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Abstract Development of the gonads under complex androgen regulation is critical for germ cells specification. In this work we addressed the relationship between androgens and genomic integrity determining human fertility. We used different study groups: individuals with Differences of Sex Development (DSD), including Complete Androgen Insensitivity Syndrome (CAIS) due to mutated androgen receptor (AR), and men with idiopathic nonobstructive azoospermia. Both showed genome integrity status influenced by androgen signaling via innate immune response activation in blood and gonads. Whole proteome analysis connected low AR to interleukin-specific gene expression, while compromised genome stability and tumorigenesis were also supported by interferons. AR expression was associated with predominant DNA damage phenotype, that eliminated AR-positive Sertoli cells as the degeneration of gonads increased. Low AR contributed to resistance from the inhibition of DNA repair in primary leukocytes. Downregulation of androgen promoted apoptosis and specific innate immune response with higher susceptibility in cells carrying genomic instability.

Abstract The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) pandemic has challenged the current understanding of the complement cascade mechanisms of host immune responses during infection-induced nonresolvable lung disease. While the complement system is involved in opsonization and phagocytosis of the invading pathogens, uncontrolled complement activation also leads to aberrant autophagic response and tissue damage. Our recent study revealed unique pathologic and fibrotic signature genes associated with epithelial bronchiolization in the lung tissues of patients with nonresolvable COVID-19 (NR-COVID-19) requiring lung transplantation. However, there is a knowledge gap if complement components are modulated to contribute to tissue damage and the fibrotic phenotype during NR-COVID-19. We, therefore, aimed to study the role of the complement factors and their corresponding regulatory proteins in the pathogenesis of NR-COVID-19. We further examined the association of complement components with mediators of the host autophagic response. We observed significant upregulation of the expression of the classical pathway factor C1qrs and alternative complement factors C3 and C5a, as well as the anaphylatoxin receptor C5aR1, in NR-COVID-19 lung tissues. Of note, complement regulatory protein, decay accelerating factor (DAF; CD55) was significantly downregulated at both transcript and protein levels in the NR-COVID-19 lungs, indicating a dampened host protective response. Furthermore, we observed significantly decreased levels of the autophagy mediators PPARγ and LC3a/b, which was corroborated by decreased expression of factor P and the C3b receptor CR1, indicating impaired clearance of damaged cells that may contribute to the fibrotic phenotype in NR-COVID-19 patients. Thus, our study revealed previously unrecognized complement dysregulation associated with impaired cell death and clearance of damaged cells, which may promote NR-COVID-19 in patients, ultimately necessitating lung transplantation. The identified network of dysregulated complement cascade activity indicates the interplay of regulatory factors and the receptor-mediated modulation of host immune and autophagic responses as potential therapeutic targets for treating NR-COVID-19.

Abstract The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to antigen recognition by the T cell receptor (TCR) in the thymus and are implicated in clonal deletion, but the mechanisms by which they operate are not clear. Moreover, their role in central tolerance is obscured by redundancy among the Nr4a family members and by their reported functions in Treg generation and maintenance. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to show that Nr4a1 and Nr4a3 are essential for the upregulation of Bcl2l11/BIM and thymic clonal deletion by self-antigen. Importantly, thymocytes lacking Nr4a1/3 acquire an anergy-like signature after escaping clonal deletion and Treg lineage diversion. We further show that the Nr4a family helps mediate a broad transcriptional program in self-reactive thymocytes that resembles anergy and may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress.

The purpose of this work is to evaluate the feasibility of lung imaging using 3D electrical impedance tomography (EIT) during spontaneous breathing trials (SBTs) in patients with acute hypoxic respiratory failure. EIT is a noninvasive, nonionizing, real-time functional imaging technique, suitable for bedside monitoring in critically ill patients. EIT data were collected in 24 mechanically ventilated patients immediately preceding and during a SBT on two rows of 16 electrodes using a simultaneous multicurrent source EIT system for 3D imaging. Dynamic 3D EIT images of conductivity were computed, as well as the EIT-derived rapid shallow breathing index, regional ventilation delay, global inhomogeneity index, and time traces of tidal volumes. 3D reconstructions and derived measures demonstrated inhomogeneity in ventilation distribution within patients. We conclude that 3D EIT images can provide information regarding ventilatory heterogeneity across the lung and may be useful in guiding ventilator management.

