Axonal endoplasmic reticulum tubules control local translation via P180/RRBP1-mediated ribosome interactions.

Local mRNA translation in axons is critical for the spatiotemporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons; however, how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing rat hippocampal cultured neurons. Axonal ER tubule disruption impairs local translation and ribosome distribution. Using nanoscale resolution imaging, we find that ribosomes make frequent contacts with axonal ER tubules in a translation-dependent manner and are influenced by specific extrinsic cues. We identify P180/RRBP1 as an axonally distributed ribosome receptor that regulates local translation and binds to mRNAs enriched for axonal membrane proteins. Importantly, the impairment of axonal ER-ribosome interactions causes defects in axon morphology. Our results establish a role for the axonal ER in dynamically localizing mRNA translation, which is important for proper neuron development.

American Society of Pain and Neuroscience Best Practice (ASPN) Guideline for the Treatment of Sacroiliac Disorders.

Clinical management of sacroiliac disease has proven challenging from both diagnostic and therapeutic perspectives. Although it is widely regarded as a common source of low back pain, little consensus exists on the appropriate clinical management of sacroiliac joint pain and dysfunction. Understanding the biomechanics, innervation, and function of this complex load bearing joint is critical to formulating appropriate treatment algorithms for SI joint disorders. ASPN has developed this comprehensive practice guideline to serve as a foundational reference on the appropriate management of SI joint disorders utilizing the best available evidence and serve as a foundational guide for the treatment of adult patients in the United States and globally.

Endoplasmic reticulum - condensate interactions in protein synthesis and secretion.

In the past decade, a growing amount of evidence has demonstrated that organelles do not act autonomously and independently but rather communicate with each other to coordinate different processes for proper cellular function. With a highly extended network throughout the cell, the endoplasmic reticulum (ER) plays a central role in interorganelle communication through membrane contact sites. Here, we highlight recent evidence indicating that the ER also forms contacts with membrane-less organelles. These interactions contribute to the dynamic assembly and disassembly of condensates and controlled protein secretion. Additionally, emerging evidence suggests their involvement in mRNA localization and localized translation. We further explore exciting future directions of this emerging theme in the organelle contact site field.

Home Therapies to Neutralize Button Battery Injury in a Porcine Esophageal Model.

STUDY OBJECTIVE: Button battery ingestion can cause alkaline esophageal injury. There is interest in first-aid household products to neutralize the injury. The objective was to investigate which household products are effective at reducing button battery injury. METHODS: Two cadaveric porcine experiments were performed. Experiment 1 utilized esophageal mucosal segments. A button battery (3VCR2032) was placed onto the mucosa, and substances (saline control, honey, jam, orange juice, yogurt, milk, and cola) were applied every 10 minutes for 6 applications. Tissue pH was measured every 10 minutes, and macroscopic ulceration size was assessed at 120 minutes. Experiment 2 used an intact esophageal model with a battery inserted into the lumen and jam, honey, and saline irrigation as per experiment 1. Tissue pH, macroscopic and histopathology changes were evaluated at 60, 90 and 120 minutes. RESULTS: In experiment 1, only honey and jam had a lower mean tissue pH at 120 minutes (8.0 [standard deviation [SD] 0.9, n=12] and 7.1 [SD 1.7, n=12], respectively) compared to saline solution 11.9 (SD 0.6, n=6, P<.0001). Both honey (0.24 cm2, SD 0.17) and jam (0.37 cm2, SD 0.40) had smaller mean areas of ulceration compared to saline solution (3.90 cm2, SD 1.03, P<.0001). In experiment 2, honey and jam had significantly lower mean tissue pH at all timepoints compared to saline solution. Histologic changes were evident at 60 minutes in the saline group, whereas honey and jam exhibited no or minimal changes until 120 minutes. CONCLUSIONS: Honey and jam were able to neutralize injury caused by a button battery resulting in a smaller area of ulceration. Jam should be further explored as a possible first-aid option as an alternative to honey in suspected button battery ingestion prior to definitive management.

Results of an International Survey on Spinal Imaging by the ASNR/ASSR/ESNR/ESSR "Nomenclature 3.0" Working Group.

