bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Flame Describing Functions Measured in Single and Multiple Injector Configurations
Authors: Rajendram Soundararajan Preethi , Durox Daniel , Vignat Guillaume , Renaud Antoine , Beaunier Jérôme , Candel Sébastien
Published: September 2022

Recent investigations of combustion instabilities in annular systems indicate that considerable insights may be gained by using information gathered in single-sector experiments. Such experiments are, for example, employed to measure flame describing functions (FDFs), which represent the flame response to incident perturbations. These data may be used in combination with low-order models to interpret instabilities in multiple injector annular systems. It is known, however, that the structure and dynamical behavior of an isolated flame do not necessarily coincide with those of a flame placed in an annular environment with neighboring side flames. It is then worth analyzing effects that may be induced by the difference in lateral boundary conditions and specifically examining the extent to which the FDF data from single-sector experiments portrays the dynamical response of the flame in the annular environment. These issues are investigated with a new setup named TICCA-Spray, which comprises a linear arrangement of three injectors. The central flame is surrounded by two identical side flames in a rectangular geometry with key dimensions, sidewall separation, and spacing between injectors identical to those of the annular system MICCA-Spray. The describing function of the central flame is determined with techniques recently developed in single-sector experiments (SICCA-Spray). The FDFs obtained in the two configurations are compared for two swirler types having different swirl numbers and pressure drops. The effect of the swirl direction of the neighboring injectors is also explored by operating with co- and counter-swirl combinations. Differences between FDFs determined in the two test facilities, sometimes modest and in other cases less negligible, are found to depend on the flames' spatial extension and interactions. The general inference is that the FDFs measured in a single-injector combustor are better suited if the flame-wall interaction is weak, and provided that the area is equivalent to that of a single sector of an annular combustor. Nonetheless, using a multi-injector system would be more appropriate for a more precise FDF determination.
Investigation of Water Films Shed From an Airfoil in a High-Speed Flow
Authors: Esquivias Brandon , Hickey Brendan , McDonell Vincent , Tabata Soichiro , Senoo Shigeki
Published: September 2022

The breakup of liquid films in high-speed flows is found in many applications. These include prefilming air blast atomization found in fuel injectors and shedding of droplet off of airfoils. In this work, a test rig has been developed and applied to study the breakup of water films from the trailing edge of an NACA 0012 airfoil placed in a high-speed air flow. The results provided reflect a new detailed dataset focused on air velocities above 75 m/s. Computational fluid dynamic (CFD) simulations were used to guide the development of the rig and the associated boundary and inlet conditions. In this work, air velocities up to 175 m/s were used with water films between 0.4 cm2/s and 3.6 cm2/s. The water film was introduced onto one surface through a series of 0.5 mm holes separated by 1 mm at a location 35 mm downstream of the leading edge of the vane. High speed video was used to document the sheet breakup behavior from the edge of the airfoil. Image analysis was used to identify the breakup length of ligaments formed. Laser diffraction was used 50 mm downstream of the trailing edge of the vane to determine the droplet size distribution and associated representative average diameters generated. A series of test conditions were run between 50 m/s and 175 m/s using multilevel factorial designed experiments. The results obtained were subjected to analysis of variance to generate correlations for breakup length and droplet representative diameters as a function of the conditions studied. The analysis was conducted on dimensionless versions of the variables studied to help connect the results to the physics of the situation. For example, rather than using air velocity to correlate the behavior, the Weber number (based on gas phase density and velocity) was used owing to its historical ability to describe liquid breakup processes. The results obtained are compared with other studies in the literature, and good agreement was found for the conditions at which a comparison could be made. It is observed that, for the conditions studied, liquid film thickness has little effect on the resulting droplet sizes—especially for the higher air velocity cases studied. The results also illustrate the sensitivity to choice of the characteristic length, which is generally consisted of trailing edge geometry or boundary layer thickness. In contrast, liquid film does influence the ligament breakup length, although the time to break up is less affected. Overall, the correlations developed provide engineering tools to help estimate ligament and drop size behavior for water films shed from airfoils in a high-speed flow.
Design Methodology and Concept Demonstration of Preassembled Additively Manufactured Turbomachinery Systems: Case Study of Turbocharger Based Medical Ventilators
Authors: Çelik Acar , Linsky David , Miezner Ron , Kleiman Alex , Leizeronok Boris , Palman Michael , Acarer Sercan , Cukurel Beni
Published: September 2022

