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Background: Medial displacement calcaneal osteotomy (MDCO) is routinely used in hindfoot valgus realignment. Minimally invasive surgery (MIS) calcaneal osteotomies have been reported to be as safe and effective compared to open techniques. The aim of this cadaveric study was to compare the amount of medial tuberosity displacement obtained with fine-cut saw-based MIS vs open MDCO techniques. Methods: Eight matched cadaveric specimens had one side randomly assigned to either open or MIS MDCO. The contralateral limb was then assigned to the alternative osteotomy. The amount of medial displacement provided by the osteotomy was measured manually using a flexible metric ruler and radiographically on standardized axial calcaneal radiographs. Results: Manual measurements showed that a mean displacement of the MIS osteotomy was 7.9 mm compared with 8.7 mm for the open technique ( P = .36). Radiograph measurement showed a mean displacement of the MIS osteotomy was 7.1 mm compared with 7.4 mm for the open technique ( P = .83). No significant difference was found on manual and radiographic measurement of medial displacement between MIS and open MDCO. Conclusion: In a cadaveric model, we found similar magnitude of calcaneal tuberosity displacement using fine-cut saw-based MIS and open techniques for medial displacement calcaneal osteotomies. Level of Evidence: Level V, cadaveric study.

Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool of motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue, demonstrating that by manipulating the activity of CREB-transfected neurons it is possible to turn off and on stroke recovery. CREB transfection enhances remapping of injured somatosensory and motor circuits, and induces the formation of new connections within these circuits. CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits.

Aims: Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown. Methods: Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. Results: Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases. Conclusions: In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible antiseizure treatment for RE may involve the use of gap junction blockers.

Achalasia and diffuse esophageal spasm (DES) are 2 of the more well-known esophageal motility disorders diagnosed on barium studies and manometry. The purpose of this article is to review the spectrum of clinical, radiographic, and manometric findings in patients with achalasia (including primary and secondary achalasia) and DES and to discuss the complementary roles of barium studies and manometry in diagnosing these esophageal motility disorders. [ABSTRACT FROM AUTHOR]

Objective: To determine the findings on videofluoroscopy of the pharynx and esophagus in patients with a globus sensation and compare them with a similar group of patients with dysphagia. Methods: A computerized search of radiology files revealed 83 patients with a globus sensation who had videofluoroscopic examinations of the pharynx and esophagus during a 10-year period from 1989-1999. A computerized search was also performed to generate an age- and sex-matched group of 83 patients with dysphagia who also had videofluoroscopic examinations during this period. Original radiologic reports were reviewed to determine the frequency of morphologic and functional abnormalities of the pharynx and esophagus in these 2 groups. Results: Early closure of the cricopharyngeus was found in 13 (16%) patients with globus versus 2 (2%) with dysphagia (p less than 0.01). Enlarged pharyngeal tonsils were found in 31 (37%) patients with globus versus 17 (21%) with dysphagia (p less than 0.05). Enlarged lingual tonsils were characterized on barium studies by modularity or lobulation of the posterior-inferior base of the tongue and valleculae in all patients, and the palatine tonsils were symmetrically enlarged in all but 2 patients. No other radiographic findings were significantly associated with a globus sensation. Conclusion: Early closure of the cricopharyngeus and enlarged lingual or palatine tonsils may contribute to the development of a globus sensation, but the pathophysiologic basis for this association remains unclear. [ABSTRACT FROM AUTHOR]

Centrioles define centrosome structure and function. Deregulation of centriole numbers can cause developmental defects and cancer. The p53 tumor suppressor limits the growth of cells lacking or harboring additional centrosomes and can be engaged by the "mitotic surveillance" or the "PIDDosome pathway", respectively. Here, we show that early B cell progenitors frequently present extra centrioles, ensuing their high proliferative activity and related DNA damage. Extra centrioles are efficiently cleared during B cell maturation. In contrast, centriole loss upon Polo-like kinase 4 (Plk4) deletion causes apoptosis and arrests B cell development. This defect can be rescued by co-deletion of Usp28, a critical component of the mitotic surveillance pathway, that restores cell survival and maturation. Centriole-deficient mature B cells are proliferation competent and mount a humoral immune response. Our findings imply that progenitor B cells are intolerant to centriole loss but permissive to centriole amplification, a feature potentially facilitating their malignant transformation., (© 2024. The Author(s).)

