bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood product resuscitation mitigates the effects of aeromedical evacuation after polytrauma
Authors: Wallen Taylor E. , Singer Kathleen E. , Morris Mackenzie C. , Blakeman Thomas , Stevens-Topie Sabre M. , Strilka Richard , Pritts Timothy A. , Goodman Michael D.
Published: October 2021

BACKGROUND

The combined injury of traumatic brain injury and hemorrhagic shock has been shown to worsen coagulopathy and systemic inflammation, thereby increasing posttraumatic morbidity and mortality. Aeromedical evacuation to definitive care may exacerbate postinjury morbidity because of the inherent hypobaric hypoxic environment. We hypothesized that blood product resuscitation may mitigate the adverse physiologic effects of postinjury flight.

METHODS

An established porcine model of controlled cortical injury was used to induce traumatic brain injury. Intracerebral monitors were placed to record intracranial pressure, brain tissue oxygenation, and cerebral perfusion. Each of the 42 pigs was hemorrhaged to a goal mean arterial pressure of 40 ± 5 mm Hg for 1 hour. Pigs were grouped according to resuscitation strategy used—Lactated Ringer's (LR) or shed whole blood (WB)—then placed in an altitude chamber for 2 hours at ground, 8,000 ft, or 22,000 ft, and then observed for 4 hours. Hourly blood samples were analyzed for proinflammatory cytokines and lactate. Internal jugular vein blood flow was monitored continuously for microbubble formation with altitude changes.

RESULTS

Cerebral perfusion, tissue oxygenation, and intracranial pressure were unchanged among the six study groups. Venous microbubbles were not observed even with differing altitude or resuscitation strategy. Serum lactate levels from hour 2 of flight to the end of observation were significantly elevated in 22,000 + LR compared with 8,000 + LR and 22,000 + WB. Serum IL-6 levels were significantly elevated in 22,000 + LR compared with 22,000 + WB, 8,000 + LR and ground+LR at hour 1 of observation. Serum tumor necrosis factor-α was significantly elevated at hour 2 of flight in 8,000 + LR versus ground+LR, and in 22,000 + LR vs. 22,000 + WB at hour 1 of observation. Serum IL-1β was significantly elevated hour 1 of flight between 8,000 + LR and ground+LR.

CONCLUSION

Crystalloid resuscitation during aeromedical transport may cause a prolonged lactic acidosis and proinflammatory response that can predispose multiple-injury patients to secondary cellular injury. This physiologic insult may be prevented by using blood product resuscitation strategies.
Nonlinear effects in memristors with mobile vacancies
Authors: Boylo I. V. , Metlov K. L.
Published: October 2021

Because local concentration of vacancies in any material is bounded, their motion must be accompanied by nonlinear effects. Here, we look for such effects in a simple model for electric field-driven vacancy motion in a memristor, solving the corresponding nonlinear Burgers’ equation with impermeable nonlinear boundary conditions exactly. We find non-monotonous relaxation of the resistance while switching between the stable (‘on’ and ‘off’) states, and qualitatively different dependencies of switching time (under applied current) and relaxation time (under no current) on the memristor length. Our solution can serve as a useful benchmark for simulations of more complex memristor models.
The original Wigner’s friend paradox within a realist toy model
Authors: Lostaglio Matteo , Bowles Joseph
Published: October 2021

The original Wigner’s friend paradox is a gedankenexperiment involving an observer described by an external agent. The paradox highlights the tension between unitary evolution and collapse in quantum theory, and is sometimes taken as requiring a reassessment of the notion of objective reality. In this note, however, we present a classical toy model in which (i) the contradicting predictions at the heart of the thought experiment are reproduced (ii) every system is in a well-defined state at all times. The toy model shows how puzzles such as Wigner’s friend’s experience of being in a superposition, conflicts between different agents’ descriptions of the experiment, the positioning of the Heisenberg’s cut and the apparent lack of objectivity of measurement outcomes can be explained within a classical model where there exists an objective state of affairs about every physical system at all times. Within the model, the debate surrounding the original Wigner’s friend thought experiment and its resolution have striking similarities with arguments concerning the nature of the second law of thermodynamics. The same conclusion however does not apply to more recent extensions of the gedankenexperiment featuring multiple encapsulated observers, and shows that such extensions are indeed necessary avoid simple classical explanations.
Cost efficiency of institutional incentives for promoting cooperation in finite populations
Authors: Duong Manh Hong , Han The Anh
Published: October 2021

Institutions can provide incentives to enhance cooperation in a population where this behaviour is infrequent. This process is costly, and it is thus important to optimize the overall spending. This problem can be mathematically formulated as a multi-objective optimization problem where one wishes to minimize the cost of providing incentives while ensuring a minimum level of cooperation, sustained over time. Prior works that consider this question usually omit the stochastic effects that drive population dynamics. In this paper, we provide a rigorous analysis of this optimization problem, in a finite population and stochastic setting, studying both pairwise and multi-player cooperation dilemmas. We prove the regularity of the cost functions for providing incentives over time, characterize their asymptotic limits (infinite population size, weak selection and large selection) and show exactly when reward or punishment is more cost efficient. We show that these cost functions exhibit a phase transition phenomenon when the intensity of selection varies. By determining the critical threshold of this phase transition, we provide exact calculations for the optimal cost of the incentive, for any given intensity of selection. Numerical simulations are also provided to demonstrate analytical observations. Overall, our analysis provides for the first time a selection-dependent calculation of the optimal cost of institutional incentives (for both reward and punishment) that guarantees a minimum level of cooperation over time. It is of crucial importance for real-world applications of institutional incentives since the intensity of selection is often found to be non-extreme and specific for a given population.
Immune lag is a major cost of prokaryotic adaptive immunity during viral outbreaks
Authors: Weissman JL , Alseth Ellinor O. , Meaden Sean , Westra Edze R. , Fuhrman Jed A.
Published: October 2021