The present research focuses on analyzing the feasibility of manufacturing complex turbomachinery geometries in a pre-assembled manner through an uninterrupted additive manufacturing process, absent of internal support structures, or postprocessing. In the context of the present COVID-19 pandemic, the concept is illustrated by a three-dimensional (3D)-printable turbine-driven blower-type medical ventilator, which solely relies on availability of high-pressure oxygen supply and a conventional plastic-printer. Forming a fully pre-assembled turbomachine in its final form, the architecture consists of two concentric parts, a static casing with an embedded hydrostatic bearing surrounding a rotating monolithic shell structure that includes a radial turbine mechanically driving a centrifugal blower, which in turn supplies the oxygen enriched air to the lungs of the patient. Although the component level turbomachinery design of the described architecture relies on well-established guidelines and computational fluid dynamics methods, this approach has the capability to shift the focus of additive manufacturing methods to design for pre-assembled turbomachinery systems. Upon finalizing the topology, the geometry is manufactured from polyethylene terephthalate (PETG) plastic using a simple tabletop extrusion-based machine and its performance is evaluated in a test facility. The findings of the experimental campaign are reported in terms of flow and loading coefficients and are compared with simulation results. A good agreement is observed between the two data sets, thereby fully corroborating the applied design approach and the viability of additively manufactured pre-assembled turbomachines. Eliminating long and costly processes due to presence of numerous parts, different manufacturing methods, logistics of various subcontractors, and complex assembly procedures, the proposed concept has the potential to reduce the cost of a turbomachine to capital equipment depreciation and raw material.
Transient Nature of Flight and Its Impact on Thermal Management for All Electric Aircraft
Authors: Kasitz Joshua , Lad Aniket Ajay , Hoque Muhammad Jahidul , Miljkovic Nenad , Huitink David
Published: September 2022

High power electronics are a key component in the electrification of aircraft. Large amounts of power need to be handled onboard to generate sufficient lift for flight. The transient nature of the aircraft's mission profile produces varied loading and environmental influences, making consistent cooling and device reliability difficult to maintain. Due to limitations in weight and performance metrics, the thermal management capability becomes a key inhibiting factor in preventing adoption of all electric aircraft. Many efforts are focused on the improvement of high-powered electronics such as the inverters, batteries, and motors, but there is a need for increased focus on the implications of each improved device on the total system with regard to thermal management. To address the many concerns for thermal management within aviation, this paper will review the prevalent factors of flight and couple them to their respective challenges to highlight the overarching effort needed to successfully integrate efficient electric propulsion devices with their protective thermal management systems. A review will be combined with a brief analytical study over inverter cooling to examine the effects of various transient parameters on the device temperature of an inverter in flight. The impact of failure in the cooling systems on the shutdown process will also be examined. Both studies are tied to the motivation for examining the impacts of new and transient challenges faced by electric power systems and help signify the importance of this focus as these systems become more present and capable within the aviation industry.
Diagnosis and Prognosis of Fatigue Damage in Adhesively Bonded Joints Using Ultrasound Non-Destructive Evaluation
Authors: Palanisamy Rajendra P. , Banerjee Portia , Haq Mahmoodul , Deng Yiming
Published: September 2022

Increased effort for lightweighting of automotive structures results in the replacement of traditional metals with composites. Adhesive bonding is the best joining solution for composite components owing to its superior stress distribution and lightweighting. However, adhesive and adhesive-adhered interfaces are the weakest links in the structure. During fatigue crack propagation, joints do not show any significant visual changes. Thus, fatigue damage in adhesive bond lines is one of the challenging and complex failure mechanisms that requires real-time diagnostic and prognostic techniques to avoid any catastrophic failure. This paper proposes an acoustic technique for real-time fatigue damage diagnosis and prognosis. Based on experimental guided wave modal analysis, symmetric mode at 85 kHz is found to be the most sensitive mode–frequency combination for fatigue monitoring of selected lap-joint specimens. Further, a hybrid data-driven damage propagation model is used to estimate the remaining useful life in the bond line. The developed techniques were successfully implemented and validated on a single lap joint under fatigue loading. Estimated damage levels and remaining useful life are in good agreement with reference measurements. Successful validation is an indicator of the potential application of this technology in automotive industries.
Remotely Operated Vehicle Taxonomy and Emerging Methods of Inspection, Maintenance, and Repair Operations: An Overview and Outlook
Authors: Dalhatu Abdullahi Abba , Sa’ad Amir Muhammed , Cabral de Azevedo Ricardo , de Tomi Giorgio
Published: September 2022

Remotely operated vehicle (ROV)-based inspection, maintenance, and repairs (IMR) services are costly because operations are traditionally executed by a hired subsea contractor, who then hires a specialized vessel with an entire crew from the vessel owner or the shipping company. Even though this is an established method considered relatively reliable in comparison to human divers, there is a growing need for more versatile, efficient, and economical IMR methods. Innovations that require no or less use of support vessels are mitigating this challenge. The current ROV classifications do not adapt to these innovations. Hence, the lack of a widely accepted ROV classification. Thus, this paper reviews ROV classifications and proposes a classification that poses no hindrance to innovation and conforms to modern developments. The paper then illustrates and reviews the emerging methods of conducting IMR operations by putting together in a concise, yet resourceful manner the ROV technologies and their various configurations to provide a basic meaningful understanding to the audience. This paper also provides a summary of the comparison of the methods and some of their challenges.
DEVELOPING EFL TEACHERS IDENTITY: SOCIALIZING/EMPATHIZING SKILLS & CODESWITCHING FROM THE ACCULTURATORS ROLE
Authors:   UNIDAD EDUCATIVA CARDENAL SPELLMAN, Ramírez Basantes Raúl
Published: September 2022

