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"Lu, Adam"
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A view from the stars
A View from the Stars is a collection of short fiction and nonfiction pieces from Cixin Liu, the New York Times bestselling author of The Three-Body Problem. Included are essays and interviews that shed light on Liu's experiences as a reader, writer, and lover of science fiction throughout his life, as well as short fiction that gives glimpses into the evolution of his imaginative voice over the years\"--Back cover.
BOOK
Respiratory alkalosis provokes spike-wave discharges in seizure-prone rats
Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. By utilizing gas exchange manipulations and optogenetics in the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.
Journal Article
Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic oscillations
Absence seizures result from 3 to 5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens human seizures. Here, we show that blocking GABA transporters (GATs) in acute rat brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations into single-neuron and network-level computational models shows how a non-linear dependence of T-type calcium channel gating on GABA B receptor activity regulates network oscillations. Receptor activity that is either too brief or too protracted fails to sufficiently open T-type channels necessary for sustaining oscillations. Only within a narrow range does prolonging GABA B receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate inhibition kinetics.
Journal Article
Angiotensin II induces coordinated calcium bursts in aldosterone-producing adrenal rosettes
Aldosterone-producing zona glomerulosa (zG) cells of the adrenal gland arrange in distinct multi-cellular rosettes that provide a structural framework for adrenal cortex morphogenesis and plasticity. Whether this cyto-architecture also plays functional roles in signaling remains unexplored. To determine if structure informs function, we generated mice with zG-specific expression of GCaMP3 and imaged zG cells within their native rosette structure. Here we demonstrate that within the rosette, angiotensin II evokes periodic Ca
v
3-dependent calcium events that form bursts that are stereotypic in form. Our data reveal a critical role for angiotensin II in regulating burst occurrence, and a multifunctional role for the rosette structure in activity-prolongation and coordination. Combined our data define the calcium burst as the fundamental unit of zG layer activity evoked by angiotensin II and highlight a novel role for the rosette as a facilitator of cell communication.
Aldosterone-producing zona glomerulosa cells in the adrenal gland arrange into rosette structures known to be important for morphogenesis. Here the authors show that the cells in the rosettes produce coordinated calcium activity bursts in response to angiotensin II that correlate with aldosterone production level.
Journal Article
Respiratory Alkalosis Provokes Spike-Wave Discharges in Seizure-Prone Rats
Hyperventilation reliably provokes seizures in patients diagnosed with absence epilepsy. Despite this predictable patient response, the mechanisms that enable hyperventilation to powerfully activate absence seizure-generating circuits remain entirely unknown. Using the WAG/Rij rat, an established rodent model of absence epilepsy, we demonstrate that absence seizures are highly sensitive to arterial carbon dioxide, suggesting that seizure-generating circuits are sensitive to pH. Moreover, hyperventilation consistently activated neurons within the intralaminar nuclei of the thalamus, a structure implicated in seizure generation. We show that intralaminar thalamus also contains pH-sensitive neurons. Collectively, these observations suggest that hyperventilation activates pH-sensitive neurons of the intralaminar nuclei to provoke absence seizures.
Paper
Adam's Law: Textual Frequency Law on Large Language Models
While textual frequency has been validated as relevant to human cognition in reading speed, its relatedness to Large Language Models (LLMs) is seldom studied. We propose a novel research direction in terms of textual data frequency, which is an understudied topic, to the best of our knowledge. Our framework is composed of three units. First, this paper proposes Textual Frequency Law (TFL), which indicates that frequent textual data should be preferred for LLMs for both prompting and fine-tuning. Since many LLMs are closed-source in their training data, we propose using online resources to estimate the sentence-level frequency. We then utilize an input paraphraser to paraphrase the input into a more frequent textual expression. Next, we propose Textual Frequency Distillation (TFD) by querying LLMs to conduct story completion by further extending the sentences in the datasets, and the resulting corpora are used to adjust the initial estimation. Finally, we propose Curriculum Textual Frequency Training (CTFT) that fine-tunes LLMs in an increasing order of sentence-level frequency. Experiments are conducted on our curated dataset Textual Frequency Paired Dataset (TFPD) on math reasoning, machine translation, commonsense reasoning and agentic tool calling. Results show the effectiveness of our framework.
