Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol ...1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains. Rescue of the ER-mitochondrial juxtaposition with drug-inducible interorganelle linkers reveals a kinetic disruption, which when overcome in Bok−/− cells is still insufficient to rescue thapsigargin-induced calcium transfer and apoptosis. Likewise, a BOK mutant unable to interact with IP3R restores ER-mitochondrial proximity, but not ER-mitochondrial calcium transfer, MAM protein composition, or apoptosis. This work identifies the dynamic coordination of ER-mitochondrial contact by BOK as an important control point for apoptosis.
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•BOK interacts with the IP3Rs in mitochondria-associated membranes (MAMs)•BOK potentiates ER-mitochondrial contact sites and protein expression in MAMs•BOK regulates Ca2+ transfer from the ER to the mitochondria•The transfer of Ca2+ at MAMs by BOK is an apoptotic control point
Carpio et al. demonstrate that the pro-apoptotic BCL-2 family member BOK is present in mitochondrial associated membranes (MAMs). The interaction of BOK with the IP3Rs is critical for its regulation of Ca2+ transfer to the mitochondria, ER-mitochondrial contact sites, and apoptosis.
Systems of correlated particles appear in many fields of modern science and represent some of the most intractable computational problems in nature. The computational challenge in these systems ...arises when interactions become comparable to other energy scales, which makes the state of each particle depend on all other particles
. The lack of general solutions for the three-body problem and acceptable theory for strongly correlated electrons shows that our understanding of correlated systems fades when the particle number or the interaction strength increases. One of the hallmarks of interacting systems is the formation of multiparticle bound states
. Here we develop a high-fidelity parameterizable fSim gate and implement the periodic quantum circuit of the spin-½ XXZ model in a ring of 24 superconducting qubits. We study the propagation of these excitations and observe their bound nature for up to five photons. We devise a phase-sensitive method for constructing the few-body spectrum of the bound states and extract their pseudo-charge by introducing a synthetic flux. By introducing interactions between the ring and additional qubits, we observe an unexpected resilience of the bound states to integrability breaking. This finding goes against the idea that bound states in non-integrable systems are unstable when their energies overlap with the continuum spectrum. Our work provides experimental evidence for bound states of interacting photons and discovers their stability beyond the integrability limit.
Inherent symmetry of a quantum system may protect its otherwise fragile states. Leveraging such protection requires testing its robustness against uncontrolled environmental interactions. Using 47 ...superconducting qubits, we implement the one-dimensional kicked Ising model, which exhibits nonlocal Majorana edge modes (MEMs) with
ℤ
2
parity symmetry. We find that any multiqubit Pauli operator overlapping with the MEMs exhibits a uniform late-time decay rate comparable to single-qubit relaxation rates, irrespective of its size or composition. This characteristic allows us to accurately reconstruct the exponentially localized spatial profiles of the MEMs. Furthermore, the MEMs are found to be resilient against certain symmetry-breaking noise owing to a prethermalization mechanism. Our work elucidates the complex interplay between noise and symmetry-protected edge modes in a solid-state environment.
Tough edges
The dynamics of quantum many-body systems can be profoundly affected by their interaction with the environment. This includes systems that have topological protection from certain kinds of perturbations due to symmetry. Mi
et al
. studied the interplay between symmetry and noise using a chain of 47 superconducting qubits. They implemented a periodically driven transverse Ising spin model, and found that the system’s edge modes were surprisingly resilient to some types of symmetry-breaking noise. —JS
A 47-qubit chain was used to study the interplay of noise and symmetry in an open quantum system.
Addition of an affinity tag is a useful method for differentiating recombinant proteins expressed in bacterial and eukaryotic expression systems from the background of total cellular proteins, as ...well as for detecting protein-protein interactions. This overview describes the historical basis for the development of affinity tags, affinity tags that are commonly used today, how to choose an appropriate affinity tag for a particular purpose, and several recently developed affinity tag technologies that may prove useful in the near future.
Engineered heart tissues (EHTs) have emerged as a robust in vitro model to study cardiac physiology. Although biomimetic culture environments have been developed to better approximate in vivo ...conditions, currently available methods do not permit full recapitulation of the four phases of the cardiac cycle. We have developed a bioreactor which allows EHTs to undergo cyclic loading sequences that mimic in vivo work loops. EHTs cultured under these working conditions exhibited enhanced concentric contractions but similar isometric contractions compared to EHTs cultured isometrically. EHTs that were allowed to shorten cyclically in culture had increased capacity for contractile work when tested acutely. Increased work production was correlated with higher levels of mitochondrial proteins and mitochondrial biogenesis; this effect was eliminated when tissues were cyclically shortened in the presence of a myosin ATPase inhibitor. Leveraging our novel in vitro method to precisely apply mechanical loads in culture, we grew EHTs under two loading regimes prescribing the same work output but with different associated afterloads. These groups showed no difference in mitochondrial protein expression. In loading regimes with the same afterload but different work output, tissues subjected to higher work demand exhibited elevated levels of mitochondrial protein. Our findings suggest that regulation of mitochondrial mass in cultured human EHTs is potently modulated by the mechanical work the tissue is permitted to perform in culture, presumably communicated through ATP demand. Precise application of mechanical loads to engineered heart tissues in culture represents a novel in vitro method for studying physiological and pathological cardiac adaptation.
