cAMP signaling: a remarkably regional affair.

Louis Pasteur once famously said 'in the fields of observation chance favors only the prepared mind'. Much of chance is being in the right place at the right time. This is particularly true in the crowded molecular environment of the cell where being in the right place is often more important than timing. Although Brownian motion argues that enzymes will eventually bump into substrates, this probability is greatly enhanced if both molecules reside in the same subcellular compartment. However, activation of cell signaling enzymes often requires the transmission of chemical signals from extracellular stimuli to intracellular sites of action. This review highlights new developments in our understanding of cAMP generation and the 3D utilization of this second messenger inside cells.

Visual event boundaries restrict anchoring effects in decision-making.

Research on higher-level thought has revealed many principles of reasoning and decision-making but has rarely made contact with how we perceive the world in the first place. Here we show how a lower-level property of perception-the spontaneous and task-irrelevant segmentation of continuous visual stimulation into discrete events-can restrict one of the most notorious biases in decision-making: numerical anchoring. Subjects walked down a long room in an immersive three dimensional (3D) animation and then made a numerical judgment (e.g., of how much a suitcase is worth, or of how many hours of community service a minor crime deserved). Critically, some subjects passed through a doorway (a visual event boundary) during their virtual walk, while others did not-equating time, distance traveled, and visual complexity. The anchoring manipulation was especially innocuous, not appearing to be part of the experiment at all. Before the online trial began, subjects reported the two-digit numerical value from a visually distorted "CAPTCHA" ("to verify that you are human")-where this task-irrelevant anchor was either low (e.g., 29) or high (e.g., 92). With no doorway, we observed reliable anchoring effects: Higher CAPTCHA values produced higher estimates. With the doorway, however, such effects were attenuated or even eliminated. This generalized across tasks involving item valuations, factual questions, and legal judgments and in tests of both incidental and explicit anchoring. This demonstrates how spontaneous visual event segmentation can have profound consequences for higher-level thought.

Understanding the first-offer conundrum: How buyer offers impact sale price and impasse risk in 26 million eBay negotiations.

How low is the ideal first offer? Prior to any negotiation, decision-makers must balance a crucial tradeoff between two opposing effects. While lower first offers benefit buyers by anchoring the price in their favor, an overly ambitious offer increases the impasse risk, thus potentially precluding an agreement altogether. Past research with simulated laboratory or classroom exercises has demonstrated either a first offer's anchoring benefits or its impasse risk detriments, while largely ignoring the other effect. In short, there is no empirical answer to the conundrum of how low an ideal first offer should be. Our results from over 26 million incentivized real-world negotiations on eBay document (a) a linear anchoring effect of buyer offers on sales price, (b) a nonlinear, quartic effect on impasse risk, and (c) specific offer values with particularly low impasse risks but high anchoring benefits. Integrating these findings suggests that the ideal buyer offer lies at 80% of the seller's list price across all products-although this value ranges from 33% to 95% depending on the type of product, demand, and buyers' weighting of price versus impasse risk. We empirically amend the well-known midpoint bias, the assumption that buyer and seller eventually meet in the middle of their opening offers, and find evidence for a "buyer bias." Product demand moderates the (non)linear effects, the ideal buyer offer, and the buyer bias. Finally, we apply machine learning analyses to predict impasses and present a website with customizable first-offer advice configured to different products, prices, and buyers' risk preferences.

Molecular basis for dual functions in pilus assembly modulated by the lid of a pilus-specific sortase.