Clustered regularly interspaced short palindromic repeat (CRISPR)-Cas adaptive immune systems enable bacteria and archaea to efficiently respond to viral pathogens by creating a genomic record of previous encounters. These systems are broadly distributed across prokaryotic taxa, yet are surprisingly absent in a majority of organisms, suggesting that the benefits of adaptive immunity frequently do not outweigh the costs. Here, combining experiments and models, we show that a delayed immune response which allows viruses to transiently redirect cellular resources to reproduction, which we call ‘immune lag’, is extremely costly during viral outbreaks, even to completely immune hosts. Critically, the costs of lag are only revealed by examining the early, transient dynamics of a host–virus system occurring immediately after viral challenge. Lag is a basic parameter of microbial defence, relevant to all intracellular, post-infection antiviral defence systems, that has to-date been largely ignored by theoretical and experimental treatments of host-phage systems.
Erosion of the sella turcica and pituitary expansion secondary to polymicrobial brain abscesses: a case report
Authors: Ryu Brendan , Khatri Deepak , Zlochower Avraham , Maslak Stephen , D’Amico Randy S.
Published: October 2021

Introduction. Brain abscesses can lead to a diverse array of complications, especially when they are polymicrobial in nature. Multiple underlying pathogens may present with a unique set of clinical symptoms which require an early identification and treatment. Skull base osteomyelitis with sellar floor erosion and pituitary involvement with SIADH are such rare complications of brain abscesses which have never been reported previously in the literature.

Case Presentation. We report the case of an immunocompetent 38-year-old male with altered mental sensorium and left hemiparesis due to polymicrobial brain abscess which required surgical evacuation. The post-operative recovery was complicated by severe hyponatremia secondary to SIADH which was treated uneventfully. Radiological imaging demonstrated pituitary enlargement with herniation through an eroded sella turcica without active CSF leak. Patient responded well to the antibiotic therapy based on microbiological susceptibility testing with a complete resolution of the pituitary enlargement on radiological follow-up.

Conclusion. Conservative treatment with targeted antibiotics can lead to the resolution of pituitary enlargement secondary to a brain abscess. However, a close clinical follow-up is required to look for a CSF leak considering the sellar floor erosion due to osteomyelitis.
Impact of SARS-CoV-2 infection on vaccine-induced immune responses over time
Authors: Havervall Sebastian , Marking Ulrika , Greilert-Norin Nina , Gordon Max , Ng Henry , Christ Wanda , Phillipson Mia , Nilsson Peter , Hober Sophia , Blom Kim , Klingström Jonas , Mangsbo Sara , Åberg Mikael , Thålin Charlotte
Published: October 2021

People with previous SARS-CoV-2 infection mount potent immune responses to COVID-19 vaccination, but long-term effects of prior infection on these immune responses are unknown. We investigated the long-term impact of prior SARS-CoV-2 infection on humoral and cellular immune responses in healthcare workers receiving the mRNA BNT162b2 or the adenovirus vectored ChAdOx1 nCoV-19 vaccine. Vaccination with both vaccine platforms resulted in substantially enhanced T cell immune responses, antibody responses to spike and neutralizing antibodies effective against ten SARS-CoV-2 variants following SARS-CoV-2 infection, compared to in naïve individuals. The enhanced immune responses sustained over seven months following vaccination. These findings imply that prior infection should be taken into consideration when planning booster doses and design of current and future COVID-19 vaccine programs.

One-Sentence Summary

SARS-CoV-2 infection prior to vaccination leads to substantial and durable increases in immune memory responses.
Long-term Complications of Unintentional Dural Puncture During Labor Epidural Analgesia: A Case-Control Study
Authors: Lacombe Alexandre , Downey Kristi , Ye Xiang Y. , Carvalho Jose C.A.
Published: October 2021

Introduction

Epidural analgesia is the preferred method to manage pain during labor and delivery. The insertion of the epidural catheter can be complicated by unintentional dural puncture that may result in postdural puncture headache. There is limited evidence on the long term implications of this complication. We sought to investigate if women who sustained a dural puncture have a higher risk of developing chronic headache, low back pain and visual or auditory impairment.

Methods

We conducted a 1:1 case-control study with women who delivered at our institution from January 2015 to December 2019. Cases were women who received epidural analgesia and sustained an unintentional dural puncture and controls were women who received epidural analgesia but did not sustain such complication. We matched cases and controls for date of delivery, age, and BMI. All women completed an online survey with validated questionnaires for diagnosis of chronic headache and chronic back pain. We used dichotomic (yes/no) questions to look for the presence of chronic visual and auditory impairment.