Our goal was to determine if "Nomenclature 2.0," the classification of lumbar disk pathology consensus, should be updated. We conducted a social media and e-mail-based survey on preferences regarding the use of classification on magnetic resonance spine reporting. Members of the European Society of Neuroradiology, European Society of Musculoskeletal Radiology, American Society of Neuroradiology, and American Society of Spine Radiology received a 15-question online survey between February and March 2022. A total of 600 responses were received from 63 countries. The largest number of responses came from Italy and the United States. We found that 71.28% of respondents used Nomenclature 2.0, Classification of Lumbar Disk Pathology. But classification on stenosis is used less often: 53.94% and 60% of respondents do not use any classification of spinal canal stenosis and foraminal stenosis, respectively. When queried about which part of Nomenclature needs improving, most respondents asked for a Structured Reporting Template (SRT), even though 58.85% of respondents do not currently use any template and 54% routinely use a clinical information questionnaire. These results highlight the importance of an updated Nomenclature 3.0 version that integrates the classifications of lumbar disk disease and spinal canal and foraminal stenosis. Further attention should also be directed toward developing a robust endorsed SRT.

Screen for Modulation of Nucleocapsid Protein Condensation Identifies Small Molecules with Anti-Coronavirus Activity.

Biomolecular condensates formed by liquid-liquid phase separation have been implicated in multiple diseases. Modulation of condensate dynamics by small molecules has therapeutic potential, but so far, few condensate modulators have been disclosed. The SARS-CoV-2 nucleocapsid (N) protein forms phase-separated condensates that are hypothesized to play critical roles in viral replication, transcription, and packaging, suggesting that N condensation modulators might have anti-coronavirus activity across multiple strains and species. Here, we show that N proteins from all seven human coronaviruses (HCoVs) vary in their tendency to undergo phase separation when expressed in human lung epithelial cells. We developed a cell-based high-content screening platform and identified small molecules that both promote and inhibit condensation of SARS-CoV-2 N. Interestingly, these host-targeted small molecules exhibited condensate-modulatory effects across all HCoV Ns. Some have also been reported to exhibit antiviral activity against SARS-CoV-2, HCoV-OC43, and HCoV-229E viral infections in cell culture. Our work reveals that the assembly dynamics of N condensates can be regulated by small molecules with therapeutic potential. Our approach allows for screening based on viral genome sequences alone and might enable rapid paths to drug discovery with value for confronting future pandemics.

Stress-induced phase separation of ERES components into Sec bodies precedes ER exit inhibition in mammalian cells.

Phase separation of components of ER exit sites (ERES) into membraneless compartments, the Sec bodies, occurs in Drosophila cells upon exposure to specific cellular stressors, namely, salt stress and amino acid starvation, and their formation is linked to the early secretory pathway inhibition. Here, we show Sec bodies also form in secretory mammalian cells upon the same stress. These reversible and membraneless structures are positive for ERES components, including both Sec16A and Sec16B isoforms and COPII subunits. We find that Sec16A, but not Sec16B, is a driver for Sec body formation, and that the coalescence of ERES components into Sec bodies occurs by fusion. Finally, we show that the stress-induced coalescence of ERES components into Sec bodies precedes ER exit inhibition, leading to their progressive depletion from ERES that become non-functional. Stress relief causes an immediate dissolution of Sec bodies and the concomitant restoration of ER exit. We propose that the dynamic conversion between ERES and Sec body assembly, driven by Sec16A, regulates protein exit from the ER during stress and upon stress relief in mammalian cells, thus providing a conserved pro-survival mechanism in response to stress.

Natural and Designed Proteins Inspired by Extremotolerant Organisms Can Form Condensates and Attenuate Apoptosis in Human Cells.

Many organisms can survive extreme conditions and successfully recover to normal life. This extremotolerant behavior has been attributed in part to repetitive, amphipathic, and intrinsically disordered proteins that are upregulated in the protected state. Here, we assemble a library of approximately 300 naturally occurring and designed extremotolerance-associated proteins to assess their ability to protect human cells from chemically induced apoptosis. We show that several proteins from tardigrades, nematodes, and the Chinese giant salamander are apoptosis-protective. Notably, we identify a region of the human ApoE protein with similarity to extremotolerance-associated proteins that also protects against apoptosis. This region mirrors the phase separation behavior seen with such proteins, like the tardigrade protein CAHS2. Moreover, we identify a synthetic protein, DHR81, that shares this combination of elevated phase separation propensity and apoptosis protection. Finally, we demonstrate that driving protective proteins into the condensate state increases apoptosis protection, and highlights the ability of DHR81 condensates to sequester caspase-7. Taken together, this work draws a link between extremotolerance-associated proteins, condensate formation, and designing human cellular protection.