Algal toxicity studies are required by regulatory agencies for a variety of purposes including classification and labeling and environmental risk assessment of chemicals. Algae are also frequently ...the most sensitive taxonomic group tested. Acute to chronic ratios (ACRs) have been challenging to derive for algal species because of the complexities of the underlying experimental data including: a lack of universally agreed upon algal inhibition endpoints; evolution of experimental designs over time and by different standardization authorities; and differing statistical approaches (e.g., regression versus hypothesis-based effect concentrations). Experimental data for developing globally accepted algal ACRs have been limited because of data availability, and in most regulatory frameworks an ACR of 10 is used regardless of species, chemical type or mode of action. Acute and chronic toxicity (inhibition) data on 17 algal species and 442 chemicals were compiled from the EnviroTox database (https://envirotoxdatabase.org/) and a proprietary database of algal toxicity records. Information was probed for growth rate, yield, and final cell density endpoints focusing primarily on studies of 72 and 96 h duration. Comparisons of acute and chronic data based on either single (e.g., growth rate) and multiple (e.g., growth rate, final cell density) endpoints were used to assess acute and chronic relationships. Linear regressions of various model permutations were used to compute ACRs for multiple combinations of taxa, chemicals, and endpoints, and showed that ACRs for algae were consistently around 4 (ranging from 2.43 to 5.62). An ACR of 4 for algal toxicity is proposed as an alternative to a default value of 10, and recommendations for consideration and additional research and development are provided.
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•Algae are often the most sensitive taxonomic group in environmental risk assessments.•Application of acute to chronic ratios (ACRs) are often used to estimate chronic toxicity values.•An ACR of 10 is commonly used for all test species (algae, invertebrates and fish).•A detailed literature review suggests algal inhibition assays do not fit this profile.•An ACR of 4 is proposed for algal toxicity as an alternative to a default value of 10.
Changes in intracellular calcium (Ca2+) signaling can modulate cellular machinery required for cancer progression. Neuronal calcium sensor 1 (NCS1) is a ubiquitously expressed Ca2+‐binding protein ...that promotes tumor aggressiveness by enhancing cell survival and metastasis. However, the underlying mechanism by which NCS1 contributes to increased tumor aggressiveness has yet to be identified. In this study, we aimed to determine (a) whether NCS1 expression changes in response to external stimuli, (b) the importance of NCS1 for cell survival and migration, and (c) the cellular mechanism(s) through which NSC1 modulates these outcomes. We found that NCS1 abundance increases under conditions of stress, most prominently after stimulation with the pro‐inflammatory cytokine tumor necrosis factor α, in a manner dependent on nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB). We found that NFκB signaling is activated in human breast cancer tissue, which was accompanied by an increase in NCS1 mRNA expression. Further exploration into the relevance of NCS1 in breast cancer progression showed that knockout of NCS1 (NCS1 KO) caused decreased cell survival and motility, increased baseline intracellular Ca2+ levels, and decreased inositol 1,4,5‐trisphosphate‐mediated Ca2+ responses. Protein kinase B (Akt) activity was decreased in NCS1 KO cells, which could be rescued by buffering intracellular Ca2+. Conversely, Akt activity was increased in cells overexpressing NCS1 (NCS1 OE). We therefore conclude that NCS1 acts as cellular stress response protein up‐regulated by stress‐induced NFκB signaling and that NCS1 influences cell survival and motility through effects on Ca2+ signaling and Akt pathway activation.
This study investigates the underlying mechanism by which the calcium (Ca2+)‐binding protein NCS1 promotes increased tumor aggressiveness. We characterize NCS1 as a stress response protein that is up‐regulated by exogenous stressors, including the cytokine tumor necrosis factor α, through a nuclear factor kappa‐light‐chain‐enhancer of activated B cells‐dependent mechanism. Increased NCS1 expression leads to disrupted intracellular Ca2+ signaling and activation of the protein kinase B pathway, leading to increased cell survival and migration.
Polycystin 2 (PC2) is one of two main protein types responsible for the underlying etiology of autosomal dominant polycystic kidney disease (ADPKD), the most prevalent monogenic renal disease in the ...world. This debilitating and currently incurable condition is caused by loss-of-function mutations in PKD2 and PKD1, the genes encoding for PC2 and Polycystin 1 (PC1), respectively. Two-hit mutation events in these genes lead to renal cyst formation and eventual kidney failure, the main hallmarks of ADPKD. Though much is known concerning the physiological consequences and dysfunctional signaling mechanisms resulting from ADPKD development, to best understand the requirement of PC2 in maintaining organ homeostasis, it is important to recognize how PC2 acts under normal conditions. As such, an array of work has been performed characterizing the endogenous function of PC2, revealing it to be a member of the transient receptor potential (TRP) channel family of proteins. As a TRP protein, PC2 is a nonselective, cation-permeant, calcium-sensitive channel expressed in all tissue types, where it localizes primarily on the endoplasmic reticulum (ER), primary cilia, and plasma membrane. In addition to its channel function, PC2 interacts with and acts as a regulator of a number of other channels, ultimately further affecting intracellular signaling and leading to dysfunction in its absence. In this review, we describe the biophysical and physiological properties of PC2 as a cation channel and modulator of intracellular calcium channels, along with how these properties are altered in ADPKD.
•Polycystin 2, encoded by PKD2, resides on the ER, primary cilia, and plasma membrane.•Polycystin 2 is a nonselective tetrameric cation channel, of the TRP channel family.•Polycystin 2 interacts with many ion channels to modulate intracellular Ca2+ signaling.•Mutated polycystin 2 has altered function and leads to polycystic kidney disease.
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