Results

Sixty-three case-control pairs were studied. Women who sustained a dural puncture during their epidural catheter insertion had a higher risk of developing chronic headache [14.3%, versus 4.8%, p=0.049, AOR: 3.36 (1.05, 12.82)] and chronic back pain [39.7% versus 19.1%, p=0.009, AOR: 2.67 (1.25, 5.72)] than women who did not sustain a dural puncture. The incidence of chronic auditory impairment was also higher in the dural puncture group [14.3% versus 1.6%, p=0.007, AOR: 9.98 (1.21, 82.62)].

Conclusions

An unintentional dural puncture during epidural catheter insertion in parturients is associated with increased risk of chronic headache, back pain and auditory impairment.
SSIM can robustly identify changes in 3D genome conformation maps
Authors: Ing-Simmons Elizabeth , Machnik Nick , Vaquerizas Juan M.
Published: October 2021

We previously presented Comparison of Hi-C Experiments using Structural Similarity (CHESS), an approach that applies the concept of the structural similarity index (SSIM) to Hi-C matrices1, and demonstrated that it could be used to identify both regions with similar 3D chromatin conformation across species, and regions with different chromatin conformation in different conditions. In contrast to the claim of Lee et al.2 that the SSIM output of CHESS is ‘independent’ of the input data, here we confirm that SSIM depends on both local and global properties of the input Hi-C matrices. We provide two approaches for using CHESS to highlight regions of differential genome organisation for further investigation, and expanded guidelines for choosing appropriate parameters and controls for these analyses.
Mass-selective and ice-free cryo-EM protein sample preparation via native electrospray ion-beam deposition
Authors: Esser Tim K. , Böhning Jan , Fremdling Paul , Agasid Mark T. , Costin Adam , Fort Kyle , Konijnenberg Albert , Bahm Alan , Makarov Alexander , Robinson Carol V. , Benesch Justin L. P. , Baker Lindsay , Bharat Tanmay A.M. , Gault Joseph , Rauschenbach Stephan
Published: October 2021

Electron cryomicroscopy (cryo-EM) and single-particle analysis (SPA) have revolutionized structure determination of homogeneous proteins. However, obtaining high-resolution structures from heterogeneous samples remains a major challenge, as the various protein states embedded in thin films of vitreous ice may be classified incorrectly, resulting in detrimental averaging of features. Here we present native electrospray ion-beam deposition (native ES-IBD) for the preparation of extremely high-purity cryo-EM samples, based on mass selection in vacuum. Folded protein ions are generated by native electrospray ionization, mass-filtered, and gently deposited on cryo-EM grids, and subsequently frozen in liquid nitrogen. We demonstrate homogeneous coverage of ice-free cryo-EM grids with mass-selected proteins and protein assemblies. SPA reveals that they remain structurally intact, but variations in secondary and tertiary structure are currently limiting information in 2D classes and 3D EM density maps. Our results show the potential of native ES-IBD to increase the scope and throughput of cryo-EM structure determination.
Acute silencing uncovers multiple forms of activity-dependent neuronal survival in the mature entorhinal cortex
Authors: Zhao Rong , Grunke Stacy D. , Li Ming-Hua , Wood Caleb A. , Perez Gabriella A. , Comstock Melissa , Singh Anand K. , Park Kyung-Won , Jankowsky Joanna L.
Published: October 2021

Neurodegenerative diseases are characterized by selective vulnerability of distinct cell populations; however, the cause for this specificity remains elusive. Many circuits that degenerate in disease are shaped by neural activity during development, raising the possibility that mechanisms governing early cell loss may be misused when activity is compromised in the mature brain. Here we show that electrical activity and synaptic transmission are both required for neuronal survival in the adult entorhinal cortex, but these silencing methods trigger distinct means of degeneration in the same neuronal population. Competition between active and inactive cells drives axonal disintegration caused by synaptic inhibition, but not axon retraction due to electrical suppression. These findings suggest that activity-dependence may persist in some areas of the adult brain long after developmental critical periods have closed. We speculate that lifelong plasticity required to support memory may render entorhinal neurons vulnerable to prolonged activity changes in disease.
Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination
Authors: Zhao Hongchang , Hartono Stella , De Vera Kirtney Mae , Yu Zheyuan , Satchi Krishni , Zhao Tracy , Sanz Lionel , Chedin Frederic , Barlow Jacqueline
Published: October 2021

Class switch recombination generates antibody distinct isotypes critical to a robust adaptive immune system and defects are associated with auto-immune disorders and lymphomagenesis. Transcription is required during class switch to recruit the cytidine deaminase AID—an essential step for the formation of DNA double-strand breaks—and strongly induces the formation of R loops within the immunoglobulin heavy chain locus. However, the impact of R loops on double-strand break formation and repair during class switch recombination remains unclear. Here we report that cells lacking two enzymes involved in R loop removal— Senataxin and RNase H2—exhibit increased R loop formation and genome instability at the immunoglobulin heavy chain locus without impacting class switch recombination efficiency, transcriptional activity, or AID recruitment. Senataxin and RNase H2-deficient cells also exhibit increased insertion mutations at switch junctions, a hallmark of alternative end joining. Importantly, these phenotypes were not observed in cells lacking Senataxin or RNase H2B alone. We propose that Senataxin acts redundantly with RNase H2 to mediate timely R loop removal, promoting efficient repair while suppressing AID-dependent genome instability and insertional mutagenesis.
MIR822 modulates monosporic female gametogenesis through an ARGONAUTE9-dependent pathway in Arabidopsis thaliana
Authors: Tovar-Aguilar Andrea , Grimanelli Daniel , Acosta-García Gerardo , Vielle-Calzada Jean-Philippe , Badillo-Corona Jesús Agustín , Durán-Figueroa Noé
Published: October 2021