Early experiences as a student become a cultural reference for English as a Foreign Language teachers. This background, along with tools and strategies gathered from training and teaching experience, shape roles that are constantly tested and negotiated within the classroom, developing an EFL teacher’s identity. The following is a case study on three EFL teachers’ identity development from the Pontificia Universidad Católica del Ecuador. EFL teaching roles were identified through semi-participant observation and compiled in an observation grid. The origin of the tools and strategies involved in the described roles was deepened using the biographical methodology through life-story interviews. The results show that Socializing / Empathizing skills from the Acculturator role were present on teachers that codeswitch using an Ecuadorian pitch during class, which allowed them to develop successful emotional transactions in the class. Previous working experience and training provided teachers with new tools and strategies for their EFL teaching roles. Role models that come from the family and the working context played a crucial role in the establishment of emotional tools that allowed teachers to negotiate roles within the class using low emotional labor. With emotional skills that allow to incorporate new tools and strategies with low emotional labor, teachers can build roles that later will be part of their EFL teacher’s identity.
Effect of lockdown amid second wave of COVID-19 on environmental noise scenario of the megacity Delhi, India
Authors: Kumar S. , Garg N. , Chauhan B. S. , Gautam C. , Chand T. , George M. P. , Jayachandran K. S.
Published: September 2022

This paper analyzes the impact of second wave of COVID-19 lockdown on environmental noise levels of 25 sites in Delhi city and compares the noise scenario during pre-lockdown, lockdown, and post-lockdown periods. The study utilized the noise monitoring data acquired from 25 real-time ambient noise monitoring stations, installed by the Delhi Pollution Control Committee, Delhi, at various sites throughout Delhi city. A significant reduction of up to 10 and 3 dB(A) in day and night equivalent noise levels, respectively, had been observed during the lockdown period as compared to the pre-lockdown and post-lockdown periods. The study also revealed that only nine sites, including four industrial and five commercial zone sites, complied with the ambient noise standards during lockdown period, and no silence or residential zone sites complied with the ambient noise standards even during the lockdown period. A roadmap for environmental noise management and control is suggested. The study also reports the community's perception toward the change in acoustic environment of Delhi city during the lockdown period by conducting an environmental noise perception survey. The present study should be helpful in devising noise control action plans and policy interventions for environmental noise management and control in the metropolitan city Delhi, India.
Radiation forces on highly reflecting circular cylinders in two slanted plane waves: Specular-reflection contributions
Authors: Marston Philip L. , Fortuner Auberry R.
Published: September 2022

Situations arise where it is desirable to understand and estimate the radiation force on large smooth highly reflecting objects in water illuminated by beams of ultrasound. The approach examined here is to extend a formulation experimentally confirmed by Herrey [J. Acoust. Soc. Am. 27, 891–896 (1955)] for tilted reflecting surfaces in fluids that are modeled as being inviscid. The formulation applies Brillouin's analysis of the Langevin-like radiation force on objects in open containers. The specular reflection contributions to the radiation force of two slanted plane waves incident on a rigid cylinder is approximated and compared with a full partial wave series (PWS) solution for an infinitely long cylinder in an inviscid fluid. The availability of the PWS solution gives support to approximations introduced in the geometric analysis, provided ka (the wave number-cylinder-radius product) is sufficiently large. The normalized force projection is plotted as a function of the wave slant angle relative to the symmetry axis. Deviations between the specular and PWS analysis for ka of 7.5 are diminished for ka of 15 and 25. A region of enhanced force associated with constructive interference narrows with increasing ka.
Modeling the effect of random roughness on synthetic aperture sonar image statistics
Authors: Lyons Anthony P. , Olson Derek R. , Hansen Roy E.
Published: September 2022

A model has been developed to predict the effect of random seafloor roughness on synthetic aperture sonar (SAS) image statistics, based on the composite roughness approximation–a physical scattering model. The continuous variation in scattering strength produced by a random slope field is treated as an intensity scaling on the image speckle produced by the coherent SAS imaging process. Changes in image statistics caused by roughness are quantified in terms of the scintillation index (SI). Factors influencing the SI include the seafloor slope variance, geo-acoustic properties of the seafloor, the probability density function describing the speckle, and the signal-to-noise ratio. Example model-data comparisons are shown for SAS images taken at three different sites using three different high-frequency SAS systems. Agreement between the modeled and measured SI show that it is possible to link range-dependent image statistics to measurable geo-acoustic properties, providing the foundation necessary for solving problems related to the detection of targets using high-frequency imaging sonars, including performance prediction or adaptation of automated detection algorithms. Additionally, this work illustrates the possible use of SAS systems for remote sensing of roughness parameters such as root mean square slope or height.
Adding noise is a confounded nuisance
Authors: Francis Alexander L.
Published: September 2022

