge from the interaction of thermal and tactile signals within the nervous system. How do thermal and mechanical signals modify each other as they interact along the pathway from skin to conscious experience? In this thesis, we study how mechanical touch modulates cooling responses by combining psychophysics in humans and neural recordings in rodents. For this, we developed a novel stimulator to deliver focal, temperature-controlled cooling without touch. First, we used this method to study in humans the sensitivity to focal cooling with and without touch. We found that touch reduces the sensitivity to near-threshold cooling, which is perhaps analogous to the well-established ‘gating’ of pain by touch. Second, we studied the perceived intensity of cooling with and without touch. We found that tactile input enhances the perceived intensity of cooling. Third, we measured the responses of the mouse primary somatosensory cortex to cooling and mechanical stimuli using imaging and electrophysiological methods. We found multisensory stimuli elicited non-linear cortical responses at both the population and cellular level. Altogether, in this thesis, we show perceptual and cortical responses to non-tactile cooling for the first time. Based on our observations, we propose a new model to explain the interactions between cooling and mechanical signals in the nervous system. This thesis advances our understanding of how touch modulates cold sensations during thermotactile stimulation