In the ovule of flowering plants, the establishment of the haploid generation occurs when a somatic subepidermal cell specified as the gametophytic precursor differentiates into a Megaspore Mother Cell (MMC) and initiates meiosis. As most flowering plants, Arabidopsis thaliana (Arabidopsis) undergoes a monosporic type of gametogenesis as three meiotically derived cells degenerate without further division, and a single one – the functional megaspore (FM) - divides mitotically to form the female gametophyte. The genetic basis and molecular mechanisms that control monosporic gametogenesis remain largely unknown. In Arabidopsis, ARGONAUTE proteins are involved the control of megasporogenesis. In particular, mutations in ARGONAUTE9 (AGO9) lead to the ectopic differentiation of gametic precursors that can give rise to apomeiotically derived female gametophytes. Here, we show that Arabidopsis plants carrying loss-of-function mutations in the AGO9-interacting microRNA miR822a give rise to extranumerary surviving megaspores that acquire a FM identity and divide without giving rise to differentiated female gametophytes. The overexpression of three miR822a target genes encoding Cysteine/Histidine-Rich C1 domain proteins (At5g02350, At5g02330 and At2g13900) results in defects equivalent to those found in mir822 plants. All three miR822a targets are overexpressed in ago9 mutant ovules, confirming that miR822a acts through an AGO9-dependent pathway to negatively regulate Cysteine/Histidine-Rich C1 domain proteins and restricts the survival of meiotically derived cells to a single megaspore. Our results identify a microRNA-dependent mechanism that is involved in the control of megaspore degeneration and the most prevalent form of female gametogenesis in flowering plants.
Preclinical Efficacy of IMM-BCP-01, a Highly Active Patient-Derived Anti-SARS-CoV-2 Antibody Cocktail
Authors: Nikitin Pavel A. , DiMuzio Jillian M. , Dowling John P. , Patel Nirja B. , Bingaman-Steele Jamie L. , Heimbach Baron C. , Henriquez Noeleya , Nicolescu Chris , Polley Antonio , Sikorski Eden L. , Howanski Raymond J. , Nath Mitchell , Shukla Halley , Scheaffer Suzanne M. , Finn James P. , Liang Li-Fang , Smith Todd , Storm Nadia , McKay Lindsay G. A. , Johnson Rebecca I. , Malsick Lauren E. , Honko Anna N. , Griffiths Anthony , Diamond Michael S. , Sarma Purnanand , Geising Dennis H. , Morin Michael J. , Robinson Matthew K.
Published: October 2021

Using an unbiased interrogation of the memory B cell repertoire of convalescent COVID-19 patients, we identified human antibodies that demonstrated robust antiviral activity in vitro and efficacy in vivo against all tested SARS-CoV-2 variants. Here, we describe the pre-clinical characterization of an antibody cocktail, IMM-BCP-01, that consists of three unique, patient-derived recombinant neutralizing antibodies directed at non-overlapping surfaces on the SARS-CoV-2 spike protein. Two antibodies, IMM20184 and IMM20190 directly block spike binding to the ACE2 receptor. Binding of the third antibody, IMM20253, to its unique epitope on the outer surface of RBD, alters the conformation of the spike trimer, promoting release of spike monomers. These antibodies decreased SARS-CoV-2 infection in the lungs of Syrian golden hamsters, and efficacy in vivo efficacy was associated with broad antiviral neutralizing activity against multiple SARS-CoV-2 variants and robust antiviral effector function response, including phagocytosis, ADCC, and complement pathway activation. Our pre-clinical data demonstrate that the three antibody cocktail IMM-BCP-01 shows promising potential for preventing or treating SARS-CoV-2 infection in susceptible individuals.

One sentence summary

IMM-BCP-01 cocktail triggers Spike Trimer dissociation, neutralizes all tested variants in vitro, activates a robust effector response and dose-dependently inhibits virus in vivo.
The landscape of extrachromosomal circular DNA in medulloblastoma
Authors: Chapman Owen S , Luebeck Jens , Wani Sameena , Tiwari Ashutosh , Pagadala Meghana , Wang Shanqing , Larson Jon D , Lange Joshua T , Wong Ivy Tsz-Lo , Dehkordi Siavash R , Chandran Sahaana , Adam Miriam , Lin Yingxi , Juarez Edwin , Robinson James T , Sridhar Sunita , Malicki Denise M , Coufal Nicole , Levy Michael , Crawford John R , Pomeroy Scott L , Rich Jeremy , Scheuermann Richard H , Carter Hannah , Dixon Jesse , Mischel Paul S , Fraenkel Ernest , Wechsler-Reya Robert J , Bafna Vineet , Mesirov Jill P , Chavez Lukas
Published: October 2021