The biphasic assembly of Gram-positive pili begins with the covalent polymerization of distinct pilins catalyzed by a pilus-specific sortase, followed by the cell wall anchoring of the resulting polymers mediated by the housekeeping sortase. In Actinomyces oris, the pilus-specific sortase SrtC2 not only polymerizes FimA pilins to assemble type 2 fimbriae with CafA at the tip, but it can also act as the anchoring sortase, linking both FimA polymers and SrtC1-catalyzed FimP polymers (type 1 fimbriae) to peptidoglycan when the housekeeping sortase SrtA is inactive. To date, the structure-function determinants governing the unique substrate specificity and dual enzymatic activity of SrtC2 have not been illuminated. Here, we present the crystal structure of SrtC2 solved to 2.10-Å resolution. SrtC2 harbors a canonical sortase fold and a lid typical for class C sortases and additional features specific to SrtC2. Structural, biochemical, and mutational analyses of SrtC2 reveal that the extended lid of SrtC2 modulates its dual activity. Specifically, we demonstrate that the polymerizing activity of SrtC2 is still maintained by alanine-substitution, partial deletion, and replacement of the SrtC2 lid with the SrtC1 lid. Strikingly, pilus incorporation of CafA is significantly reduced by these mutations, leading to compromised polymicrobial interactions mediated by CafA. In a srtA mutant, the partial deletion of the SrtC2 lid reduces surface anchoring of FimP polymers, and the lid-swapping mutation enhances this process, while both mutations diminish surface anchoring of FimA pili. Evidently, the extended lid of SrtC2 enables the enzyme the cell wall-anchoring activity in a substrate-selective fashion.

Structural basis of binding the unique N-terminal domain of microtubule-associated protein 2c to proteins regulating kinases of signaling pathways.

Isoforms of microtubule-associated protein 2 (MAP2) differ from their homolog Tau in the sequence and interactions of the N-terminal region. Binding of the N-terminal region of MAP2c (N-MAP2c) to the dimerization/docking domains of the regulatory subunit RIIα of cAMP-dependent protein kinase (RIIDD2) and to the Src-homology domain 2 (SH2) of growth factor receptor-bound protein 2 (Grb2) have been described long time ago. However, the structural features of the complexes remained unknown due to the disordered nature of MAP2. Here, we provide structural description of the complexes. We have solved solution structure of N-MAP2c in complex with RIIDD2, confirming formation of an amphiphilic α-helix of MAP2c upon binding, defining orientation of the α-helix in the complex and showing that its binding register differs from previous predictions. Using chemical shift mapping, we characterized the binding interface of SH2-Grb2 and rat MAP2c phosphorylated by the tyrosine kinase Fyn in their complex and proposed a model explaining differences between SH2-Grb2 complexes with rat MAP2c and phosphopeptides with a Grb2-specific sequence. The results provide the structural basis of a potential role of MAP2 in regulating cAMP-dependent phosphorylation cascade via interactions with RIIDD2 and Ras signaling pathway via interactions with SH2-Grb2.

Structure and function of distal and subdistal appendages of the mother centriole.

Centrosomes are composed of centrioles surrounded by pericentriolar material. The two centrioles in G1 phase are distinguished by the localization of their appendages in the distal and subdistal regions; the centriole possessing both types of appendage is older and referred to as the mother centriole, whereas the other centriole lacking appendages is the daughter centriole. Both distal and subdistal appendages in vertebrate cells consist of multiple proteins assembled in a hierarchical manner. Distal appendages function mainly in the initial process of ciliogenesis, and subdistal appendages are involved in microtubule anchoring, mitotic spindle regulation and maintenance of ciliary signaling. Mutations in genes encoding components of both appendage types are implicated in ciliopathies and developmental defects. In this Review, we discuss recent advances in knowledge regarding the composition and assembly of centriolar appendages, as well as their roles in development and disease.

Structure and Function of the Glycosylphosphatidylinositol Transamidase, a Transmembrane Complex Catalyzing GPI Anchoring of Proteins.

