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Cerebellum Gates Plasticity of Somatosensory Cortex
No full textIn classic theories of motor learning, the cerebellar cortex is the primary storage site of the engram. In addition to its role in motor control, cerebellar activity influences sensory perception and cognition. For these forms of learning, the engram may be stored in cerebellar target regions including the neocortex, where plasticity is known to underlie changes in sensory perception and complex behavior. While modulation of cerebellar output has indeed been shown to influence the activity and plasticity of most neocortical areas, the cellular details of this interaction are not known. A compelling possibility is that cerebellar climbing fiber (CF) signals – required for normal activity and plasticity of the cerebellar cortex – also control activity and plasticity of the neocortex. In this thesis, I test whether CF activation in the cerebellar cortex is sufficient to influence sensory-evoked responses and experience-dependent plasticity of primary somatosensory cortical (S1) neurons. I demonstrate that sensory experience – here, a bout of rhythmic whisker stimulation – increases the activity of excitatory neurons and concomitantly decreases the activity of inhibitory neurons in L2/3 of S1 in awake mice, effects which are blocked by CF co-activation during the sensory experience. Importantly, S1 plasticity phenomena are associated with increased behavioral responsivity to subsequent sensory stimuli, which does not occur if CFs are co-activated. Using two-photon calcium imaging and bidirectional chemogenetic manipulation of S1 neurons, I found that CFs control S1 plasticity by differentially modulating S1 SST- and VIP-expressing interneurons. Transsynaptic labeling, electrophysiological, and two-photon calcium imaging approaches identify the zona incerta as a critical node in the transmission of CF signals to S1. Taken together, these findings reveal that CFs gate S1 plasticity, thereby modulating responsivity to sensory stimuli
Hitting the Thermal Target for Leptophilic Dark Matter at Future Lepton Colliders
No full textWe study future lepton collider prospects for testing predictive models of leptophilic dark matter (DM) candidates with a thermal origin. We calculate experimental milestones for testing the parameter space compatible with freeze-out and the associated collider signals at past, present, and future facilities. This analysis places new limits on such models by leveraging the utility of lepton colliders. At +− machines, we make projections using precision -pole observables from +−→ℓ+ℓ−+ signatures at large electron-positron collider and future projections for future circular collider (ee) in these channels. Additionally, a muon collider could also probe new thermal relic parameter space in this scenario via +−→+, where is any easily identifiable standard model object. Collectively, these processes can probe much of the parameter space for which DM direct annihilation to ℓ+ℓ− yields the observed relic density in Higgs-like models with mass-proportional couplings to charged leptons
PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: A phase 1 dose escalation trial
Get PDFHere we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid. Thirty-three patients received BPX-601 with or without rimiducid, 24 patients with mPDAC and 9 with mCRPC. Two dose-limiting toxicities and two treatment-related deaths occurred in the highest-dose mCRPC cohort, after which the study was terminated, without determination of the RP2D. Two mCRPC patients experienced partial responses (one unconfirmed), and 56% of mCRPC patients achieved ≥50% reduction in prostate-specific antigen. BPX-601 cell expansion, long-term persistence in peripheral blood, and tumor infiltration were observed. Rimiducid increased circulating inflammatory cytokines/chemokines consistent with GoCAR-T® cell activation. These results suggest that pharmacological activation of GoCAR-T® cells is feasible and may offer a promising avenue to control chimeric antigen receptor-T cell activity with continued dose-optimization to improve tolerability
Increasing Aridity May Threaten the Maintenance of a Plant Defence Polymorphism
Get PDFIt is unclear how environmental change influences standing genetic variation in wild populations. Here, we characterised environmental conditions that protect versus erode polymorphic chemical defences in Boechera stricta (Brassicaceae), a short-lived perennial wildflower. By manipulating drought and herbivory in a 4-year field experiment, we measured the effects of driver variation on vital rates of genotypes varying in defence chemistry and then assessed interacting driver effects on total fitness (estimated as each genotype's lineage growth rate, λ) using demographic models. Drought and herbivory interacted to shape vital rates, but contrasting defence genotypes had equivalent total fitness in many environments. Defence polymorphism thus may persist under a range of conditions; however, ambient field conditions fall close to the boundary of putatively polymorphic environment space, and increasing aridity may drive populations to monomorphism. Consequently, elevated intensity and/or frequency of drought under climate change may erode genetic variation for defence chemistry in B. stricta
Characterization of DNA methylation clock algorithms applied to diverse tissue types
Get PDFBackground: DNA methylation (DNAm) data from human samples has been leveraged to develop “epigenetic clock” algorithms that predict age and other aging-related phenotypes. Some DNAm clocks were trained using DNAm obtained from blood cells, while other clocks were trained using data from diverse tissue/cell types. To assess how DNAm clocks perform across non-blood tissue types, we applied DNAm algorithms to DNAm data generated from 9 different human tissue types. Methods: We generated array-based DNAm measurements for 973 samples from deceased tissue donors from the GTEx (Genotype Tissue Expression) project representing nine distinct tissue types: lung, colon, prostate, ovary, breast, kidney, testis, skeletal muscle, and whole blood. For all samples, we generated DNAm clock estimates for 8 epigenetic clocks and characterized these tissue-specific clock estimates in terms of their distributions, correlations with chronological age, correlations of clock estimates between tissue types, and association with participant characteristics. Results: For each clock, the mean DNAm age estimate varied substantially across tissue types, and the mean values for the different clocks varied substantially within tissue types. For most clocks, the correlation with chronological age varied across tissue types, with blood often showing the strongest correlation. Each clock showed strong correlation across tissues, with some evidence of some residual correlation after adjusting for chronological age. In lung tissue, smoking generally had a positive association with epigenetic age. Conclusions: This work demonstrates how differences in epigenetic aging among tissue types leads to clear differences in DNAm clock characteristics across tissue types. Tissue or cell-type specific epigenetic clocks are needed to optimize predictive performance of DNAm clocks in non-blood tissues and cell types.</p