Extrachromosomal circular DNA (ecDNA) is an important driver of aggressive tumor growth, promoting high oncogene copy number, intratumoral heterogeneity, accelerated evolution of drug resistance, enhancer rewiring, and poor outcome. ecDNA has been reported in medulloblastoma (MB), the most common malignant pediatric brain tumor, but the ecDNA landscape and its association with specific MB subgroups, its impact on enhancer rewiring, and its potential clinical implications, are not known. We assembled a retrospective cohort of 468 MB patient samples with available whole genome sequencing (WGS) data covering the four major MB subgroups WNT, SHH, Group 3 and Group 4. Using computational methods for the detection and reconstruction of ecDNA1, we find ecDNA in 82 patients (18%) and observe that ecDNA+ MB patients are more than twice as likely to relapse and three times as likely to die of disease. In addition, we find that individual medulloblastoma tumors often harbor multiple ecDNAs, each containing different amplified oncogenes along with co-amplified non-coding regulatory enhancers. ecDNA was substantially more prevalent among 31 analyzed patient-derived xenograft (PDX) models and cell lines than in our patient cohort. By mapping the accessible chromatin and 3D conformation landscapes of MB tumors that harbor ecDNA, we observe frequent candidate “enhancer rewiring” events that spatially link oncogenes with co-amplified enhancers. Our study reveals the frequency and diversity of ecDNA in a subset of highly aggressive tumors and suggests enhancer rewiring as a frequent oncogenic mechanism of ecDNAs in MB. Further, these results demonstrate that ecDNA is a frequent and potent driver of poor outcome in MB patients.
Intensive Single Cell Analysis Reveals Immune Cell Diversity among Healthy Individuals
Authors: Kashima Yukie , Kaneko Keiya , Reteng Patrick , Yoshitake Nina , Runtuwene Lucky Ronald , Nagasawa Satoi , Onishi Masaya , Seki Masahide , Suzuki Ayako , Sugano Sumio , Sakata-Yanagimoto Mamiko , Imai Yumiko , Nakayama-Hosoya Kaori , Kawana-Tachikawa Ai , Mizutani Taketoshi , Suzuki Yutaka
Published: October 2021

It is believed that immune responses are different between individuals and at different times. In addition, personal health histories and unique environmental conditions should collectively determine the present state of immune cells. However, the cellular and molecular system mechanisms underlying such heterogeneity remain largely elusive. In this study, we conducted a systematic time-lapse single-cell analysis, using 171 single-cell libraries and 30 mass cytometry datasets intensively for seven healthy individuals. We found substantial diversity in immune cell populations and their gene expression patterns between different individuals. These patterns showed daily fluctuations even within the same individual spending a usual life. Similar diversities were also observed for the T cell receptor and B cell receptor repertoires. Detailed immune cell profiles at healthy statuses should give an essential background information to understand their immune responses, when the individual is exposed to various environmental conditions. To demonstrate this idea, we conducted the similar analysis for the same individuals on the vaccination of Influenza and SARS-CoV-2, since the date and the dose of the antigens are well-defined in these cases. In fact, we found that the distinct responses to vaccines between individuals, althougth key responses are common. Single cell immune cell profile data should make fundamental data resource to understand variable immune responses, which are unique to each individual.
Interleukin-1 is overexpressed in injured muscles following spinal cord injury and promotes neurogenic heterotopic ossification
Authors: Tseng Hsu-Wen , Kulina Irina , Girard Dorothée , Gueguen Jules , Vaquette Cedryck , Salga Marjorie , Fleming Whitney , Jose Beulah , Millard Susan M , Pettit Allison R , Schroder Kate , Thomas Gethin , Wheeler Lawrie , Genêt François , Banzet Sébastien , Alexander Kylie A , Levesque Jean-Pierre
Published: October 2021

Neurogenic heterotopic ossifications (NHOs) form in periarticular muscles following severe spinal cord (SCI) and traumatic brain injuries. The pathogenesis of NHO is poorly understood with no effective preventive treatment. The only curative treatment remains surgical resection of pathological NHOs. In a mouse model of SCI-induced NHO that involves a transection of the spinal cord combined with a muscle injury, a differential gene expression analysis revealed that genes involved in inflammation such as interleukin-1β (IL-1β) were overexpressed in muscles developing NHO. Using mice knocked-out for the gene encoding IL-1 receptor (IL1R1) and neutralizing antibodies for IL-1α and IL-1β, we show that IL-1 signaling contributes to NHO development following SCI in mice. Interestingly, other proteins involved in inflammation that were also overexpressed in muscles developing NHO, such as colony-stimulating factor-1, tumor necrosis factor or C-C chemokine ligand-2 did not promote NHO development. Finally using NHO biopsies from SCI and TBI patients, we show that IL-1β is expressed by CD68+ macrophages. IL-1α and IL-1β produced by activated human monocytes promote calcium mineralization of fibro-adipogenic progenitors isolated from muscles surrounding NHOs. Altogether these data suggest that interleukin-1 promotes NHO development in both humans and mice.
Single-molecule analysis of the entire perfringolysin O pore formation pathway
Authors: Guinness Conall Mc , Walsh James C. , Bayly-Jones Charles , Dunstone Michelle A. , Christie Michelle P. , Morton Craig J. , Parker Michael W. , Böcking Till
Published: October 2021

The cholesterol-dependent cytolysin perfringolysin O (PFO) is secreted by Clostridium perfringens as a bacterial virulence factor able to form giant ring-shaped pores that perforate and ultimately lyse mammalian cell membranes. To resolve the kinetics of all steps in the assembly pathway, we have used single-molecule fluorescence imaging to follow the dynamics of PFO on dye-loaded liposomes that lead to opening of a pore and release of the encapsulated dye. Formation of a long-lived membrane-bound PFO dimer nucleates the growth of an irreversible oligomer. The growing oligomer can insert into the membrane and open a pore at stoichiometries ranging from tetramers to full rings (∼35-mers), whereby the rate of insertion increases linearly with the number of subunits. Oligomers that insert before the ring is complete continue to grow by monomer addition post insertion. Overall, our observations suggest that PFO membrane insertion is kinetically controlled.
Facing the green threat: A waterflea’s defenses against a carnivorous plant
Authors: Kruppert Sebastian , Horstmann Martin , Weiss Linda C. , Barmaeva Elena , Kubitza Nadja , Poppinga Simon , Westermeier Anna S. , Speck Thomas , Tollrian Ralph
Published: October 2021

