Chronic Nicotine Selectively Enhances α4β2* Nicotinic Acetylcholine Receptors in the Nigrostriatal Dopamine Pathway

These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional α4β2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and α4 nicotinic acetylcholine receptor (nAChR) subunit knock-out mice. Chronic nicotine enhanced methyllycaconitine citrate hydrate-resistant, dihydro-β-erythroidine hydrobromide-sensitive nicotinic currents elicited by 3–1000 µM ACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional α4* nAChRs were not found on the neuronal somata; however, nicotine acts via α4β2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons. Chronic nicotine also increased the number and/or function of these α4β2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of α4β2* nAChRs displays selectivity in cell type and in nAChR subtype as well as in cellular compartment. These selective events augment inhibition of SNc DA neurons by SNr GABAergic neurons and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson's disease

Writing DNA with GenoCAD™

Chemical synthesis of custom DNA made to order calls for software streamlining the design of synthetic DNA sequences. GenoCAD™ (www.genocad.org) is a free web-based application to design protein expression vectors, artificial gene networks and other genetic constructs composed of multiple functional blocks called genetic parts. By capturing design strategies in grammatical models of DNA sequences, GenoCAD guides the user through the design process. By successively clicking on icons representing structural features or actual genetic parts, complex constructs composed of dozens of functional blocks can be designed in a matter of minutes. GenoCAD automatically derives the construct sequence from its comprehensive libraries of genetic parts. Upon completion of the design process, users can download the sequence for synthesis or further analysis. Users who elect to create a personal account on the system can customize their workspace by creating their own parts libraries, adding new parts to the libraries, or reusing designs to quickly generate sets of related constructs

A Silicon Surface Code Architecture Resilient Against Leakage Errors

Spin qubits in silicon quantum dots are one of the most promising building blocks for large scale quantum computers thanks to their high qubit density and compatibility with the existing semiconductor technologies. High fidelity single-qubit gates exceeding the threshold of error correction codes like the surface code have been demonstrated, while two-qubit gates have reached 98\% fidelity and are improving rapidly. However, there are other types of error --- such as charge leakage and propagation --- that may occur in quantum dot arrays and which cannot be corrected by quantum error correction codes, making them potentially damaging even when their probability is small. We propose a surface code architecture for silicon quantum dot spin qubits that is robust against leakage errors by incorporating multi-electron mediator dots. Charge leakage in the qubit dots is transferred to the mediator dots via charge relaxation processes and then removed using charge reservoirs attached to the mediators. A stabiliser-check cycle, optimised for our hardware, then removes the correlations between the residual physical errors. Through simulations we obtain the surface code threshold for the charge leakage errors and show that in our architecture the damage due to charge leakage errors is reduced to a similar level to that of the usual depolarising gate noise. Spin leakage errors in our architecture are constrained to only ancilla qubits and can be removed during quantum error correction via reinitialisations of ancillae, which ensure the robustness of our architecture against spin leakage as well. Our use of an elongated mediator dots creates spaces throughout the quantum dot array for charge reservoirs, measuring devices and control gates, providing the scalability in the design

PromptInfuser: How Tightly Coupling AI and UI Design Impacts Designers' Workflows

Prototyping AI applications is notoriously difficult. While large language model (LLM) prompting has dramatically lowered the barriers to AI prototyping, designers are still prototyping AI functionality and UI separately. We investigate how coupling prompt and UI design affects designers' workflows. Grounding this research, we developed PromptInfuser, a Figma plugin that enables users to create semi-functional mockups, by connecting UI elements to the inputs and outputs of prompts. In a study with 14 designers, we compare PromptInfuser to designers' current AI-prototyping workflow. PromptInfuser was perceived to be significantly more useful for communicating product ideas, more capable of producing prototypes that realistically represent the envisioned artifact, more efficient for prototyping, and more helpful for anticipating UI issues and technical constraints. PromptInfuser encouraged iteration over prompt and UI together, which helped designers identify UI and prompt incompatibilities and reflect upon their total solution. Together, these findings inform future systems for prototyping AI applications

