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- ItemA neuroimaging study of phonological and semantic processing in healthy ageing and patients with primary progressive aphasia(2025) Toloza Ramírez, David Isaías; Méndez Orellana, Carolina; Pontificia Universidad Católica de Chile. Facultad de Ciencias Biológicas; Pontificia Universidad Católica de Chile. Facultad de Ciencias Sociales; Pontificia Universidad Católica de Chile. Facultad de Química y Farmacia; Pontificia Universidad Católica de Chile. Facultad de MedicinaA strong interest in cognitive neuroscience lies in understanding how and where language processing occurs in the brain (Fridriksson et al., 2016). The widely accepted model for studying language processing, proposed by Hickok and Poeppel (Hickok & Poeppel, 2004, 2007), describes a dual-route network: the dorsal and the ventral streams. The dorsal stream connects temporal and frontal regions and is primarily lateralized to the left hemisphere. The ventral stream is a bilateral pathway (recruiting both the left and right hemispheres) and connects frontal regions to the parietal, temporal, and occipital lobes. These streams have been studied through verbal fluency (VF) tasks, with the dorsal stream associated with phonological processing and the ventral stream linked with semantic processing (Jobard et al., 2003).According to the dual-route network, many functional MRI (fMRI) studies on language processing report conflicting findings regarding the brain areas responsible for phonological and semantic processing (PP and SP, respectively). Some investigations (McDermott et al., 2003; Rimol et al., 2005; Sekiyama et al., 2003) using fMRI suggest that the inferior frontal gyrus, superior temporal gyrus, and middle temporal gyrus are activated during both types of processing. Indeed, Abrahams et al. (2003) and Heim et al. (2008) suggest that Broca's area is activated during both PP and SP tasks. However, other fMRI studies report significant differences in the brain areas associated with each type of processing. For example, Broca's area appears to be activated only during PP (S. Wagner et al., 2014), while the posterior left middle frontal gyrus is activated only during SP (Zhuang et al., 2016). In addition, findings by Meinzer et al. (2009) indicate that another brain region, such as the precuneus, shows significant activation during language processing, but exclusively during SP tasks. A subsequent study by Strijkers et al. (2017), employing magnetoencephalography and structural MRI, proposed the existence of a unified neural network underlying both types of processing, thereby supporting the notion of parallel processing. This finding highlights the absence of brain areas exclusively dedicated to PP and SP. Language abilities change and often decline with age, affecting both phonological and semantic levels of processing (Gordon & Kindred, 2011; Kavé & Knafo-Noam, 2015). Some authors (James & Burke, 2000; Taylor & Burke, 2002), however, suggest that PP and SP do not undergo age-related decline and may even improve with aging. PP and SP are of significant interest in the context of pathological aging, particularly for understanding language impairments associated with dementia (Olmos-Villaseñor et al., 2023). This is especially relevant in Primary Progressive Aphasia (PPA), an atypical neurodegenerative condition characterized by language processing deterioration (Tee & Gorno-Tempini, 2019). Specific linguistic deficits form part of the diagnostic criteria for PPA (Marshall et al., 2018). A more recent systematic review highlights that SP and PP could serve as early markers for this neurodegenerative condition and other dementia subtypes (Toloza-Ramírez et al., 2021).Functional fMRI is the preferred technique in cognitive neuroscience for studying language processing in the brain. Understanding the neural basis of language processing is essential for evaluating the effects of aging and for improving diagnostic criteria for neurodegenerative conditions such as PPA (M. L. Henry et al., 2018; Rotte, 2005). Through the current language processing model proposed by Hickok and Poeppel (2004, 2007), it is possible to identify relevant brain areas underlying SP and PP. However, this model (the dual-route network) is limited in explaining how these brain areas interact and modulate one another during VF tasks across different stages of aging and under neurodegenerative conditions. Future research should consider not only the neural basis of language processing but also the interconnection of brain regions using innovative models such as Dynamic Causal Modeling (DCM). DCM enables researchers to examine how regions within a network interact, revealing the functional integration and modulation of specific cortical pathways (K. J. Friston et al., 2003), especially in healthy aging and clinical populations. This approach could provide a better diagnostic framework, not limited to classical cognitive domains such as memory or executive functions, or to structural damage alone.This PhD proposal aims to study changes in activation and connectivity patterns for PP and SP in healthy older volunteers and patients with PPA. Likewise, it is also proposed that the effective connectivity of DCM be studied for both types of linguistic processing in normal aging and clinical populations.