Pre-babbling infants can track nonadjacent dependencies (NADs) in the auditory domain. While this forms a crucial prerequisite for language acquisition, the neurodevelopmental origins of this ability remain unknown. We applied functional near-infrared spectroscopy in neonates and 6- to 7-month-old infants to investigate the neural substrate supporting NAD learning and detection using tone sequences in an artificial grammar learning paradigm. Detection of NADs was indicated by left prefrontal activation in neonates while by left supramarginal gyrus (SMG), superior temporal gyrus (STG), and inferior frontal gyrus activation in 6- to 7-month-olds. Functional connectivity analyses further indicated that the neonate activation pattern during the test phase benefited from a brain network consisting of prefrontal regions, left SMG and STG during the rest and learning phases. These findings suggest a left-hemispheric learning-related functional brain network may emerge at birth and serve as the foundation for the later engagement of these regions for NAD detection, thus, providing a neural basis for language acquisition.

This review highlights opportunities to develop accessible ablative therapies to reduce the cancer burden in LMICs.

Summary: A critical component of language is the ability to recombine sounds into larger structures. Although animals also reuse sound elements across call combinations to generate meaning, examples are generally limited to pairs of distinct elements, even when repertoires contain sufficient sounds to generate hundreds of combinations. This combinatoriality might be constrained by the perceptual-cognitive demands of disambiguating between complex sound sequences that share elements. We test this hypothesis by probing the capacity of chestnut-crowned babblers to process combinations of two versus three distinct acoustic elements. We found babblers responded quicker and for longer toward playbacks of recombined versus familiar bi-element sequences, but no evidence of differential responses toward playbacks of recombined versus familiar tri-element sequences, suggesting a cognitively prohibitive jump in processing demands. We propose that overcoming constraints in the ability to process increasingly complex combinatorial signals was necessary for the productive combinatoriality that is characteristic of language to emerge.

Abstract Mammalian sex chromosomes are enriched for large, nearly-identical, palindromic sequences harboring genes expressed predominately in testicular germ cells. Discerning if individual palindrome-associated gene families are essential for male reproduction is difficult due to challenges in disrupting all copies of a gene family. Here we generate precise, independent, deletions to assess the reproductive roles of two X-linked palindromic gene families with spermatid-predominant expression, 4930567H17Rik and Mageb5. Sequence analyses reveals mouse 4930567H17Rik and Mageb5 are orthologs of human HSFX3 and MAGEB5, respectively, where 4930567H17Rik/HSFX3 is harbored in a palindrome in humans and mice, while Mageb5 is not. Additional sequence analyses show 4930567H17Rik and HSFX3 are rapidly diverging in rodents and primates, respectively. Mice lacking either 4930567H17Rik or Mageb5 gene families do not have detectable defects in male fertility, fecundity, spermatogenesis, or in gene regulation, but do show differences in sperm head morphology, suggesting a potential role in sperm function. We conclude that while all palindrome-associated gene families are not essential for male fertility, large palindromes influence the evolution of their associated gene families.

The progress made in recent years in the derivation and culture of pluripotent stem cells from farm animals opens up the possibility of creating livestock chimeras. Chimeras producing gametes exclusively derived from elite donor stem cells could pass superior genetics on to the next generation and thereby reduce the genetic lag that typically exists between the elite breeding sector and the commercial production sector, especially for industries like beef and sheep where genetics is commonly disseminated through natural service mating. Chimeras carrying germ cells generated from genome-edited or genetically engineered pluripotent stem cells could further disseminate useful genomic alterations such as climate adaptation, animal welfare improvements, the repair of deleterious genetic conditions, and/or the elimination of undesired traits such as disease susceptibility to the next generation. Despite the successful production of chimeras with germ cells generated from pluripotent donor stem cells injected into preimplantation-stage blastocysts in model species, there are no documented cases of this occurring in livestock. Here, we review the literature on the derivation of pluripotent stem cells from ungulates, and progress in the production of chimeric ungulate livestock for agricultural applications, drawing on insights from studies done in model species, and discuss future possibilities of this fast-moving and developing field. Aside from the technical aspects, the consistency of the regulatory approach taken by different jurisdictions towards chimeric ungulate livestock with germ cells generated from pluripotent stem cells and their progeny will be an important determinant of breeding industry uptake and adoption in animal agriculture.