Glycosylphosphatidylinositol (GPI) anchoring of proteins is a ubiquitous posttranslational modification in eukaryotic cells. GPI-anchored proteins (GPI-APs) play critical roles in enzymatic, signaling, regulatory, and adhesion processes. Over 20 enzymes are involved in GPI synthesis, attachment to client proteins, and remodeling after attachment. The GPI transamidase (GPI-T), a large complex located in the endoplasmic reticulum membrane, catalyzes the attachment step by replacing a C-terminal signal peptide of proproteins with GPI. In the last three decades, extensive research has been conducted on the mechanism of the transamidation reaction, the components of the GPI-T complex, the role of each subunit, and the substrate specificity. Two recent studies have reported the three-dimensional architecture of GPI-T, which represent the first structures of the pathway. The structures provide detailed mechanisms for assembly that rationalizes previous biochemical results and subunit-dependent stability data. While the structural data confirm the catalytic role of PIGK, which likely uses a caspase-like mechanism to cleave the proproteins, they suggest that unlike previously proposed, GPAA1 is not a catalytic subunit. The structures also reveal a shared cavity for GPI binding. Somewhat unexpectedly, PIGT, a single-pass membrane protein, plays a crucial role in GPI recognition. Consistent with the assembly mechanisms and the active site architecture, most of the disease mutations occur near the active site or the subunit interfaces. Finally, the catalytic dyad is located ~22 Å away from the membrane interface of the GPI-binding site, and this architecture may confer substrate specificity through topological matching between the substrates and the elongated active site. The research conducted thus far sheds light on the intricate processes involved in GPI anchoring and paves the way for further mechanistic studies of GPI-T.

On-demand anchoring of wireless soft miniature robots on soft surfaces.

Untethered soft miniature robots capable of accessing hard-to-reach regions can enable new, disruptive, and minimally invasive medical procedures. However, once the control input is removed, these robots easily move from their target location because of the dynamic motion of body tissues or fluids, thereby restricting their use in many long-term medical applications. To overcome this, we propose a wireless spring-preloaded barbed needle release mechanism, which can provide up to 1.6 N of force to drive a barbed needle into soft tissues to allow robust on-demand anchoring on three-dimensional (3D) surfaces. The mechanism is wirelessly triggered using radio-frequency remote heating and can be easily integrated into existing untethered soft robotic platforms without sacrificing their mobility. Design guidelines aimed at maximizing anchoring over the range of the most biological tissues (kPa range) and extending the operating depth of the device inside the body (up to 75%) are also presented. Enabled by these advances, we achieve robust anchoring on a variety of ex vivo tissues and demonstrate the usage of such a device when integrated with existing soft robotic platforms and medical imaging. Moreover, by simply changing the needle, we demonstrate additional functionalities such as controlled detachment and subsurface drug delivery into 3D cancer spheroids. Given these capabilities, our proposed mechanism could enable the development of a new class of biomedical-related functionalities, such as local drug delivery, disease monitoring, and hyperthermia for future untethered soft medical robots.

Interfacial Stereoelectronic Effect Induced by Anchoring Orientation.

Heterogeneous interfaces in most devices play a key role in the material performance. Exploring the atomic structure and electronic properties of metal-molecule interfaces is critical for various potential applications, such as surface sensing, molecular recognition, and molecular electronic devices. This study unveils a ubiquitous interfacial stereoelectronic effect in conjugated molecular junctions by combining first-principles simulation and scanning tunneling microscopy break junction technology. Single-molecule junctions with same-side interfacial anchoring (cis configuration) exhibit higher conductance than those with opposite-side interfacial anchoring (trans configuration). The cis and trans configurations can undergo reversible conversions, resulting in a conductance switching. The stability of these configurations can be adjusted by an electric field, achieving precise regulation of conductance states. Our findings provide important insights for designing high-quality materials and enhancing the device performance.

A-Kinase-Anchoring-Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle.

A-kinase-anchoring proteins (AKAPs) act as scaffold proteins that anchor the regulatory subunits of the cAMP-dependent protein kinase A (PKA) to coordinate and compartmentalize signaling elements and signals downstream of Gs-coupled G protein-coupled receptors (GPCRs). The beta-2-adrenoceptor (ß2AR), as well as the Gs-coupled EP2 and EP4 receptor subtypes of the E-prostanoid (EP) receptor subfamily, are effective regulators of multiple airway smooth muscle (ASM) cell functions whose dysregulation contributes of asthma pathobiology. Here, we identify specific roles of the AKAPs Ezrin and Gravin, in differentially regulating PKA substrates downstream of the ß2AR, EP2 receptor (EP2R) and EP4 receptor (EP4R). Knockdown of Ezrin, Gravin, or both in primary human ASM cells caused differential phosphorylation of the PKA substrates vasodilator-stimulated phosphoprotein (VASP) and heat shock protein 20 (HSP20). Ezrin knockdown, as well as combined Ezrin + Gravin knockdown significantly reduced the induction of phospho-VASP and phospho-HSP20 by ß2AR, EP2R, and EP4R agonists. Gravin knockdown inhibited the induction of phospho-HSP20 by ß2AR, EP2R, and EP4R agonists. Knockdown of Ezrin, Gravin, or both also attenuated histamine-induced phosphorylation of MLC20. Moreover, knockdown of Ezrin, Gravin or both suppressed the inhibitory effects of Gs-coupled receptor agonists on cell migration in ASM cells. These findings demonstrate the role of AKAPs in regulating Gs-coupled GPCR signaling and function in ASM, and suggest the therapeutic utility of targeting specific AKAP family members in the management of asthma.