Water fleas of the family Daphniidae are keystone species in many lentic ecosystems and, as most abundant filter feeders, link the primary production to higher trophic levels. As a response to the high predatory pressures, water fleas have evolved a range of defenses, including inducible defenses against animal predators. Here we show inCeriodaphnia dubiaa first example of such defenses induced by the presence of a coexisting plant predator, i.e. the carnivorous southern bladderwort (Utricularia australis, Lentibulariaceae), which possesses ultrafast underwater suction traps. When the bladderwort is present,C. dubiashows changes in morphology, life-history and behavior. While the morphological and behavioral adaptations improveC. dubia’ssurvival rate in the presence of this predator, the life-history parameters likely reflect trade-offs for the defense. Our study demonstrates plant-induced animal defenses, implying their potential relevance in freshwater ecosystems and contributing to an overall yet underestimated biodiversity of inducible defenses.

Open Research Statement

Data is not finally prepared for upload yet. Once most fitting file types are determined and metadata is created we aim to upload all raw data as supporting information.
Activation of SGK1.1 up-regulates the M-current in the presence of epilepsy mutations
Authors: Martin-Batista Elva , Manville Rían W. , Rivero-Pérez Belinda , Bartolomé-Martín David , de la Rosa Diego Alvarez , Abbott Geoffrey W. , Giraldez Teresa
Published: October 2021

In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 is able to up-regulate M-channel activity in the presence of two different epilepsy mutations found in Kv7.2 subunit, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying M-channel up-regulation by SGK1.1
Pupil Dilation and Response Slowing Distinguish Deliberate Explorative Choices in the Probabilistic Learning Task
Authors: Kozunova Galina L. , Sayfulina Ksenia E. , Prokofyev Andrey O. , Medvedev Vladimir A. , Rytikova Anna M. , Stroganova Tatiana A. , Chernyshev Boris V.
Published: October 2021

This study examined whether pupil size and response time would distinguish directed exploration from random exploration and exploitation. Eighty-nine participants performed the two-choice probabilistic learning task while their pupil size and response time were continuously recorded. Using LMM analysis, we estimated differences in the pupil size and response time between the advantageous and disadvantageous choices as a function of learning success, i.e., whether or not a participant has learned the probabilistic contingency between choices and their outcomes. We proposed that before a true value of each choice became known to a decision-maker, both advantageous and disadvantageous choices represented a random exploration of the two options with an equally uncertain outcome, whereas the same choices after learning manifested exploitation and direct exploration strategies, respectively. We found that disadvantageous choices were associated with increases both in response time and pupil size, but only after the participants had learned the choice-reward contingencies. For the pupil size, this effect was strongly amplified for those disadvantageous choices that immediately followed gains as compared to losses in the preceding choice. Pupil size modulations were evident during the behavioral choice rather than during the pretrial baseline. These findings suggest that occasional disadvantageous choices, which violate the acquired internal utility model, represent directed exploration. This exploratory strategy shifts choice priorities in favor of information seeking and its autonomic and behavioral concomitants are mainly driven by the conflict between the behavioral plan of the intended exploratory choice and its strong alternative, which has already proven to be more rewarding.
An intranasally administrated SARS-CoV-2 beta variant subunit booster vaccine prevents beta variant viral replication in rhesus macaques
Authors: Sui Yongjun , Li Jianping , Andersen Hanne , Zhang Roushu , Prabhu Sunaina Kiran , Hoang Tanya , Venzon David , Cook Anthony , Brown Renita , Teow Elyse , Velasco Jason , Pessaint Laurent , Moore Ian N. , Lagenaur Laurel , Talton Jim , Breed Matthew W. , Kramer Josh , Bock Kevin W. , Minai Mahnaz , Nagata Bianca M. , Choo-Wosoba Hyoyoung , Lewis Mark G. , Wang Lai-Xi , Berzofsky Jay A.
Published: October 2021

Emerging of SARS-CoV-2 variants and waning of vaccine/infection-induced immunity poses threats to curbing the COVID-19 pandemic. An effective, safe, and convenient booster vaccine will be needed. We hypothesized that a variant-modified mucosal booster vaccine might induce local immunity to prevent SARS-CoV-2 infection at the port of entry. The beta-variant is hardest to cross-neutralize. Herein we assessed the protective efficacy of an intranasal booster composed of beta variant-spike protein S1 with IL-15 and TLR agonists in previously immunized macaques. The macaques were first vaccinated with Wuhan strain S1 with the same adjuvant. One year later, negligibly detectable SARS-CoV-2-specific antibody remained. Nevertheless, the booster induced vigorous humoral immunity including serum- and bronchoalveolar lavage (BAL)-IgG, secretory nasal- and BAL-IgA, and neutralizing antibody against the original strain and/or beta variant. Beta-variant S1-specifc CD4+and CD8+T cell responses were also elicited in PBMC and BAL. Following SARS-CoV-2 beta variant challenge, the vaccinated group demonstrated significant protection against viral replication in the upper and lower respiratory tracts, with almost full protection in the nasal cavity. The fact that one intranasal beta-variant booster administrated one year after the first vaccination provoked protective immunity against beta variant infections may inform future SARS-CoV-2 booster design and administration timing.
CombPDX: a unified statistical framework for evaluating drug synergism in patient-derived xenografts
Authors: Huang Licai , Wang Jing , Fang Bingliang , Meric-Bernstam Funda , Roth Jack A. , Ha Min Jin
Published: October 2021