A wide variety of research and clinical assessments involve presenting speech stimuli in the presence of some kind of noise. Here, I selectively review two theoretical perspectives and discuss ways in which these perspectives may help researchers understand the consequences for listeners of adding noise to a speech signal. I argue that adding noise changes more about the listening task than merely making the signal more difficult to perceive. To fully understand the effects of an added noise on speech perception, we must consider not just how much the noise affects task difficulty, but also how it affects all of the systems involved in understanding speech: increasing message uncertainty, modifying attentional demand, altering affective response, and changing motivation to perform the task.
scAllele: A versatile tool for the detection and analysis of variants in scRNA-seq
Authors: Quinones-Valdez Giovanni , Fu Ting , Chan Tracey W. , Xiao Xinshu
Published: September 2022

Single-cell RNA sequencing (scRNA-seq) data contain rich information at the gene, transcript, and nucleotide levels. Most analyses of scRNA-seq have focused on gene expression profiles, and it remains challenging to extract nucleotide variants and isoform-specific information. Here, we present scAllele, an integrative approach that detects single-nucleotide variants, insertions, deletions, and their allelic linkage with splicing patterns in scRNA-seq. We demonstrate that scAllele achieves better performance in identifying nucleotide variants than other commonly used tools. In addition, the read-specific variant calls by scAllele enables allele-specific splicing analysis, a unique feature not afforded by other methods. Applied to a lung cancer scRNA-seq dataset, scAllele identified variants with strong allelic linkage to alternative splicing, some of which are cancer specific and enriched in cancer-relevant pathways. scAllele represents a versatile tool to uncover multilayer information and previously unidentified biological insights from scRNA-seq data.
Seasonal changes in day length induce multisynaptic neurotransmitter switching to regulate hypothalamic network activity and behavior
Authors: Porcu Alessandra , Nilsson Anna , Booreddy Sathwik , Barnes Samuel A. , Welsh David K. , Dulcis Davide
Published: September 2022

Seasonal changes in day length (photoperiod) affect numerous physiological functions. The suprachiasmatic nucleus (SCN)–paraventricular nucleus (PVN) axis plays a key role in processing photoperiod-related information. Seasonal variations in SCN and PVN neurotransmitter expression have been observed in humans and animal models. However, the molecular mechanisms by which the SCN-PVN network responds to altered photoperiod is unknown. Here, we show in mice that neuromedin S (NMS) and vasoactive intestinal polypeptide (VIP) neurons in the SCN display photoperiod-induced neurotransmitter plasticity. In vivo recording of calcium dynamics revealed that NMS neurons alter PVN network activity in response to winter-like photoperiod. Chronic manipulation of NMS neurons is sufficient to induce neurotransmitter switching in PVN neurons and affects locomotor activity. Our findings reveal previously unidentified molecular adaptations of the SCN-PVN network in response to seasonality and the role for NMS neurons in adjusting hypothalamic function to day length via a coordinated multisynaptic neurotransmitter switching affecting behavior.
A red nucleus–VTA glutamate pathway underlies exercise reward and the therapeutic effect of exercise on cocaine use
Authors: He Yi , Madeo Graziella , Liang Ying , Zhang Cindy , Hempel Briana , Liu Xiaojie , Mu Lianwei , Liu Shui , Bi Guo-Hua , Galaj Ewa , Zhang Hai-Ying , Shen Hui , McDevitt Ross A. , Gardner Eliot L. , Liu Qing-song , Xi Zheng-Xiong
Published: September 2022

Physical exercise is rewarding and protective against drug abuse and addiction. However, the neural mechanisms underlying these actions remain unclear. Here, we report that long-term wheel-running produced a more robust increase in c-fos expression in the red nucleus (RN) than in other brain regions. Anatomic and functional assays demonstrated that most RN magnocellular portion (RNm) neurons are glutamatergic. Wheel-running activates a subset of RNm glutamate neurons that project to ventral tegmental area (VTA) dopamine neurons. Optogenetic stimulation of this pathway was rewarding, as assessed by intracranial self-stimulation and conditioned place preference, whereas optical inhibition blocked wheel-running behavior. Running wheel access decreased cocaine self-administration and cocaine seeking during extinction. Last, optogenetic stimulation of the RNm-to-VTA glutamate pathway inhibited responding to cocaine. Together, these findings indicate that physical exercise activates a specific RNm-to-VTA glutamatergic pathway, producing exercise reward and reducing cocaine intake.
An extra-clock ultradian brain oscillator sustains circadian timekeeping
Authors: Tang Min , Cao Li-Hui , Yang Tian , Ma Si-Xing , Jing Bi-Yang , Xiao Na , Xu Shuang , Leng Kang-Rui , Yang Dong , Li Meng-Tong , Luo Dong-Gen
Published: September 2022