An A-kinase anchoring protein (ACBD3) coordinates traffic-induced PKA activation at the Golgi.

KDEL receptor (KDELR) is a key protein that recycles escaped endoplasmic reticulum (ER) resident proteins from the Golgi apparatus back to the ER and maintains a dynamic balance between these two organelles in the early secretory pathway. Studies have shown that this retrograde transport pathway is partly regulated by two KDELR-interacting proteins, acyl-CoA-binding domain-containing 3 (ACBD3), and cyclic AMP-dependent protein kinase A (PKA). However, whether Golgi-localized ACBD3, which was first discovered as a PKA-anchoring protein in mitochondria, directly interacts with PKA at the Golgi and coordinates its signaling in Golgi-to-ER traffic has remained unclear. In this study, we showed that the GOLD domain of ACBD3 directly interacts with the regulatory subunit II (RII) of PKA and effectively recruits PKA holoenzyme to the Golgi. Forward trafficking of proteins from the ER triggers activation of PKA by releasing the catalytic subunit from RII. Furthermore, we determined that depletion of ACBD3 reduces the Golgi fraction of RII, resulting in moderate, but constitutive activation of PKA and KDELR retrograde transport, independent of cargo influx from the ER. Taken together, these data demonstrate that ACBD3 coordinates the protein secretory pathway at the Golgi by facilitating KDELR/PKA-containing protein complex formation.

Experience and Reporting of Postnatal Depression Across Cultures: A Comparison Using Anchoring Vignettes of Mothers in the United Kingdom and India.

Postnatal mental health is often assessed using self-assessment questionnaires in epidemiologic research. Differences in response style, influenced by language, culture, and experience, may mean that the same response may not have the same meaning in different settings. These differences need to be identified and accounted for in cross-cultural comparisons. Here we describe the development and application of anchoring vignettes to investigate the cross-cultural functioning of the Edinburgh Postnatal Depression Scale (EPDS) in urban community samples in India (n = 549) and the United Kingdom (n = 828), alongside a UK calibration sample (n = 226). Participants completed the EPDS and anchoring vignettes when their children were 12-24 months old. In an unadjusted item-response theory model, UK mothers reported higher depressive symptoms than Indian mothers (d = 0.48, 95% confidence interval: 0.358, 0.599). Following adjustment for differences in response style, these positions were reversed (d = -0.25, 95% confidence interval: -0.391, -0.103). Response styles vary between India and the United Kingdom, indicating a need to take these differences into account when making cross-cultural comparisons. Anchoring vignettes offer a valid and feasible method for global data harmonization.

Drugs That Regulate Local Cell Signaling: AKAP Targeting as a Therapeutic Option.

Cells respond to environmental cues by mobilizing signal transduction cascades that engage protein kinases and phosphoprotein phosphatases. Correct organization of these enzymes in space and time enables the efficient and precise transmission of chemical signals. The cyclic AMP-dependent protein kinase A is compartmentalized through its association with A-kinase anchoring proteins (AKAPs). AKAPs are a family of multivalent scaffolds that constrain signaling enzymes and effectors at subcellular locations to drive essential physiological events. More recently, it has been recognized that defective signaling in certain endocrine disorders and cancers proceeds through pathological AKAP complexes. Consequently, pharmacologically targeting these macromolecular complexes unlocks new therapeutic opportunities for a growing number of clinical indications. This review highlights recent findings on AKAP signaling in disease, particularly in certain cancers, and offers an overview of peptides and small molecules that locally regulate AKAP-binding partners.