The evolution of gene expression programs underlying the development of vertebrates remains poorly characterized. Here, we present a comprehensive proteome atlas of the model chordate Ciona , covering eight developmental stages and ∼7,000 translated genes, accompanied by a multi-omics analysis of co-evolution with the vertebrate Xenopus . Quantitative proteome comparisons argue against the widely held hourglass model, based solely on transcriptomic profiles, whereby peak conservation is observed during mid-developmental stages. Our analysis reveals maximal divergence at these stages, particularly gastrulation and neurulation. Together, our work provides a valuable resource for evaluating conservation and divergence of multi-omics profiles underlying the diversification of vertebrates., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Huntington's disease (HD), a genetic neurodegenerative disorder, primarily affects the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that, with short-term hNSC transplantation into the striatum of HD R6/2 mice, human cells differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here, we show that long-term (8 months) implantation of hNSCs into the striatum of HD zQ175 mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) levels, and reduces mutant huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry, single-nucleus RNA sequencing (RNA-seq), and electron microscopy demonstrate that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells, and form connections. Single-nucleus RNA-seq analysis also shows restoration of several mHTT-mediated transcriptional changes of endogenous striatal HD mouse cells. Remarkably, engrafted cells receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD., Competing Interests: Declaration of interests L.M.T. and J.C.R. have greater than 5% ownership in NeuroAirmid, a newly launched company that has related interests in cell therapy treatments for neurodegenerative diseases., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Thalidomide has a dark history as a teratogen, but in recent years, its derivates have been shown to function as potent chemotherapeutic agents. These drugs bind cereblon (CRBN), the substrate receptor of an E3 ubiquitin ligase complex, and modify its degradation targets. Despite these insights, remarkably little is known about the normal function of cereblon in development. Here, we employ Ciona , a simple invertebrate chordate, to identify endogenous Crbn targets. In Ciona, Crbn is specifically expressed in developing muscles during tail elongation before they acquire contractile activity. Crbn expression is activated by Mrf, the ortholog of MYOD1, a transcription factor important for muscle differentiation. CRISPR/Cas9-mediated mutations of Crbn lead to precocious onset of muscle contractions. By contrast, overexpression of Crbn delays contractions and is associated with decreased expression of contractile protein genes such as troponin. This reduction is possibly due to reduced Mrf protein levels without altering Mrf mRNA levels. Our findings suggest that Mrf and Crbn form a negative feedback loop to control the precision of muscle differentiation during tail elongation.

Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations., Competing Interests: Declaration of interests S.R. developed MUSE technology marketed by arcoris bio AG, has shares, and sits on the board., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non-small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC., (©2023 American Association for Cancer Research.)

Pyroptosis refers to the process of gasdermin-mediated lytic programmed cell death (PCD) characterized by the release of pro-inflammatory cytokines. Our knowledge of pyroptosis has expanded beyond the cellular level and now includes extracellular responses. In recent years, pyroptosis has attracted considerable attention due to its potential to induce host immunity. For instance, at the 2022 International Medicinal Chemistry of Natural Active Ligand Metal-Based Drugs (MCNALMD) conference, numerous researchers demonstrated an interest in photon-controlled pyroptosis activation ("PhotoPyro"), an emerging pyroptosis-engineered approach for activating systemic immunity via photoirradiation. Given this enthusiasm, we share in this Perspective our views on this emerging area and expound on how and why "PhotoPyro" could trigger antitumor immunity (i.e., turning so-called "cold" tumors "hot"). In doing so, we have tried to highlight cutting-edge breakthroughs in PhotoPyro while suggesting areas for future contributions. By providing insights into the current state of the art and serving as a resource for individuals interested in working in this area, it is hoped that this Perspective will set the stage for PhotoPyro to evolve into a broadly applicable cancer treatment strategy.