- ItemApplying catastrophe theory and population dynamics models to understanding fisheries collapses in the Humboldt marine ecosystem(2025) Montero Styles, José Tomás; Lima Arce, Mauricio; Pontificia Universidad Católica de Chile. Facultad de Ciencias BiológicasAbrupt stock and population collapses can occur due to intense fishing pressure, overfishing, orwhen intense exploitation interacts with oceanic climatic stressors; however, the latter of theseinteractions remains poorly understood in many highly productive ecosystems. This thesisexamines 18 data-rich stocks from the Humboldt Current Ecosystem (HCE), utilizingcatastrophe theory modeling in conjunction with theoretical population dynamics models byRoyama (2021) to demonstrate how changes in fishing intensity, combined with climaticvariables, can drive fisheries across ecological tipping points and ultimately lead to collapse.Paper 1 of this thesis utilizes the stochastic cusp model framework, demonstrating that two-thirds of the analyzed stocks, particularly demersal fish and benthic crustaceans, transition fromnon-linear dynamics to a low-biomass equilibrium when warm sea surface Temperatures (SST°C) are considered elevated, leading to destabilizing fishing mortality and exhibitingpronounced hysteresis. The Second paper of the thesis integrates theoretical populationdynamics models developed by Royama (2021), including a predator-prey one revealing thatthe South Pacific hake (Merluccius gayi gayi) collapse was a consequence of the (El NiñoSouthern Oscillation), first providing favorable conditions for the stock to growth underrelatively low fishing pressure, for later transitioning to more La Niña and neutral regimes thatcombine with increased fishing pressure to doom the stock to a pronounced collapse.Additionally, we demonstrated that the leading cause of the collapse was fishing pressure, ratherthan intense predation by the jumbo squid, as was previously evident. This finding is supportedby the fact that the predator-prey model used to test the hypothesis of the jumbo squid did notaccount for the effect of fishing pressure. The last Paper 3 of the thesis extends the Royamaframework to three austral gadids fish stocks: Southern Blue Whiting (Micromesistiusaustralis), Patagonian Grenadier (Macruronus magellanicus), and Southern Hake (Merlucciusaustralis), showing a combination of influences in their dynamics such as SST, the SouthernAnnular Mode (SAM), and a more than a decade of megadrought (expressed as localprecipitation regimes), reforge the recruit dynamics and density dependence of the stocks. Thisthesis concludes that fisheries policies should be climate-ready and must develop adaptiveharvest control rules linked to early warning metrics provided by climatic indices andoceanographic conditions, including precautionary closures that can be triggered by bifurcationthresholds for catastrophic stocks. Finally, multi-national efforts should be carried out acrossthe HCE to buffer the effect of future regimen shifts for coastal communities and fishermenwhose survival relies on the fishing industry.
- ItemEl factor de coagulación X activado aumenta la migración transendotelial de células cancerosas vía receptores activados por proteasas (PAR)(2025) Espinoza Calvo, Cristian Alejandro; Owen, Gareth Ivor; Pontificia Universidad Católica de Chile. Facultad de Ciencias BiológicasLos pacientes con cáncer fallecen tanto por la progresión de la enfermedad como por complicaciones trombóticas. La metástasis es un marcador de progresión avanzada en el cáncer. La migración transendotelial (TEM) de células cancerosas representa un paso crítico en la formación de metástasis al permitir su extravasación desde el torrente sanguíneo. Datos de nuestro laboratorio muestran que el Factor X activado (FXa), un componente clave de la cascada de coagulación, favorece la metástasis in vivo. FXa puede activar a los Receptores Activados por Proteasas (PAR) 1 y 2 expresados en células endoteliales. Se desconoce si la activación de PAR por FXa aumenta la TEM de células cancerosas. En este trabajo proponemos que FXa favorece la metástasis promoviendo la TEM de células cancerosas. Para poner a prueba esta hipótesis, se evaluó si FXa aumenta la TEM de células cancerosas vía PAR. Se evidenció que FXa y un péptido agonista del receptor PAR-1 (aPAR-1), pero no uno de PAR-2 (aPAR-2), causan la retracción y separación de CE, mientras que un inhibidor de PAR-1 (iPAR-1) impidió el efecto de FXa, no así el inhibidor de PAR-2 (iPAR-2). Tanto FXa como aPAR-1 aumentaron la permeabilidad in vitro de células endoteliales, mientras que iPAR-1 impidió el efecto de FXa. Asimismo, FXa y aPAR-1, pero no aPAR-2, aumentaron la TEM in vitro de células cancerosas, mientras que iPAR-1 nuevamente frenó el efecto de FXa. Tanto FXa como aPAR-1 causaron una reducción de CD99, proteína involucrada en la TEM, pero no de PECAM. Finalmente, la administración de vorapaxar, un fármaco anti-PAR-1, impidió que FXa aumentara la metástasis in vivo. Estos resultados sugieren que FXa favorece la TEM de células cancerosas a través de PAR-1 endotelial, sugiriendo, además, un potencial beneficio terapéutico en pacientes con cáncer, donde el uso de inhibidores de PAR-1, además de prevenir las complicaciones trombóticas, también podría reducir la presencia de metástasis, mejorando su pronóstico.