Multifunctional protein 4.1R regulates the asymmetric segregation of Numb during terminal erythroid maturation.

The asymmetric cell division of stem or progenitor cells generates daughter cells with distinct fates that balance proliferation and differentiation. Asymmetric segregation of Notch signaling regulatory protein Numb plays a crucial role in cell diversification. However, the molecular mechanism remains unclear. Here, we examined the unequal distribution of Numb in the daughter cells of murine erythroleukemia cells (MELCs) that undergo DMSO-induced erythroid differentiation. In contrast to the cytoplasmic localization of Numb during uninduced cell division, Numb is concentrated at the cell boundary in interphase, near the one-spindle pole in metaphase, and is unequally distributed to one daughter cell in anaphase in induced cells. The inheritance of Numb guides this daughter cell toward erythroid differentiation while the other cell remains a progenitor cell. Mitotic spindle orientation, critical for distribution of cell fate determinants, requires complex communication between the spindle microtubules and the cell cortex mediated by the NuMA-LGN-dynein/dynactin complex. Depletion of each individual member of the complex randomizes the position of Numb relative to the mitotic spindle. Gene replacement confirms that multifunctional erythrocyte protein 4.1R (4.1R) functions as a member of the NuMA-LGN-dynein/dynactin complex and is necessary for regulating spindle orientation, in which interaction between 4.1R and NuMA plays an important role. These results suggest that mispositioning of Numb is the result of spindle misorientation. Finally, disruption of the 4.1R-NuMA-LGN complex increases Notch signaling and decreases the erythroblast population. Together, our results identify a critical role for 4.1R in regulating the asymmetric segregation of Numb to mediate erythropoiesis.

Minimally Invasive Treatment for Degenerative Lumbar Spine.

Degenerative lumbar spine disorder (DLSD) is a ubiquitously occurring event that may be induced or accelerated by multiple factors such as from overuse, trauma, genetic predisposition, nutrition deficiency, and others. While our understanding of this degenerative disorder is limited, in terms of prevention, the symptoms from DLSD can be significant and may lead to the reduction in the patient's quality of life and loss of work time. In the Global Burden of Disease Study, low back pain was ranked the highest of 291 different conditions, due to the number of years lost to disability, amounting to 83 million disability-adjusted life years lost in 2010. DLSD contains conditions involving disc degeneration, lumbar spinal stenosis, and spondylolisthesis, including symptoms ranging from low back pain to lower extremity radicular pain and weakness. In this issue, we will be discussing treatments for patients suffering with chronic low back pain from endplate disruption, utilizing basivertebral nerve radiofrequency ablation, also known as the INTRACEPT procedure. This issue will also cover minimally invasive lumbar decompression from lumbar spinal stenosis, due to contributory ligamentum flavum hypertrophy, utilizing the percutaneous image-guided lumbar decompression technique known as the MILD procedure.

Sequence-Controlled Adhesion and Microemulsification in a Two-Phase System of DNA Liquid Droplets.

Membrane-less organelles, the liquid droplets formed via liquid-liquid phase separation (LLPS) of biomolecules in cells, act to organize intracellular components into multiple compartments. As a model for this process, and as a potential vehicle for in vitro exploitation of its properties, we explore here a synthetic multiphase LLPS system consisting of a mixture of self-assembled DNA particles. The particles, termed "DNA nanostars" (NSs), consist of four double-stranded DNA arms that each terminate in a single-stranded overhang. NSs condense into droplets due to overhang hybridization. Using two types of NSs with orthogonal overhangs enables the creation of two types of immiscible DNA droplets. Adhesion between the droplets can be tuned by the addition of "cross-linker NSs" that have two overhang sequences of each type. We find that increasing the amount of the cross-linker NSs decreases the droplet/droplet surface tension until a microemulsion transition occurs. Controlled droplet adhesion can also be achieved, without cross-linkers, using overhangs that can weakly hybridize. Finally, we show that solutes can be specifically targeted to the DNA phases by labeling them with appropriate sticky-ends. Overall, our findings demonstrate the ability to create a multiphase LLPS system, and to control its mesoscale configuration, via sequence design of the component molecules.