Abstract Genetic improvement of cattle around the globe has been, and will continue to be, an important driver of animal agriculture sustainability. There are several reproductive and molecular biotechnologies that are used in genetic improvement of cattle, and their impact on the rate of genetic progress is maximized when combined synergistically in a structured breeding program with a clear breeding objective. One of the most recently developed and increasingly popular tools, gene editing, allows animal breeders to precisely add, delete, or replace letters in the genetic code so as to influence a specific trait of interest (e.g., disease resistance), in as little as one generation. However, for gene editing to be an important factor for genetic improvement, it must integrate smoothly into conventional cattle breeding programs to maintain or accelerate rates of genetic gain. This review first summarizes the current state of key reproductive and molecular biotechnologies available for the genetic improvement of cattle, and then discusses potential strategies for effectively incorporating gene editing into cattle genetic improvement programs and methods for disseminating traits improved via gene editing. Moreover, it examines how genetic improvement strategies, including the use of gene editing, will differ depending on the cattle industry sector (i.e., dairy or beef), and the region of the world in which they are being deployed.

Summary: The enteric nervous system (ENS) consists of glial cells (EGCs) and neurons derived from neural crest precursors. EGCs retain capacity for large-scale neurogenesis in culture, and in vivo lineage tracing has identified neurons derived from glial cells in response to inflammation. We thus hypothesize that EGCs possess a chromatin structure poised for neurogenesis. We use single-cell multiome sequencing to simultaneously assess transcription and chromatin accessibility in EGCs undergoing spontaneous neurogenesis in culture, as well as small intestine myenteric plexus EGCs. Cultured EGCs maintain open chromatin at genomic loci accessible in neurons, and neurogenesis from EGCs involves dynamic chromatin rearrangements with a net decrease in accessible chromatin. A subset of in vivo EGCs, highly enriched within the myenteric ganglia and that persist into adulthood, have a gene expression program and chromatin state consistent with neurogenic potential. These results clarify the mechanisms underlying EGC potential for neuronal fate transition.

Introduction: There are more than 80,000 emergency department (ED) visits for non-fatal bullet-related injuries (BRI) per year in the United States. Approximately half of these patients are discharged home from the ED. Our objective in this study was to characterize the discharge instructions, prescriptions, and follow-up plans provided to patients discharged from the ED after BRI. Methods: This was a single-center, cross-sectional study of the first 100 consecutive patients who presented to an urban, academic, Level I trauma center ED with an acute BRI beginning on January 1, 2020. We queried the electronic health record for patient demographics, insurance status, cause of injury, hospital arrival and discharge timestamps, discharge prescriptions, and documented instructions regarding wound care, pain management, and follow-up plans. We analyzed data using descriptive statistics and chi-square tests. Results: During the study period, 100 patients presented to the ED with an acute firearm injury. Patients were predominantly young (median age 29, interquartile range 23–38 years), male (86%), Black (85%), non-Hispanic (98%), and uninsured (70%). We found that 12% of patients did not receive any type of written wound care instruction, while 37% received discharge paperwork that included instructions to take both an NSAID and acetaminophen. Fifty-one percent of patients received an opioid prescription, with a range from 3–42 tablets (median 10 tablets). The proportion of patients receiving an opioid prescription was significantly higher among White patients (77%) than among Black patients (47%). Conclusion: There is variability in prescriptions and instructions provided to survivors of bullet injuries upon ED discharge at our institution. Our data indicates that standardized discharge protocols could improve quality of care and equity in the treatment of patients who have survived a BRI. Current variable quality in discharge planning is an entry point for structural racism and disparity.

Language acquisition requires infants’ ability to track dependencies between distant speech elements. Infants as young as 3 months have been shown to successfully identify such non-adjacent dependencies between syllables, and this ability has been related to the maturity of infants’ pitch processing. The present study tested whether 8- to 10-month-old infants (N = 68) can also learn dependencies at smaller segmental levels and whether the relation between dependency and pitch processing extends to other auditory features. Infants heard either syllable sequences encoding an item-specific dependency between non-adjacent vowels or between consonants. These frequent standard sequences were interspersed with infrequent intensity deviants and dependency deviants, which violated the non-adjacent relationship. Both vowel and consonant groups showed electrophysiological evidence for detection of the intensity manipulation. However, evidence for dependency learning was only found for infants hearing the dependencies across vowels, not consonants, and only in a subgroup of infants who had an above-average language score in a behavioral test. In a correlation analysis, we found no relation between intensity and dependency processing. We conclude that item-specific, segment-based non-adjacent dependencies are not easily learned by infants and if so, vowels are more accessible to the task, but only to infants who display advanced language skills.