- ItemContribution of the Inflammasome on Carotid Body Potentiation in Heart Failure with Preserved Ejection Fraction: Role in Disease Progression(2025) Pereyra Florián, Katherin Vanessa; Río Troncoso, Rodrigo Andre del; Pontificia Universidad Católica de Chile. Facultad de Ciencias BiológicasHeart failure with preserved ejection fraction (HFpEF) is a highly prevalent pathological condition in the elderly population characterized by impaired cardiac function. Several compensatory mechanisms get activated to support the failing heart; however, some of them became maladaptive and hastens disease progression. Recently, we found that the carotid body (CB)-mediated chemoreflex was enhanced in experimental HFpEF and that increases in chemoreflex drive was closely associated with a high incidence of breathing disorders (i.e. apneas, hypopneas) ultimately adding more stress to the failing heart. However, the precise mechanisms underpinning carotid body potentiation in the setting of HFpEF has never been studied. Interestingly, HFpEF has been characterized as an inflammatory disease since HFpEF patients shown increased circulating levels of pro-inflammatory cytokines that positively and significantly correlates with a worsening in functional class, increased rate of hospitalizations and poor survival. Although the role of inflammation in cardiac function regulation has been widely studied the potential role of carotid body inflammation on hemodynamic and respiratory distress in the setting of HFpEF has never been addressed. Previous investigations described that glomus cell, the functional unit of CB, express all the molecular machinery necessary to transduce inflammatory signals. Indeed, constitutive expression of functional interleukin receptors type 1 (IL-R1) and TNF-α receptor (TNFR) within the CB tissue has been described. Indeed, pro-inflammatory cytokines increases intracellular calcium in glomus cells and stimulate catecholamine release upon afferent terminals from petrosal ganglion neurons leading to an increase in the firing rate of afferent fibers. Importantly, it is well known that chronic inflammatory states result in inflammasome activation. The inflammasome is a cytosolic multiprotein oligomer that mediates the cleavage of inactive pro-inflammatory cytokines (among other functions) that perpetuates the inflammatory niche in several tissues. The role of the inflammasome in CB function and its contribution, if any, to the potentiation of CB activity in HFpEF are completely unknown. Accordingly, we hypothesized that activation of the inflammasome in CBs of HFpEF mice contributes to the potentiation of the peripheral chemoreflex through the regulation of cytokine release within the CB tissue being the outcome the maintenance of cardiorespiratory disorders in HFpEF. We expect that this PhD thesis provides first evidence of the role of the inflammasome pathway in CB function in health and disease conditions, particularly in the setting of HFpEF.
- ItemContribution of medullary pre-sympathetic neurons on cardiovascular dysfunction during transition to menopause(2025) Schwarz Flores, Karla Gabriele; Río Troncoso, Rodrigo Andre del; Inestrosa Cantín, Nibaldo; Pontificia Universidad Católica de Chile. Facultad de Ciencias BiológicasCardiovascular disease is a highly prevalent condition in middle-aged women and are among the leading cause of poor patient’s quality of life and is recognized as the woman’s greatest health threat. Importantly, recent evidence suggests the existence of an intimate crosstalk between the heart and the brain, resulting from a complex network of neurohumoral circuits. From a pathophysiological perspective, the higher prevalence of heart disease in elderly women, may be explained in part by sex-related differences in cardiovascular disease’s risk factors. The autonomic nervous system is a major physiological actor affecting heart-brain axis in health and disease. Importantly, accumulating evidence support the negative impact of decreased estrogen due to menopause transition as a risk factor for adverse cardiovascular events, possibly contributing to autonomic imbalance in middle-aged women, however this hypothesis has not been comprehensive tested before. Central autonomic nuclei, such as the rostral ventrolateral medulla (RVLM) encompasses a pivotal circuit of control of sympathetic flow and blood pressure. Overactivity of sympathetic tone is a hallmark of cardiovascular disorders, including hypertension, stroke and HF. In fact, it was suggested that estrogens exert direct effects on RVLM through estrogen receptors (ERα and ERβ), thereby leading to sympathoinhibitory effects, which may be crucial for cardiovascular protection. While a strong causal-association between sympathetic overactivity and development of cardiovascular diseases has been previously established, further interdisciplinary studies are needed to better understand the underlying cellular/molecular and physiological mechanisms, particularly in the perimenopausal and postmenopausal women. If a reduced estrogen signaling through neuronal ERs contributes to aberrant pre-sympathetic neural activity during menopause leads to autonomic imbalance, cardiovascular disorders and exercise capacity remains totally unknown. My underlying hypothesis is that normalizing autonomic nervous function during perimenopause will have a positive impact on cardiac function in experimentally healthy menopause. I proposed an integrative approach by combining freely moving animal recordings, chemogenetic and hormone treatment to assess cardiovascular/autonomic function in a preclinical model of menopause transition using 4-vinylcyclohexane- mediated accelerated ovarian failure. Furthermore, cellular and molecular mechanisms associated with ERs signaling were elucidated using in vitro model of menopause. In this proposal, I determined, for the first time that, i) estrogen decrease during perimenopause triggers brainstem pre-sympathetic neurons (RVLM C1) overactivity WT mice, leading to cardiac autonomic imbalance, arrhythmogenesis and cardiac diastolic and systolic dysfunction; ii) RVLM C1 neurons contribute to cardiac sympathetic overactivity, cardiac arrythmias and cardiac impairment in postmenopausal mice; iii) long-term 17β-estradiol treatment during perimenopause decrease RVLM C1 activity, improving cardiac function in postmenopausal stage. Together, the results suggest that RVLM C1 neurons play a major role in cardiovascular remodeling during female reproductive senescence.