Quantum Walks in Periodic and Quasiperiodic Fibonacci Fibers.

Quantum walk is a key operation in quantum computing, simulation, communication and information. Here, we report for the first time the demonstration of quantum walks and localized quantum walks in a new type of optical fibers having a ring of cores constructed with both periodic and quasiperiodic Fibonacci sequences, respectively. Good agreement between theoretical and experimental results has been achieved. The new multicore ring fibers provide a new platform for experiments of quantum effects in low-loss optical fibers which is critical for scalability of real applications with large-size problems. Furthermore, our new quasiperiodic Fibonacci multicore ring fibers provide a new class of quasiperiodic photonics lattices possessing both on- and off-diagonal deterministic disorders for realizing localized quantum walks deterministically. The proposed Fibonacci fibers are simple and straightforward to fabricate and have a rich set of properties that are of potential use for quantum applications. Our simulation and experimental results show that, in contrast with randomly disordered structures, localized quantum walks in new proposed quasiperiodic photonics lattices are highly controllable due to the deterministic disordered nature of quasiperiodic systems.

Length-Dependence and Spatial Structure of DNA Partitioning into a DNA Liquid.

Cells can spatially and temporally control biochemistry using liquid-liquid phase separation to form membrane-less organelles. Synthetic biomolecular liquids offer a means to study the mechanisms of this process, as well as offering a route to the creation of functional biomimetic materials. With these goals in mind, we here examine the partitioning of long double-stranded DNA linkers into a liquid composed of small DNA particles ("nanostars") whose phase separation is driven by base pairing. We find that linker partitioning is length-dependent because of a confinement penalty of inserting long strands within the liquid's characteristic mesh size. We quantify this entropic-confinement effect using a simple partitioning theory and show that its magnitude is consistent with classic Odijk pictures of confined worm-like chains. Linker partitioning can also lead to inhomogeneous structures: long linkers excluded from the liquid interior tend to preferentially accumulate on the surface of liquid droplets (i.e., acting as surfactants), while linkers forced at high concentrations into the liquid undergo a secondary phase separation, forming metastable droplet-in-droplet structures. Altogether, our work demonstrates the ability to rationally engineer the composition and structure of a model biomolecular liquid.

A single shot coherent Ising machine based on a network of injection-locked multicore fiber lasers.

Combinatorial optimization problems over large and complex systems have many applications in social networks, image processing, artificial intelligence, computational biology and a variety of other areas. Finding the optimized solution for such problems in general are usually in non-deterministic polynomial time (NP)-hard complexity class. Some NP-hard problems can be easily mapped to minimizing an Ising energy function. Here, we present an analog all-optical implementation of a coherent Ising machine (CIM) based on a network of injection-locked multicore fiber (MCF) lasers. The Zeeman terms and the mutual couplings appearing in the Ising Hamiltonians are implemented using spatial light modulators (SLMs). As a proof-of-principle, we demonstrate the use of optics to solve several Ising Hamiltonians for up to thirteen nodes. Overall, the average accuracy of the CIM to find the ground state energy was ~90% for 120 trials. The fundamental bottlenecks for the scalability and programmability of the presented CIM are discussed as well.

Localized quantum walks in quasi-periodic Fibonacci arrays of waveguides.

New quasi-periodic arrays of waveguides (AWs) constructed with Fibonacci sequences are proposed to realize localized quantum walks (LQWs). The proposed Fibonacci arrays of waveguides (FAWs) are simple and straightforward to make, but have a rich set of properties that are of potential use for applications in quantum communication. Our simulations show that, in contrast with randomly disordered AWs, LQWs in FAWs are highly controllable due to the deterministic disorder nature of quasi-periodic systems. Furthermore, unique LQWs with symmetrical probability distribution can be conveniently realized in the FAWs.

Triggered disassembly and reassembly of actin networks induces rigidity phase transitions.