Abstract In low-income countries, up to 80% of women diagnosed with cervical dysplasia do not return for follow-up care, primarily due to treatment being inaccessible. Here, we describe development of a low-cost, portable treatment suitable for such settings. It is based on injection of ethyl cellulose (EC)-ethanol to ablate the transformation zone around the os, the site most impacted by dysplasia. EC is a polymer that sequesters the ethanol within a prescribed volume when injected into tissue, and this is modulated by the injected volume and delivery parameters (needle gauge, bevel orientation, insertion rate, depth, and infusion rate). Salient injection-based delivery parameters were varied in excised swine cervices. The resulting injection distribution volume was imaged with a wide-field fluorescence imaging device or computed tomography. A 27G needle and insertion rate of 10 mm/s achieved the desired insertion depth in tissue. Orienting the needle bevel towards the outer edge of the cervix and keeping infusion volumes ≤ 500 µL minimized leakage into off-target tissue. These results guided development of a custom hand-held injector, which was used to locate and ablate the upper quadrant of a swine cervix in vivo with no adverse events or changes in host temperature or heart rate. After 24 h, a distinct region of necrosis was detected that covered a majority (> 75%) of the upper quadrant of the cervix, indicating four injections could effectively cover the full cervix. The work here informs follow up large animal in vivo studies, e.g. in swine, to further assess safety and efficacy of EC-ethanol ablation in the cervix.

OBJECTIVES:. Older age is a key risk factor for adverse outcomes in critically ill patients with COVID-19. However, few studies have investigated whether preexisting comorbidities and acute physiologic ICU factors modify the association between age and death. DESIGN:. Multicenter cohort study. SETTING:. ICUs at 68 hospitals across the United States. PATIENTS:. A total of 5,037 critically ill adults with COVID-19 admitted to ICUs between March 1, 2020, and July 1, 2020. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. The primary exposure was age, modeled as a continuous variable. The primary outcome was 28-day inhospital mortality. Multivariable logistic regression tested the association between age and death. Effect modification by the number of risk factors was assessed through a multiplicative interaction term in the logistic regression model. Among the 5,037 patients included (mean age, 60.9 yr [± 14.7], 3,179 [63.1%] male), 1,786 (35.4%) died within 28 days. Age had a nonlinear association with 28-day mortality (p for nonlinearity

ABSTRACT Inactivated influenza vaccines induce greater antibody responses in females than males among both humans and mice. To test the breadth of protection, we used recombinant mouse-adapted A/California/2009 (maA/Cal/09) H1N1 viruses containing mutations at one (1M), two (2M), or three (3M) antigenic sites, in addition to a virus containing the 1M mutation and a substitution of the Ca2 antigenic site (Sub) with one derived from an H5 hemagglutinin (HA) to challenge mice of both sexes. Following maA/Cal/09 vaccination, females produced greater virus-specific, class-switched total IgG and IgG2c antibodies against the vaccine and all mutant viruses, and antibodies from females recognized a greater number of unique, linear HA epitopes than did antibodies from males. While females had greater neutralizing antibody titers against the vaccine virus, both sexes showed a lower neutralization capacity against mutant viruses. After virus challenge, vaccinated females had lower pulmonary virus titers and reduced morbidity than males for the 1M and 2M viruses, but not the Sub virus. Females generated greater numbers of germinal center (GC) B cells containing superior somatic hypermutation (SHM) frequencies than vaccinated males. Deletion of activation-induced cytidine deaminase (Aicda) eliminated female-biased immunity and protection against the 2M virus. Harnessing methods to improve GC B cell responses and frequencies of SHM, especially in males, should be considered in the development of universal influenza vaccines. IMPORTANCE Adult females develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection would be dependent on the extent of virus diversity as well as molecular mechanisms in B cells which constrain the breadth of epitope recognition. We developed a panel of mouse-adapted (ma) A/Cal/09 viruses that had mutations in the immunodominant hemagglutinin. Following vaccination against maA/Cal/09, females were better able to neutralize maA/Cal/09 than males, but neutralization of mutant maA/Cal/09 viruses was equally poor in both sexes, despite vaccinated females being better protected against these viruses. Vaccinated females benefited from the greater production of class-switched, somatically hypermutated antibodies generated in germinal center B cells, which increased recognition of more diverse maA/Cal/09 hemagglutinin antigen epitopes. Female-biased protection against influenza infection and disease after vaccination is driven by differential mechanisms in males versus females and should be considered in the design of novel vaccine platforms.