The master circadian clock generates 24-hour rhythms to orchestrate daily behavior, even running freely under constant conditions. Traditionally, the master clock is considered self-sufficient in sustaining free-running timekeeping via its cell-autonomous molecular clocks and interneuronal communications within the circadian neural network. Here, we find a set of bona fide ultradian oscillators in the
Drosophila
brain that support free-running timekeeping, despite being located outside the master clock circuit and lacking clock gene expression. These extra-clock electrical oscillators (xCEOs) generate cell-autonomous ultradian bursts, pacing widespread burst firing and promoting rhythmic resting membrane potentials in clock neurons via parallel monosynaptic connections. Silencing xCEOs disrupts daily electrical rhythms in clock neurons and impairs cycling of neuropeptide pigment dispersing factor, leading to the loss of free-running locomotor rhythms. Together, we conclude that the master clock is not self-sufficient to sustain free-running behavior rhythms but requires additional endogenous inputs to the clock from the extra-clock ultradian brain oscillators.
Structure of the vasopressin hormone–V2 receptor–β-arrestin1 ternary complex
Authors: Bous Julien , Fouillen Aurélien , Orcel Hélène , Trapani Stefano , Cong Xiaojing , Fontanel Simon , Saint-Paul Julie , Lai-Kee-Him Joséphine , Urbach Serge , Sibille Nathalie , Sounier Rémy , Granier Sébastien , Mouillac Bernard , Bron Patrick
Published: September 2022

Arrestins interact with G protein–coupled receptors (GPCRs) to stop G protein activation and to initiate key signaling pathways. Recent structural studies shed light on the molecular mechanisms involved in GPCR-arrestin coupling, but whether this process is conserved among GPCRs is poorly understood. Here, we report the cryo–electron microscopy active structure of the wild-type arginine-vasopressin V2 receptor (V2R) in complex with β-arrestin1. It reveals an atypical position of β-arrestin1 compared to previously described GPCR-arrestin assemblies, associated with an original V2R/β-arrestin1 interface involving all receptor intracellular loops. Phosphorylated sites of the V2R carboxyl terminus are clearly identified and interact extensively with the β-arrestin1 N-lobe, in agreement with structural data obtained with chimeric or synthetic systems. Overall, these findings highlight a notable structural variability among GPCR-arrestin signaling complexes.
Genome-wide in vivo screen of circulating tumor cells identifies
SLIT2
as a regulator of metastasis
Authors: Xia Fan , Ma Yuan , Chen Kangfu , Duong Bill , Ahmed Sharif , Atwal Randy , Philpott David , Ketela Troy , Pantea Jennifer , Lin Sichun , Angers Stephane , Kelley Shana O.
Published: September 2022

Circulating tumor cells (CTCs) break free from primary tumors and travel through the circulation system to seed metastatic tumors, which are the major cause of death from cancer. The identification of the major genetic factors that enhance production and persistence of CTCs in the bloodstream at a whole genome level would enable more comprehensive molecular mechanisms of metastasis to be elucidated and the identification of novel therapeutic targets, but this remains a challenging task due to the heterogeneity and extreme rarity of CTCs. Here, we describe an in vivo genome-wide CRISPR knockout screen using CTCs directly isolated from a mouse xenograft. This screen elucidated
SLIT2
—a gene encoding a secreted protein acting as a cellular migration cue—as the most significantly represented gene knockout in the CTC population.
SLIT2
knockout cells are highly metastatic with hypermigratory and mesenchymal phenotype, resulting in enhanced cancer progression in xenograft models.
Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice
Authors: Landry David A. , Yakubovich Edward , Cook David P. , Fasih Sijyl , Upham Jeremy , Vanderhyden Barbara C.
Published: September 2022

Ovarian fibrosis is a pathological condition associated with aging and is responsible for a variety of ovarian dysfunctions. Given the known contributions of tissue fibrosis to tumorigenesis, it is anticipated that ovarian fibrosis may contribute to ovarian cancer risk. We recently reported that diabetic postmenopausal women using metformin had ovarian collagen abundance and organization that were similar to premenopausal ovaries from nondiabetic women. In this study, we investigated the effects of aging and metformin on mouse ovarian fibrosis at a single-cell level. We discovered that metformin treatment prevented age-associated ovarian fibrosis by modulating the proportion of fibroblasts, myofibroblasts, and immune cells. Senescence-associated secretory phenotype (SASP)–producing fibroblasts increased in aged ovaries, and a unique metformin-responsive subpopulation of macrophages emerged in aged mice treated with metformin. The results demonstrate that metformin can modulate specific populations of immune cells and fibroblasts to prevent age-associated ovarian fibrosis and offers a new strategy to prevent ovarian fibrosis.
Evolution of a chordate-specific mechanism for myoblast fusion
Authors: Zhang Haifeng , Shang Renjie , Kim Kwantae , Zheng Wei , Johnson Christopher J. , Sun Lei , Niu Xiang , Liu Liang , Zhou Jingqi , Liu Lingshu , Zhang Zheng , Uyeno Theodore A. , Pei Jimin , Fissette Skye D. , Green Stephen A. , Samudra Sukhada P. , Wen Junfei , Zhang Jianli , Eggenschwiler Jonathan T. , Menke Douglas B. , Bronner Marianne E. , Grishin Nick V. , Li Weiming , Ye Kaixiong , Zhang Yang , Stolfi Alberto , Bi Pengpeng
Published: September 2022