Non-equilibrium soft materials, such as networks of actin proteins, have been intensely investigated over the past decade due to their promise for designing smart materials and understanding cell mechanics. However, current methods are unable to measure the time-dependent mechanics of such systems or map mechanics to the corresponding dynamic macromolecular properties. Here, we present an experimental approach that combines time-resolved optical tweezers microrheology with diffusion-controlled microfluidics to measure the time-evolution of microscale mechanical properties of dynamic systems during triggered activity. We use these methods to measure the viscoelastic moduli of entangled and crosslinked actin networks during chemically-triggered depolymerization and repolymerization of actin filaments. During disassembly, we find that the moduli exhibit two distinct exponential decays, with experimental time constants of ∼169 min and ∼47 min. Conversely, during reassembly, measured moduli initially exhibit power-law increase with time, after which steady-state values are achieved. We develop toy mathematical models that couple the time-evolution of filament lengths with rigidity percolation theory to shed light onto the molecular mechanisms underlying the observed mechanical transitions. The models suggest that these two distinct behaviors both arise from phase transitions between a rigidly percolated network and a non-rigid regime. Our approach and collective results can inform the general principles underlying the mechanics of a large class of dynamic, non-equilibrium systems and materials of current interest.

Salt-dependent properties of a coacervate-like, self-assembled DNA liquid.

Liquid-liquid phase separation of a polymer-rich phase from a polymer-dilute solution, known generally as coacervation, has been observed in a variety of biomolecular systems. Understanding of this process, and the properties of the resulting liquid, has been hampered in typical systems by the complexity of the components and of the intermolecular interactions. Here, we examine a single-component system comprised entirely of DNA, in which tetravalent DNA nanostar particles condense into liquids through attractive bonds formed from basepairing interactions. We measure the density, viscosity, particle self-diffusion, and surface tension of NS-liquid droplets. The sequence- and salt-dependent thermodynamics of basepairing accounts for most properties, particularly indicating that particle transport is an activated process whose barrier is the breaking of a single bond, and that very few bonds are broken at the surface. However, more complex effects are also seen. The relation of density to salt shows that electrostatic screening compacts the NS particles. Further, the interrelation of the transport properties indicates a breakdown of the Stokes-Einstein relation. This observation, in concert with the low surface tension and single-bond transport barrier, suggests this DNA liquid has a heterogeneous, clustered structure that is likely enabled by internal NS particle flexibility. We discuss these results in comparison to other coacervate systems.

Percutaneous Radiofrequency Ablation for Painful Spinal Metastases Resulting in Resolution of Epidural Disease: A Case Report.

Percutaneous image-guided ablation is used for treatment of both benign and malignant osseous lesions often leading to substantial pain relief and local tumor control. Paired with vertebral augmentation of the affected vertebra, patients can often become functional and experience significant pain reduction. However, bone ablation must be paired with various modalities of treatment as it only provides pain relief and local tumor control and does not address systemic metastatic disease. We describe a case of metastatic prostate cancer with epidural extension treated with percutaneous image-guided radiofrequency ablation and vertebral augmentation leading to substantial pain relief as well as resolution of the epidural disease as evidenced by short-term follow-up magnetic resonance imaging (MRI). To the best of our knowledge, the resolution of epidural disease has not been described before. This case highlights the potential of ablative therapy in metastatic bone disease, particularly in the presence of epidural disease.

Percutaneous Radiofrequency Ablation for the Treatment of Peripheral Nerve Sheath Tumors: A Case Report and Review of the Literature.

Peripheral nerve sheath tumors (PNSTs) may arise sporadically or in the presence of genetic disorders, including neurofibromatosis (NF) types 1 and 2, schwannomatosis, and in patients with large genetic deletions involving the CDKN2A gene. Surgical resection is the treatment of choice for symptomatic PNSTs and offers patients a potential cure; however, pre-existing conditions or tumor location may limit a patient's surgical options. Radiofrequency ablation (RFA) may provide an alternative therapeutic strategy for the treatment of selected PNSTs that are not amenable to surgical resection. Here, we present a case report of a 49-year-old patient with multiple neurofibromas who underwent RFA treatment of two symptomatic retroperitoneal neurofibromas and review previously reported cases of percutaneous treatment of PNSTs.