Motivation

Anticancer combination therapy has been developed to increase efficacy by enhancing synergy. Patient-derived xenografts (PDXs) have emerged as reliable preclinical models to develop effective treatments in translational cancer research. However, in most PDX combination experiments, PDXs are tested on single dose levels and dose-response surface methods are not applicable for testing synergism.

Results

We propose a comprehensive statistical framework to assess joint action of drug combinations from PDX tumor growth curve data. We provide various metrics and robust statistical inference procedures that locally (at a fixed time) and globally (across time) access combination effects under classical drug interaction models. Integrating genomic and pharmacological profiles in non-small-cell lung cancer (NSCLC), we have shown the utilities of combPDX in discovering effective therapeutic combinations and relevant biological mechanisms.

Availability

We provide an interactive web server, combPDX (https://licaih.shinyapps.io/CombPDX/), to analyze PDX tumor growth curve data and perform power analyses.

Contact

MJHa@mdanderson.org

Supplementary information

Supplementary data are available at Bioinformatics online.
Hysteresis in PIF4 and ELF3 dynamics dominates warm daytime memory in Arabidopsis
Authors: Murcia Germán , Nieto Cristina , Sellaro Romina , Prat Salomé , Casal Jorge J.
Published: October 2021

Plants may experience large diurnal temperature fluctuations. Our knowledge of the molecular mechanisms of integration of these fluctuations and the resulting growth patterns is limited. Here we show that hypocotyl growth during the night responded not only to the current temperature but also to preceding daytime temperatures, revealing a memory of previous conditions. Daytime temperature affected the nuclear levels of PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and LONG HYPOCOTYL 5 (HY5) during the next night. These jointly accounted for the observed growth kinetics, whereas memory of prior daytime temperature was impaired in thepif4andhy5mutants.PIF4promoter activity largely accounted for the temperature dependent changes in PIF4 protein levels. Noteworthy, the decrease inPIF4promoter activity triggered by cooling required a stronger temperature shift than the increase caused by warming. This hysteretic pattern required EARLY-FLOWERING 3 (ELF3). Warm temperatures promoted the formation of nuclear condensates of ELF3 in hypocotyl cells during the afternoon but not in the morning. These nuclear speckles showed poor sensitivity to subsequent cooling. We conclude that ELF3 achieves hysteresis and drives thePIF4promoter into the same behaviour, enabling a memory of daytime temperature conditions.
Spatial and temporal control of expression with light-gated LOV-LexA
Authors: Ribeiro Inês M.A. , Eßbauer Wolfgang , Kutlesa Romina , Borst Alexander
Published: October 2021

The ability to drive expression of exogenous genes in different tissues and cell types, under control of specific enhancers, has been crucial for discovery in biology. While many enhancers drive expression broadly, several genetic tricks were developed to obtain access to isolated cell types. Studies of spatially organized neuropiles in the central nervous system of insects have raised the need for a system that targets subsets of cells within a single neuron type, a feat currently dependent on stochastic flip-out methods. To access the same subsets of cells within a given expression pattern consistently across fruit flies, we developed the light-gated expression system LOV-LexA. We combined the bacterial LexA transcription factor with the plant-derived light oxygen voltage (LOV) photosensitive domain and a fluorescent protein. Exposure to blue light uncages a nuclear localizing signal in the C-terminal of the LOV domain, and leads to translocation of LOV-LexA to the nucleus, with subsequent initiation of transcription. LOV-LexA enables spatial and temporal control of expression of transgenes under LexAop sequences in larval fat body as well as pupal and adult neurons with blue light. The LOV-LexA tool is ready to use with GAL4 and Split-GAL4 drivers in its current form, and constitutes another layer of intersectional genetics, that provides light-controlled genetic access to specific subsets of cells across flies.
Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs with Trisomy 21
Authors: Klein Jenny A. , Li Zhen , Rampam Sanjeev , Cardini Jack , Ayoub Amara , Shaw Patricia , Rachubinski Angela L. , Espinosa Joaquin M. , Zeldich Ella , Haydar Tarik F.
Published: October 2021