Vertebrate myoblast fusion allows for multinucleated muscle fibers to compound the size and strength of mononucleated cells, but the evolution of this important process is unknown. We investigated the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here, we report that
Myomaker
likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while
Myomixer
appears to have evolved de novo in early vertebrates. Functional tests revealed a complex evolutionary history of myoblast fusion. A prevertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Evolutionary comparisons between vertebrate and nonvertebrate Myomaker revealed key structural and mechanistic insights into myoblast fusion. Thus, our findings suggest an evolutionary model of chordate fusogens and illustrate how new genes shape the emergence of novel morphogenetic traits and mechanisms.
Rhythmicity of intestinal IgA responses confers oscillatory commensal microbiota mutualism
Authors: Penny Hugo A. , Domingues Rita G. , Krauss Maria Z. , Melo-Gonzalez Felipe , Lawson Melissa A. E. , Dickson Suzanna , Parkinson James , Hurry Madeleine , Purse Catherine , Jegham Emna , Godinho-Silva Cristina , Rendas Miguel , Veiga-Fernandes Henrique , Bechtold David A. , Grencis Richard K. , Toellner Kai-Michael , Waisman Ari , Swann Jonathan R. , Gibbs Julie E. , Hepworth Matthew R.
Published: September 2022

Interactions between the mammalian host and commensal microbiota are enforced through a range of immune responses that confer metabolic benefits and promote tissue health and homeostasis. Immunoglobulin A (IgA) responses directly determine the composition of commensal species that colonize the intestinal tract but require substantial metabolic resources to fuel antibody production by tissue-resident plasma cells. Here, we demonstrate that IgA responses are subject to diurnal regulation over the course of a circadian day. Specifically, the magnitude of IgA secretion, as well as the transcriptome of intestinal IgA
+
plasma cells, was found to exhibit rhythmicity. Oscillatory IgA responses were found to be entrained by time of feeding and were also found to be in part coordinated by the plasma cell–intrinsic circadian clock via deletion of the master clock gene
Arntl
. Moreover, reciprocal interactions between the host and microbiota dictated oscillatory dynamics among the commensal microbial community and its associated transcriptional and metabolic activity in an IgA-dependent manner. Together, our findings suggest that circadian networks comprising intestinal IgA, diet, and the microbiota converge to align circadian biology in the intestinal tract and to ensure host-microbial mutualism.
Robustness of reported postacute health outcomes in children with SARS-CoV-2 infection: a systematic review
Authors: Hirt Julian , Janiaud Perrine , Gloy Viktoria Luise , Schandelmaier Stefan , Pereira Tiago V , Contopoulos-Ioannidis Despina , Goodman Steven N , Ioannidis John , Munkholm Klaus , Hemkens Lars G
Published: September 2022

Objective

To systematically assess the robustness of reported postacute SARS-CoV-2 infection health outcomes in children.

Methods

A search on PubMed and Web of Science was conducted to identify studies published up to 22 January 2022 that reported on postacute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, as well as the risk of bias.

Results

21 studies including 81 896 children reported up to 97 symptoms with follow-up periods of 2.0–11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16 986) and between 2.0% and 53.3% in children without SARS-CoV-2 infection (n=64 910). Only two studies made a clear causal interpretation of an association between SARS-CoV-2 infection and the main outcome of ‘post-COVID syndrome’ and provided recommendations regarding prevention measures. The robustness of all 21 studies was seriously limited due to an overall critical risk of bias.

Conclusions

The robustness of reported postacute SARS-CoV-2 infection health outcomes in children is seriously limited, at least in all the published articles we could identify. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on postacute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care.
Risk factors for knee osteoarthritis after traumatic knee injury: a systematic review and meta-analysis of randomised controlled trials and cohort studies for the OPTIKNEE Consensus
Authors: Whittaker Jackie L , Losciale Justin M , Juhl Carsten B , Thorlund Jonas Bloch , Lundberg Matilde , Truong Linda K , Miciak Maxi , van Meer Belle Lore , Culvenor Adam G , Crossley Kay M , Roos Ewa M , Lohmander Stefan , van Middelkoop Marienke
Published: September 2022

Objective

To identify and quantify potential risk factors for osteoarthritis (OA) following traumatic knee injury.

Design

Systematic review and meta-analyses that estimated the odds of OA for individual risk factors assessed in more than four studies using random-effects models. Remaining risk factors underwent semiquantitative synthesis. The modified GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach for prognostic factors guided the assessment.

Data sources

MEDLINE, EMBASE, CENTRAL, SPORTDiscus, CINAHL searched from inception to 2009–2021.

Eligibility

Randomised controlled trials and cohort studies assessing risk factors for symptomatic or structural OA in persons with a traumatic knee injury, mean injury age ≤30 years and minimum 2-year follow-up.

Results

Across 66 included studies, 81 unique potential risk factors were identified. High risk of bias due to attrition or confounding was present in 64% and 49% of studies, respectively. Ten risk factors for structural OA underwent meta-analysis (sex, rehabilitation for anterior cruciate ligament (ACL) tear, ACL reconstruction (ACLR), ACLR age, ACLR body mass index, ACLR graft source, ACLR graft augmentation, ACLR+cartilage injury, ACLR+partial meniscectomy, ACLR+total medial meniscectomy). Very-low certainty evidence suggests increased odds of structural OA related to ACLR+cartilage injury (OR=2.31; 95% CI 1.35 to 3.94), ACLR+partial meniscectomy (OR=1.87; 1.45 to 2.42) and ACLR+total medial meniscectomy (OR=3.14; 2.20 to 4.48). Semiquantitative syntheses identified moderate-certainty evidence that cruciate ligament, collateral ligament, meniscal, chondral, patellar/tibiofemoral dislocation, fracture and multistructure injuries increase the odds of symptomatic OA.