With a steadily aging population there is an increasing prevalence of neurological disorders. Given the lack of effective treatment strategies and a limited ability for the central nervous system (CNS) to regenerate endogenously, there is a critical need to better understand exogenous strategies for nervous system repair. Stem cell therapy offers a promising approach to promote the repair of neurologic tissue and function, however studies to date have been limited by various factors including challenges in harvesting donor cells from the CNS, ethical concerns regarding use of embryonic or fetal tissue, tumorigenic potential of induced pluripotent stem cells, and immune-mediated rejection of non-autologous cell sources. Here we review and propose two alternative sources of autologous cells derived from the peripheral nervous system (PNS) for CNS repair: enteric neuronal stem cells (ENSCs) and neural crest-derived Schwann cells found in subcutaneous adipose tissue (termed SAT-NSCs). ENSCs can be successfully isolated from the postnatal enteric nervous system, propagated in vitro, and transplanted successfully into models of CNS injury via both direct intracerebral injection and systemic tail vein injection. Similarly, SAT-NSCs can be readily isolated from both human and mouse adipose tissue and, although not yet utilized in models of CNS injury, have successfully been transplanted and restored function in models of colonic aganglionosis and gastroparesis. These unique sources of PNS-derived autologous cells offer an exciting option for stem cell therapies for the CNS as they have proven neurogenic potential and eliminate concerns around tumorigenic risk, ethical considerations, and immune-mediated rejection.

Mouse sex chromosomes are enriched for co-amplified gene families, present in tens to hundreds of copies. Co-amplification of Slx/Slxl1 on the X chromosome and Sly on the Y chromosome are involved in dose-dependent meiotic drive, however the role of other co-amplified genes remains poorly understood. Here we demonstrate that the co-amplified gene family on the X chromosome, Srsx, along with two additional partial gene annotations, is actually part of a larger transcription unit, which we name Laidx. Laidx is harbored in a 229 kb amplicon that represents the ancestral state as compared to a 525 kb Y-amplicon containing the rearranged Laidy. Laidx contains a 25,011 nucleotide open reading frame, predominantly expressed in round spermatids, predicted to encode an 871 kD protein. Laidx has orthologous copies with the rat and also the 825-MY diverged parasitic Chinese liver fluke, Clonorchis sinensis, the likely result of a horizontal gene transfer of rodent Laidx to an ancestor of the liver fluke. To assess the male reproductive functions of Laidx, we generated mice carrying a multi-megabase deletion of the Laidx-ampliconic region. Laidx-deficient male mice do not show detectable reproductive defects in fertility, fecundity, testis histology, and offspring sex ratio. We speculate that Laidx and Laidy represent a now inactive X vs. Y chromosome conflict that occurred in an ancestor of present day mice.

BackgroundCaregivers face new challenges and tasks when their child is diagnosed with cancer, which can be overwhelming. Mobile technology has the capacity to provide immediate support at their fingertips to aid in tracking symptoms, managing medication, and planning for emergencies. ObjectiveThe objective of this study is to engage directly with end users and proxies to co-design and create a mobile technology app to support caregivers in the medical management of their child with cancer. MethodsWe engaged directly with caregivers of children with cancer and pediatric oncology nurse coordinators (proxy end users) to co-design and create the prototype of the Cope 360 mobile health app. Alpha testing was accomplished by walking the users through a series of predetermined tasks that encompassed all aspects of the app including tracking symptoms, managing medications, and planning or practicing for a medical emergency that required seeking care in the emergency department. Evaluation was accomplished through recorded semistructured interviews and quantitative surveys to capture demographic information and measure the system usability score. Interviews were transcribed and analyzed iteratively using NVivo (version 12; QSR International). ResultsThis study included 8 caregivers (aged 33-50 years) of children with cancer, with most children receiving chemotherapy, and 6 nurse coordinators, with 3 (50%) of them having 11 to 20 years of nursing experience. The mean system usability score given by caregivers was 89.4 (95% CI 80-98.8). Results were grouped by app function assessed with focus on specific attributes that were well received and those that required refinement. The major issues requiring refinement included clarity in the medical information and terminology, improvement in design of tasks, tracking of symptoms including adjusting the look and feel of certain buttons, and changing the visual graph used to monitor symptoms to include date anchors. ConclusionsThe Cope 360 app was well received by caregivers of children with cancer but requires further refinement for clarity and visual representation. After refinement, testing among caregivers in a real-world environment is needed to finalize the Cope 360 app before its implementation in a randomized controlled trial.