Paper
Nonlinearities between inhibition and T-type calcium channel activity bidirectionally regulate thalamic network oscillations
Absence seizures result from 3-5 Hz generalized thalamocortical oscillations that depend on highly regulated inhibitory neurotransmission in the thalamus. Efficient reuptake of the inhibitory neurotransmitter GABA is essential, and reuptake failure worsens seizures. Here, we show that blocking GABA transporters (GATs) in acute brain slices containing key parts of the thalamocortical seizure network modulates epileptiform activity. As expected, we found that blocking either GAT1 or GAT3 prolonged oscillations. However, blocking both GATs unexpectedly suppressed oscillations. Integrating experimental observations into single-neuron and network-level computational models shows how a non-linear dependence of T-type calcium channel opening on GABAB receptor activity regulates network oscillations. Receptor activity that is either too brief or too protracted fails to sufficiently open T-type channels necessary for sustaining oscillations. Only within a narrow range does prolonging GABAB receptor activity promote channel opening and intensify oscillations. These results have implications for therapeutics that modulate GABA transporters.
Paper
Looped World Models
Current world models face a fundamental tension: faithful long-horizon simulation demands deep computation, but deeper models are expensive to deploy and prone to compounding errors. We resolve this by introducing Looped World Models (LoopWM), which are the first looped architectures for world modelling. Our method iteratively refines latent environment states through a parameter-shared transformer block. This yield up to 100x parameter efficiency over conventional approaches with adaptive computation that automatically scales depth to match the complexity of each prediction step. Orthogonal to scaling model size and training data, LoopWM establishes iterative latent depth as a new scaling axis for world simulation, which might significantly push the community forward.
Paper
DENV-specific IgA contributes protective and non-pathologic function during antibody-dependent enhancement of DENV infection
Dengue represents a growing public health burden worldwide, accounting for approximately 100 million symptomatic cases and tens of thousands of fatalities yearly. Prior infection with one serotype of dengue virus (DENV) is the greatest known risk factor for severe disease upon secondary infection with a heterologous serotype, a risk which increases as serotypes co-circulate in endemic regions. This disease risk is thought to be mediated by IgG-isotype antibodies raised during a primary infection, which poorly neutralize heterologous DENV serotypes and instead opsonize virions for uptake by FcγR-bearing cells. This antibody-dependent enhancement (ADE) of infection leads to a larger proportion of susceptible cells infected, higher viremia and greater immunopathology. We have previously characterized the induction of a serum IgA response, along with the typical IgM and IgG responses, during dengue infection, and have shown that DENV-reactive IgA can neutralize DENV and competitively antagonize IgG-mediated ADE. Here, we evaluate the potential for IgA itself to cause ADE. We show that IgG, but not IgA, mediated ADE of infection in cells expressing both FcαR and FcγRs. IgG-mediated ADE stimulated significantly higher pro-inflammatory cytokine production by primary human macrophages, while IgA did not affect, or slightly suppressed, this production. Mechanistically, we show that DENV/IgG immune complexes bind susceptible cells significantly more efficiently than DENV/IgA complexes or virus alone. Finally, we show that over the course of primary dengue infection, the expression of FcγRI (CD64) increases during the period of acute viremia, while FcγRIIa (CD32) and FcαR (CD89) expression decreases, thereby further limiting the ability of IgA to facilitate ADE in the presence of DENV. Overall, these data illustrate the distinct protective role of IgA during ADE of dengue infection and highlight the potential therapeutic and prognostic value of DENV-specific IgA.
Journal Article