Conclusion

Moderate-certainty evidence suggests that various single and multistructure knee injuries (beyond ACL tears) increase the odds of symptomatic OA. Risk factor heterogeneity, high risk of bias, and inconsistency in risk factors and OA definition make identifying treatment targets for preventing post-traumatic knee OA challenging.
Percutaneous coronary intervention in calcified stenoses: a protocol for a systematic review with meta-analysis, trial sequential analysis and network meta-analysis
Authors: Torp Kristensen Andreas , Jakobsen Janus C , Olsen Niels Thue
Published: September 2022

Introduction

Severely calcified coronary stenoses are difficult to treat with percutaneous coronary interventions. The presence of severe calcifications complicates lesion preparation, advancement of stents and achievement of full stent expansion. Intervention in these lesions is associated with an increased risk of complications and procedural failure compared with treatment of less calcified lesions. Due to the high burden of comorbidity, patients with severely calcified lesions are often excluded from interventional trials, and there is little evidence on how to treat these patients.

Methods and analysis

We will conduct a systematic review of randomised trials enrolling patients with calcified coronary artery disease undergoing percutaneous coronary intervention. We will investigate any percutaneous treatment option including any lesion preparation, stenting or postdilatation technique. We will search The Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, and Excerpta Medica database for studies from inception to 31 October 2022. The coprimary outcome is all-cause mortality and serious adverse events. If appropriate, we will conduct meta-analysis, trial sequential analysis and network meta-analysis.

Ethics and dissemination

No ethics approval is required for this study. The results will be published in a peer-reviewed journal in this field.

PROSPERO registration number

CRD42021226034.
Membrane anchored IL-18 linked to constitutively active TLR4 and CD40 improves human T cell antitumor capacities for adoptive cell therapy
Authors: Blokon-Kogan Dayana , Levi-Mann Maya , Malka-Levy Lior , Itzhaki Orit , Besser Michal J , Shiftan Yuval , Szöőr Árpád , Vereb György , Gross Gideon , Abken Hinrich , Weinstein-Marom Hadas
Published: September 2022

Background

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or blood T cells genetically redirected by an antitumor TCR or CAR induces a strong antitumor response in a proportion of patients with cancer; however, the therapeutic efficacy is often limited by rapid decline in T cell functions. Coadministering supportive cytokines frequently provokes systemic side effects preventing their broad clinical application. We recently showed that cytokines can be anchored to the cell membrane in a functional fashion and that cytokine receptor signaling can synergize with TLR4 and CD40 signaling. Here, we aimed at augmenting T cell activation by simultaneous signaling through the cytokine receptor, toll-like receptor and TNF-type receptor using IL-18, TLR4 and CD40 as prototypes.

Methods

Genes were expressed on electroporation of in vitro-transcribed mRNA in CD4+and CD8+T cells from healthy donors redirected against melanoma cells with an anti-melanotransferrin CAR and in TILs derived from melanoma patients. Functional assays included the activation of signaling pathways, expression of activation and differentiation markers, cytokine secretion and killing of melanoma target cells.

Results

To provide IL-18 costimulation to T cells in-cis while avoiding systemic effects, we genetically anchored IL-18 to the T cell membrane, either alone (memIL-18) or fused with constitutively active (ca)TLR4 and caCD40 signaling domains arranged in tandem, creating a synthetic ‘all-in-one’ memIL-18-TLR4-CD40 receptor. MemIL-18-TLR4-CD40, but not memIL-18, triggered strong NF-κB activation in cells lacking the IL-18 receptor, attesting to functionality of the TLR-CD40 moiety. While the membrane-anchored cytokine was found to act mainly in-cis, some T cell activation in-trans was also observed. The electroporated T cells exhibited spontaneous T-bet upregulation and IFN-γ and TNF-α secretion. Melanoma-induced activation of CAR-T cells and TILs as manifested by cytokine secretion and cytolytic activity was substantially augmented by both constructs, with memIL-18-TLR4-CD40 exerting stronger effects than memIL-18 alone.

Conclusions

Linking membrane anchored IL-18 with caTLR4 and caCD40 signaling in one hybrid transmembrane protein provides simultaneous activation of three T cell costimulatory pathways through one genetically engineered membrane molecule, strongly amplifying T cell functions for adoptive T cell therapy of cancer.
Effect of CD4+ T cell count on treatment-emergent adverse events among patients with and without HIV receiving immunotherapy for advanced cancer
Authors: Odeny Thomas A , Lurain Kathryn , Strauss Julius , Fling Steven P , Sharon Elad , Wright Anna , Martinez-Picado Javier , Moran Teresa , Gulley James L , Gonzalez-Cao Maria , Uldrick Thomas S , Yarchoan Robert , Ramaswami Ramya
Published: September 2022

Background

The Food and Drug Administration recommends that people living with HIV (PWH) with a CD4+ T cell count (CD4) ≥350 cells/µL may be eligible for any cancer clinical trial, but there is reluctance to enter patients with lower CD4 counts into cancer studies, including immune checkpoint inhibitor (ICI) studies. Patients with relapsed or refractory cancers may have low CD4 due to prior cancer therapies, irrespective of HIV status. It is unclear how baseline CD4 prior to ICI impacts the proportion of treatment-emergent adverse events (TEAE) and whether it differs by HIV status in ICI treated patients.