Pervasive Hitchhiking at Coding and Regulatory Sites in Humans

Much effort and interest have focused on assessing the importance of natural selection, particularly positive natural selection, in shaping the human genome. Although scans for positive selection have identified candidate loci that may be associated with positive selection in humans, such scans do not indicate whether adaptation is frequent in general in humans. Studies based on the reasoning of the MacDonald–Kreitman test, which, in principle, can be used to evaluate the extent of positive selection, suggested that adaptation is detectable in the human genome but that it is less common than in Drosophila or Escherichia coli. Both positive and purifying natural selection at functional sites should affect levels and patterns of polymorphism at linked nonfunctional sites. Here, we search for these effects by analyzing patterns of neutral polymorphism in humans in relation to the rates of recombination, functional density, and functional divergence with chimpanzees. We find that the levels of neutral polymorphism are lower in the regions of lower recombination and in the regions of higher functional density or divergence. These correlations persist after controlling for the variation in GC content, density of simple repeats, selective constraint, mutation rate, and depth of sequencing coverage. We argue that these results are most plausibly explained by the effects of natural selection at functional sites—either recurrent selective sweeps or background selection—on the levels of linked neutral polymorphism. Natural selection at both coding and regulatory sites appears to affect linked neutral polymorphism, reducing neutral polymorphism by 6% genome-wide and by 11% in the gene-rich half of the human genome. These findings suggest that the effects of natural selection at linked sites cannot be ignored in the study of neutral human polymorphism

Testing Complex Singlet Scalar Cosmology at the Large Hadron Collider

The Standard Model extended with a complex singlet scalar (cxSM) can admit a strong first order electroweak phase transition (SFOEWPT) as needed for electroweak baryogenesis and provide a dark matter (DM) candidate. The presence of both a DM candidate and a singlet-like scalar that mixes with the Standard Model Higgs boson leads to the possibility of a $b\bar{b}+\text{MET}$ final state in $pp$ collisions. Focusing on this channel, we analyze the prospective reach at the Large Hadron Collider (LHC) for a heavy singlet-like scalar in regions of cxSM parameter space compatible with a SFOEWT and DM phenomenology. We identify this parameter space while implementing current constraints from electroweak precision observable and Higgs boson property measurements as well as those implied by LHC heavy resonance searches

Structural Basis for the Autoinhibition of Focal Adhesion Kinase

SummaryAppropriate tyrosine kinase signaling depends on coordinated sequential coupling of protein-protein interactions with catalytic activation. Focal adhesion kinase (FAK) integrates signals from integrin and growth factor receptors to regulate cellular responses including cell adhesion, migration, and survival. Here, we describe crystal structures representing both autoinhibited and active states of FAK. The inactive structure reveals a mechanism of inhibition in which the N-terminal FERM domain directly binds the kinase domain, blocking access to the catalytic cleft and protecting the FAK activation loop from Src phosphorylation. Additionally, the FERM domain sequesters the Tyr397 autophosphorylation and Src recruitment site, which lies in the linker connecting the FERM and kinase domains. The active phosphorylated FAK kinase adopts a conformation that is immune to FERM inhibition. Our biochemical and structural analysis shows how the architecture of autoinhibited FAK orchestrates an activation sequence of FERM domain displacement, linker autophosphorylation, Src recruitment, and full catalytic activation

Creep and Creep-Recovery Models for Wood Under High Stress Levels

Forty small clear southern pine specimens were loaded under third-point bending to examine creep and creep-recovery behavior for wood under high stress levels. Stress levels of between 69% and 91% of the predicted static strength were applied for 23 h with 1 h allowed for recovery, and the resulting deflection vs. time behavior was studied. The experimental creep and creep-recovery behavior was modeled using modified power law functions. The results indicate that these functions provide the best fit to both primary and secondary experimental data. The empirical models can be used to simulate the viscoelastic behavior of wood under high stress levels. The simulation will provide a useful tool in future studies to examine duration-of-load (DOL) effect, which is one of the more important factors in wood structural design