The intellectual disability found in people with Down syndrome (DS) is associated with a decrease in white matter in the central nervous system. To study the mechanism of this myelination deficit, we differentiated two isogenic lines of induced pluripotent stem cells (iPSCs) derived from people with DS into brain-like and spinal cord-like neural progenitor cells (NPCs) and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway. In the spinal cord-like trisomic cells, we found no difference in expression of OLIG2 or NKX2.2, two transcription factors essential for commitment to the oligodendrocyte (OL) lineage. However, in the brain-like trisomic NPCs, OLIG2 is significantly upregulated and is associated with reduced expression of NKX2.2. We found that this gene dysregulation and block in NPC transition can be normalized by increasing the concentration of a SHH pathway agonist (SAG) during differentiation. These results underscore the importance of regional and cell type differences in gene expression in DS and demonstrate that modulation of SHH signaling in trisomic cells can rescue an early perturbed step in neural lineage specification in DS.
S-Phase induced RNAs control ORC1 engagement to H2A.Z and firing of early DNA replication origins
Authors: Ummarino Simone , Poluben Larysa , Ebralidze Alex K. , Autiero Ida , Zhang Yhanzou , Paniza Theodore , Deshpande Madhura , Lee Johnathan , Bassal Mahmoud , Trinh Bon Q. , Balk Steven , Flaumenhaft Robert , Gerhardt Jeannine , Mirkin Sergei , Tenen Daniel G. , Di Ruscio Annalisa
Published: October 2021

Coordinated initiation of DNA replication is essential to ensure efficient and timely DNA synthesis. Yet, the mechanism governing the “initiation” process in eukaryotic cells remains elusive. Here, we present data demonstrating a novel feature of RNAs transcribed in the proximity of actively replicating gene loci. We show that S-phAse-RNAs aNChoringORC1 (ANCORs) to the histone variant H2A.Z are licensors of the DNA replication process. The concomitant ANCOR-H2A.Z interaction is essential for the cells to initiate duplication of their genetic heritage. Widespread and locus-specific perturbations of these transcripts correlate with anomalous replication patterns and loss of the replicative marker at the origin site.

Collectively, we unveil an RNA-mediated mechanism as the missing link for the generation of active replication origins and delineate a potential strategy to modulate replication in human cells at a local and global level.
Interspecific divergence of circadian properties in duckweed plants
Authors: Isoda Minako , Ito Shogo , Oyama Tokitaka
Published: October 2021

The circadian clock system is widely conserved in plants; however, divergence in circadian rhythm properties is poorly understood. We conducted a comparative analysis of the circadian properties of closely related duckweed species.

Using a particle bombardment method, a circadian bioluminescent reporter was introduced into duckweed plants. We measured bioluminescence circadian rhythms of eight species of the genus Lemna and seven species of the genus Wolffiella at various temperatures (20, 25, and 30 °C) and light conditions (constant light or constant dark). Wolffiella species inhabit relatively warm areas and lack some tissues/organs found in Lemna species.

Lemna species tended to show robust bioluminescence circadian rhythms under all conditions, while Wolffiella species showed lower rhythm stability, especially at higher temperatures. For Lemna, two species (L. valdiviana and L. minuta) forming a clade showed relatively lower circadian stability. For Wolffiella, two species (W. hyalina and W. repanda) forming a clade showed extremely long period lengths.

The circadian properties of species primarily reflect their phylogenetic positions. The relationships between geographical and morphological factors and circadian properties are also suggested.
Geometrical-optics formalism to model contrast in dark-field X-ray microscopy
Authors: Poulsen H. F. , Dresselhaus-Marais L. E. , Carlsen M. A. , Detlefs C. , Winther G.
Published: October 2021

Dark-field X-ray microscopy, DFXM, is a new full-field imaging technique that non-destructively maps the structure and local strain inside deeply embedded crystalline elements in three dimensions. In DFXM an objective lens is placed along the diffracted beam to generate a magnified projection image of the local diffracted volume. In this work, a general formalism based on geometrical optics is provided for the diffraction imaging, valid for any crystallographic space group. This allows the simulation of DFXM images based on micro-mechanical models. Example simulations are presented with the formalism, demonstrating how this may be used to design new experiments or to interpret existing ones. In particular, it is shown how modifications to the experimental design may tailor the reciprocal-space resolution function to map specific components of the deformation-gradient tensor. The formalism supports multi-length-scale experiments, as it enables DFXM to be interfaced with 3D X-ray diffraction. To illustrate the use of the formalism, DFXM images are simulated from different contrast mechanisms on the basis of the strain field around a straight dislocation.
A two-dimensional calcium (II) coordination polymer constructed from 2,2′-[terephthaloylbis(azanediyl)]diacetate: synthesis, structure and properties
Authors: Liu Huang-Huang , Liang Chu-Heng , Liu Yan , Zhang Hong-Tao
Published: October 2021

A new two-dimensional (2D) coordination polymer, namely, poly[[diaqua-[μ4-2,2′-[terephthaloylbis(azanediyl)]diacetato]calcium(II)] monohydrate], {[Ca(C12H10N2O6)(H2O)2]·H2O}
n
, (I), has been synthesized by the reaction of CaCl2 with 2,2′-[terephthaloylbis(azanediyl)]diacetic acid (H2
L). The title compound was structurally characterized by single-crystal X-ray diffraction analysis, elemental analysis and IR spectroscopy. In the crystal structure of (I), each CaII cation binds to six carboxylate groups from four symmetry-related L
2− dianions. The hexadentate L
2− ligand links four symmetry-related calcium cations into a 2D layer-like structure, which can be simplified as a uninodal SP 2-periodic (3,6)III net with the point symbol (43·63). In the lattice, all layers pack in parallel arrays through weak interlayer hydrogen bonding and π–π interactions. The thermal stability and photoluminescence properties of (I) have been investigated. Thermogravimetric analysis reveals the different thermal stabilities of the two coordinated water molecules due to their different hydrogen-bonding interactions. The title coordination polymer exhibits an excitation-wavelength-dependent fluorescence in the solid state.