Variation in Postoperative Debridement Patterns in Endoscopic Sinus Surgery: A Retrospective Cohort Study
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Creative Moral Responses to Eco-Reproductive Concerns: Addressing Gaps in Christian Environmental Ethics
Get PDFAdults in the United States are having fewer biological children in part due to worries about climate change and population growth, yet Christian environmental ethicists frequently avoid or dismiss these “eco-reproductive” concerns. I argue that these avoidances lead to important limitations in the literature, which I address by employing a pragmatic approach for religious ethics. Learning from environmentalists who are critically engaging with their Christian inheritances, I find that informants draw upon religious repertoires to “kinnovate.” Namely, they expand notions of family beyond biological lineage by taking up vocations as godparents, youth mentors, foster parents, or chosen kin. I claim that these practices of Christian kinnovation are significant because they help to advance creative moral responses to eco-reproductive concerns in religious contexts—interventions that currently remain underdeveloped in relevant ethical and theological literatures
Scalar inference calculation through the lens of degree estimates
Get PDFScalar inference (SI), e.g., utterances containing some being enriched to mean some but not all, is a central topic in semantics and pragmatics. Of recent interest in the experimental literature is scalar diversity: different lexical scales differ in their likelihood of leading to SI. Studies of scalar diversity have almost exclusively relied on the so-called inference task. In this article, we highlight two shortcomings of the inference task: it biases participants by providing them with the stronger alternative, and it obscures pragmatic inferences other than SI. We offer as an alternative a degree estimate task to investigate utterances containing scalar terms. We validate the degree estimate task, i.a., by successfully replicating a previous finding about scalar diversity: that the distinctness of scalar terms (some versus all) is a significant predictor of it. We then use degree estimates to reassess previous inference task-based findings. Our results show that biasing discourse contexts lead to lower degree estimates (i.e., more strengthened meanings) than a manipulation with only, which contrasts with prior literature’s findings. The article concludes that the inference and degree estimate tasks both have advantages: the former offers a straightforward definition of SI calculation, while the latter avoids explicitly mentioning a negated stronger alternative
Jalāl Asīr and the Persian Poetics of Wonder between Iran and India
No full textThis dissertation studies the pervasive significance of wonder and its corollaries to Persian literary culture between Iran and India, with a particular focus on the Safavid poet Mīrzā Jalāl “Asīr” Shahristānī (b. ca. 1608 – d. ca. 1648). Characterized by complex imagery and syntax and a sustained thematic interest in astonishment (ḥayrat), Asīr’s poetry once enjoyed enormous popularity across Persianate Iran and South Asia as the exemplum of a literary style canonized as khayāl-bandī, though his renown has receded dramatically in the modern period. Through attention to a broad range of texts in Arabic and Persian that circulated around the late-medieval and early modern Islamicate world–including works of philosophy, rhetoric, cosmography, commemoration, and poetry– the main argument advanced in this dissertation is that Asīr’s poetry and its once broad appeal can be best understood through the prism of a “poetics of wonder”, an orientation towards literary language rooted in discourses that valorized complexity, contemplation, silence, mystery, and the cultivation of feelings of awe and astonishment. The dissertation is organized into two parts and four chapters. Part I, titled: Style, Wonder, and Hindustan in Persianate Cultural History, consists of two chapters, both exploring the history of the rhetorically complex school of Persian literature in which Asīr’s poetry is often situated, and its association with Persianate India. In Chapter One, “Locating Style between Iran and India: The Indian Style and its Critics”, I overview and critique the ways in which modern scholars of Persian literature have approached the study of style, and the critical legacy of the so-called “Indian style” or sabk-i hindī in particular, proposing an alternative framework. Through a close reading of Amīr Khusraw’s (d.1325) overlooked rhetorical writings, in Chapter 2, “Inimitable Complexity: Amīr Khusraw’s Poetics of Wonder”, I develop this framework by suggesting that medieval Islamicate attitudes to the emotion of wonder became an especially important element to the structure of thinking and feeling that influenced him and other Persian poets to pursue a complex and more rhetorically wrought literary style. Consisting of two chapters, Part II of the dissertation is titled Jalāl Asīr’s Poetics of Wonder and serves as an extended case study on a poet who falls squarely within the tradition of rhetorically complex Persian poetry, Jalāl “Asīr”. In Chapter Three, “Memorial, Elegy, Mythos: The Canonization of Jalāl Asīr and khayāl-bandī”, I explore how Asīr’s reputation spread from Iran to India (even though he himself never travelled there), through reading a range of commemorative texts. In the final chapter, “The School of Astonishment: Asīr’s Poetics of Wonder and his Interlocutors”, I examine Asīr’s ghazal poetry itself. Through close and comparative readings of his poems, I stress how astonishment and bewilderment were not only central themes of his poetry, but also its main affect, achieved through unusual and innovative uses of grammar, syntax, and imagery. In this way, I argue that astonishment and wonder occupy a central position in Asīr’s poetics as well as the literary style and community of feeling for which he became a figurehead