Heteroatom-Doped Defects Anchoring Nano-Pt for High-Stability and Low-Humidity Proton Exchange Membrane Fuel Cell.

To meet the ever-increasing demand of proton exchange membrane fuel cell (PEMFC), it is necessary to carry out structure optimization for low-cost and high-stability oxygen reduction reaction (ORR) catalysts. Herein, a zeolitic imidazolate framework (ZIF)-derived carbon material with a mass of heteroatoms and defects is developed and serves as advanced support for nano-Pt-based ORR catalysts. This unique structure enhances the interaction between nano-Pt and support, leading to higher ORR intrinsic activity. During fuel cell applications, it demonstrates impressive water-retaining capacity and electrochemical stability. Under H2-O2 supply without cathode humidification, this catalyst achieves high mass activity of 0.475 A mgPt -1, with only 7.4% attenuation in maximum power density after 20 000 cycles of accelerated durability test, highlighting its remarkable potential for fuel cell applications. Physicochemical characterization and theoretical simulation reveal the crucial anchoring effect of heteroatom-doped defects to nano-Pt, providing valuable insights for further ORR catalyst design and PEMFC applications.

Chemical Cross-linked Electrode-Electrolyte Interface Boosting the Structural Integrity of High Nickel Cathode Materials.

High nickel cathode material LiNixCoyMn1-x-yO2 (NCM) (x ≥ 0.6) has represented the most critical material in virtue of outstanding specific capacity and low self-discharge. However, the high surface alkalinity and detrimental interfacial stability lead to the parasitic reaction and a series of phase deterioration. Herein, in situ cross-linking binder molecular chains with a 3D network structure to construct a stable and robust electrode-electrolyte interface, which can maintain the structural integrity and restrain side reactions is designed. Simultaneously, the cross-linked polymer can form stable hydrogen bonds with the pristine binder, greatly enhancing the bonding property. More importantly, the functional groups contained in the cross-linked co-polymers can chemically anchor transition metals, effectively preventing the dissolution of transition metals. Theoretical calculations confirm the feasibility and advancement of the anchoring mechanism, driving excellent structural stability and inhibition of the NiO impurity phase. This work provides a practical strategy to realize the high stability of cathode materials.

Precise Anchoring of Fe Sites by Regulating Crystallinity of Novel Binuclear Ni-MOF for Revealing Mechanism of Electrocatalytic Oxygen Evolution.

Bimetallic metal-organic framework (BMOF) exhibits better electrocatalytic performance than mono-MOF, but deciphering the precise anchoring of foreign atoms and revealing the underlying mechanisms at the atomic level remains a major challenge. Herein, a novel binuclear NiFe-MOF with precise anchoring of Fe sites is synthesized. The low-crystallinity (LC)-NiFe0.33 -MOF exhibited abundant unsaturated active sites and demonstrated excellent electrocatalytic oxygen evolution reaction (OER) performance. It achieved an ultralow overpotential of 230 mV at 10 mA cm-2 and a Tafel slope of 41 mV dec-1 . Using a combination of modulating crystallinity, X-ray absorption spectroscopy, and theoretical calculations, the accurate metal sequence of BMOF and the synergistic effect of the active sites are identified, revealing that the adjacent active site plays a significant role in regulating the catalytic performance of the endmost active site. The proposed model of BMOF electrocatalysts facilitates the investigation of efficient OER electrocatalysts and the related catalytic mechanisms.

Ni Single-Atom Bual Catalytic Electrodes for Long Life and High Energy Efficiency Zinc-Iodine Batteries.