Methods

We conducted a pilot retrospective cohort study of participants eligible for ICI for advanced cancers from three phase 1/2 trials in the USA and Spain. We determined whether baseline CD4 counts differed by HIV status and whether the effect of CD4 counts on incidence of TEAE was modified by HIV status using a multivariable logistic regression model.

Results

Of 122 participants, 66 (54%) were PWH who received either pembrolizumab or durvalumab and 56 (46%) were HIV-negative who received bintrafusp alfa. Median CD4 at baseline was 320 cells/µL (IQR 210–495) among PWH and 356 cells/µL (IQR 260–470) among HIV-negative participants (p=0.5). Grade 3 or worse TEAE were recorded among 7/66 (11%) PWH compared with 7/56 (13%) among HIV-negative participants. When adjusted for prior therapies, age, sex, and race, the effect of baseline CD4 on incidence of TEAE was not modified by HIV status for any TEAE (interaction term p=0.7), or any grade ≥3 TEAE (interaction term p=0.1).

Conclusions

There was no significant difference in baseline CD4 or the proportions of any TEAE and grade ≥3 TEAE by HIV status. CD4 count thresholds for cancer clinical trials should be carefully reviewed to avoid unnecessarily excluding patients with HIV and cancer.
Statins and immune checkpoint inhibitors: a strategy to improve the efficacy of immunotherapy for cancer?
Authors: Vos Winnie G , Lutgens Esther , Seijkens Tom T P
Published: September 2022

In the past decade, immune checkpoint inhibitor (ICI) therapy significantly improved the prognosis of patients with cancer. Despite impressive and often unprecedented response rates, a significant portion of the patients fails to benefit from this treatment. Additional strategies to improve ICI efficacy are therefore needed. The widespread clinical use of ICIs has increased our knowledge on the effects of the concomitant use of commonly prescribed drugs on the outcome of ICI treatment. A particular interesting class of drugs in this context are statins. These HMG-CoA reductase inhibitors, which are used to treat hypercholesterolemia and reduce the risk for atherosclerotic cardiovascular disease, are frequently used by patients with (advanced) cancer. This paper addresses the hypothesis that statins improve the efficacy of ICI therapy.
LDL-C levels, lipid-lowering treatment and recurrent stroke in minor ischaemic stroke or TIA
Authors: Pan Yuesong , Wangqin Runqi , Li Hao , Jin Aoming , Li Jiejie , Lin Jinxi , Meng Xia , Xian Ying , Laskowitz Daniel T , Wang Yongjun
Published: September 2022

Background and purpose

Dyslipidaemia is a major risk factor for ischaemic stroke and transient ischaemic attack (TIA). This study aimed to investigate the association between baseline low-density lipoprotein cholesterol (LDL-C) level, lipid-lowering treatment and short-term risk of new stroke in patients with a minor ischaemic stroke or TIA.

Methods

We derived data from the Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events trial. Patients with a minor stroke or TIA were categorised by LDL-C level at baseline (<2.6 or ≥2.6 mmol/L (100 mg/dL)) and with or without lipid-lowering treatment after symptom onset. The primary outcome was a new ischaemic stroke at 3 months. The association of baseline LDL-C level, lowering treatment and outcomes were assessed.

Results

Among 3027 patients, 2154 (71.2%) patients had an initial LDL-C ≥2.6 mmol/L, of which 1267 (41.9%) received lipid-lowering treatment. Elevated LDL-C level was associated with a higher risk of new ischaemic stroke at 3 months in patients without lipid-lowering treatment (adj.HR=1.35, 95% CI: 1.19 to 1.53), but not in those with lipid-lowering treatment (adj.HR=0.99, 95% CI: 0.82 to 1.19) (p for interaction=0.007). Patients with LDL-C ≥2.6 mmol/L had a numerically higher risk of ischaemic stroke (11.8% vs 8.0%, adj.HR=1.37, 95% CI: 0.96 to 1.96) in those without lipid-lowering treatment. For patients with LDL-C ≥2.6 mmol/L, lipid-lowering treatment was associated with reduced risk of ischaemic stroke at 3 months (7.9% vs 11.8%; adj.HR=0.54, 95% CI: 0.39 to 0.75).

Conclusions

Elevated untreated baseline LDL-C level was associated with an increased short-term risk of ischaemic stroke among patients presenting with minor ischaemic stroke or TIA. There was potential benefit of lipid-lowering treatment in minor stroke or TIA patients with LDL-C ≥2.6 mmol/L.

Trial registration number

NCT00979589.