Introduction Common anesthesia practice for hand surgery combines a preoperative regional anesthetic and intraoperative monitored anesthesia care (MAC). Despite adequate regional anesthesia, patients may receive doses of intraoperative sedatives which can result in oversedation and potentially avoidable complications. VR could prove to be a valuable tool for patients and providers by distracting the mind from processing noxious stimuli resulting in minimized sedative use and reduced risk of oversedation without negatively impacting patient satisfaction. Our hypothesis was that intraoperative VR use reduces sedative dosing during elective hand surgery without detracting from patient satisfaction as compared to a usual care control. Methods Forty adults undergoing hand surgery were randomized to receive either intraoperative VR in addition to MAC, or usual MAC. Patients in both groups received preoperative regional anesthesia at provider discretion. Intraoperatively, the VR group viewed programming of their choice via a head-mounted display. The primary outcome was intraoperative propofol dose per hour (mg · hr-1). Secondary outcomes included patient reported pain and anxiety, overall satisfaction, functional outcome, and post anesthesia care unit (PACU) length of stay (LOS). Results Of the 40 enrolled patients, 34 completed the perioperative portion of the trial. VR group patients received significantly less propofol per hour than the control group (Mean (±SD): 125.3 (±296.0) vs 750.6 (±334.6) mg · hr-1, pConclusion VR immersion during hand surgery led to significant reductions in intraoperative propofol dose and PACU LOS without negatively impacting key patient reported outcomes.

BackgroundThe number of oral anticancer medications has increased over the past few decades, opening new possibilities in cancer care and improving convenience for patients and caregivers. However, adherence levels continue to be suboptimal, potentially jeopardizing therapeutic benefits. Poor adherence levels may indicate gaps in current strategies and interventions aimed at enhancing medication adherence and the extent to which they address the complex and multi-faceted medication management needs of patients and their caregivers. Beyond commonly understood barriers (e.g., forgetting to take medications), adherence interventions must address systemic barriers that may not be fully appreciated by members of the healthcare system. This scoping review aims to apply a systems framework (human factors engineering framework) to examine system elements targeted by adherence enhancing interventions.MethodsStudies published in English, reporting adherence interventions for oral anticancer medications with adherence and/or persistence as primary outcome measures will be included in this review. We will search the following electronic databases with no limits on dates: Ovid MEDLINE, Cochrane Library, Web of Science Core Collection, Embase, CINAHL Complete, PsycInfo, and Scopus. Two reviewers will independently screen study titles and abstracts for inclusion with a third reviewer adjudicating conflicts. Full text of included articles will be used to extract information on systemic barriers targeted by adherence interventions as well as information about intervention type, outcomes, and study characteristics. Extracted information will be synthesized to generate a summary of work system factors targeted by adherence interventions.DiscussionThrough application of a systems-based approach, this scoping review is expected to shed light on the complex and multifaceted nature of factors influencing adherence to oral anticancer agents. The review may also identify areas that are ripe for further research.

Abstract Background Application of an endorectal coil (ERC) for 3.0-T prostate magnetic resonance imaging (MRI) is contentious. We hypothesised that a multicoil phased-array protocol provides T2-weighted images (T2WI) and diffusion-weighted images (DWI) with reduced field-of-view (DWIreduced) and monoexponential apparent diffusion coefficient (ADC) maps that are technically equivalent with ERC or without ERC (noERC). Methods Axial T2WI (repetition time [TR] 7500 ms, echo time [TE] 98–101 ms) and DWIreduced (field-of-view 149–179 × 71–73 mm2, TR/TE 4500–5500/61–74 ms, b values, 50/800 s/mm2) ERC and noERC images were obtained on identical clinical 3.0-T scanners at two centres and compared for signal-to-noise ratio (SNR) in anterior and posterior outer pericarp (OP) and peripheral placenta (PP) in five green Hayward kiwifruit (Actinidia deliciosa, European Union regulation 543/2011 class 2). Corroboration in 21 patients with benign prostate hyperplasia (negative biopsy, prostate imaging reporting and data system version 2 ≤ 2) involved identical MRI protocols: 10 at site 1, noERC, and 11 at site 2, with ERC. Two-tailed Student’s t test was used. Results With few exceptions, signal-to-noise ratio (SNR) was similar in kiwifruits and prostates for ERC and noERC. In T2WI, SNR was higher posteriorly in noERC MRI for peripheral zone (PZ) (p

Leucine-rich repeat (LRR) domains are commonly present in immune regulatory proteins. Here the authors show that LRR exonic modularity and alternative splicing of an LRR-containing protein, NLRP3, modulate the ratio of functional/afunctional NLRP3 isoforms to instill a stochastic regulation of NLRP3-mediated inflammation and innate immunity.