Zinc-iodine batteries (Zn-I2) are extremely attractive as the safe and cost-effective scalable energy storage system in the stationary applications. However, the inefficient redox kinetics and "shuttling effect" of iodine species result in unsatisfactory energy efficiency and short cycle life, hindering their commercialization. In this work, Ni single atoms highly dispersed on carbon fibers is designed and synthesized as iodine anchoring sites and dual catalysts for Zn-I2 batteries, and successfully inhibit the iodine species shuttling and boost dual reaction kinetics. Theoretical calculations indicate that the reinforced d-p orbital hybridization and charge interaction between Ni single-atoms and iodine species effectively enhance the confinement of iodine species. Ni single-atoms also accelerate the iodine conversion reactions with tailored bonding structure of I─I bonds and reduced energy barrier for the dual conversion of iodine species. Consequently, the high-rate performance (180 mAh g-1 at 3 A g-1), cycling stability (capacity retention of 74% after 5900 cycles) and high energy efficiency (90% at 3 A g-1) are achieved. The work provides an effective strategy for the development of iodine hosts with high catalytic activity for Zn-I2 batteries.

Promoting Erroneous Divergent Opinions Increases the Wisdom of Crowds.

The aggregation of many lay judgments generates surprisingly accurate estimates. This phenomenon, called the "wisdom of crowds," has been demonstrated in domains such as medical decision-making and financial forecasting. Previous research identified two factors driving this effect: the accuracy of individual assessments and the diversity of opinions. Most available strategies to enhance the wisdom of crowds have focused on improving individual accuracy while neglecting the potential of increasing opinion diversity. Here, we study a complementary approach to reduce collective error by promoting erroneous divergent opinions. This strategy proposes to anchor half of the crowd to a small value and the other half to a large value before eliciting and averaging all estimates. Consistent with our mathematical modeling, four experiments (N = 1,362 adults) demonstrated that this method is effective for estimation and forecasting tasks. Beyond the practical implications, these findings offer new theoretical insights into the epistemic value of collective decision-making.

Fluorinated Benzimidazole-Linked Highly Conjugated Polymer Enabling Covalent Polysulfide Anchoring for Stable Sulfur Batteries.

Sulfur is one of the most abundant and economical elements in the p-block family and highly redox active, potentially utilizable as a charge-storing electrode with high theoretical capacities. However, its inherent good solubility in many electrolytes inhibits its accessibility as an electrode material in typical metal-sulfur batteries. In this work, the synthetically designed fluorinated porous polymer, when treated with elemental sulfur through a well-known nucleophilic aromatic substitution mechanism (SN Ar), allows for the covalent integration of polysulfides into a highly conjugated benzimidazole polymer by replacing the fluorine atoms. Chemically robust benzimidazole linkages allow such harsh post-synthetic treatment and facilitate the electronic activation of the anchored polysulfides for redox reactions under applied potential. The electrode amalgamated with sulfurized polymer mitigates the so-called polysulfide shuttle effect in the lithium-sulfur (Li-S) battery and also enables a reversible, more environmentally friendly, and more economical aluminum-sulfur (Al-S) battery that is configured with mostly p-block elements as cathode, anode, and electrolytes. The improved cycling stabilities and reduction of the overpotential in both cases pave the way for future sustainable energy storage solutions.

Achieving Dendrite-Free Zinc Metal Anodes via Molecule Anchoring and lon-Transport Pumping.

The potential for scale-up application has been acknowledged by researchers for rechargeable aqueous zinc-ion batteries (ZIBs). Nonetheless, the progress of the development is significantly impeded due to the instability of the interface between the zinc anode and electrolyte. Herein, efficient and environmentally benign valine (Val) were introduced as aqueous electrolyte additive to stabilize the electrode/electrolyte interface (EEI) via functional groups in additive molecules, thus achieving reversible dendrite-free zinc anode. The amino groups present in Val molecules have a strong ability to adsorb on the surface of zinc metal, enabling the construction of anchored molecular layer on the surface of zinc anodes. The strongly polar carboxyl groups in Val molecules can act as ion-transport pumps to capture zinc ions in the electric double layer (EDL) through coordination chemistry. Therefore, this reconstructed EEI could modulate the zinc ion flux and simultaneously suppress side reactions and dendritic growth of Zn. Consequently, a long stable cycling up to 1400 h at a high current density of 20 mA cm-2 is achieved. Additionally, Zn//V2O5 full cell with Val additive exhibit enhanced cyclability, retaining 77 % capacity after 3000 cycles, displaying significant potential in promoting the commercialization of ZIBs.