bluuebunny/crossref_metadata_2025 huggingface dataset:
HYDROCORTISONE, ASCORBIC ACID, AND THIAMINE THERAPY DECREASE RENAL OXIDATIVE STRESS AND ACUTE KIDNEY INJURY IN MURINE SEPSIS
Authors: Kim John , Stolarski Allan , Zhang Qiuyang , Wee Katherine , Remick Daniel
Published: November 2022

Background: Acute kidney injury (AKI) occurs frequently in septic patients and correlates with increased mortality. Because clinical studies investigating hydrocortisone, ascorbic acid, and thiamine (HAT) have demonstrated discordant results, studies were performed using mortality stratification for therapy to identify candidates for therapy and determine mechanisms of organ injury. Methods: Sepsis was induced using the cecal ligation and puncture (CLP) model of sepsis with fluid and antibiotic support. Heart rate (HR) measurements obtained 6 hours after CLP stratified mice into live predicted (P-Live) or die predicted (P-Die). Stratified mice were then randomized for treatment with HAT or vehicle given 7 hours after CLP. Physiologic measurements were taken again at 24 hours, and mice were killed to collect blood and organs. Results: The following five groups were created: (1) P-Live vehicle, (2) P-Live HAT, (3) P-Die vehicle, (4) P-Die HAT, and (5) naive mice. Comparisons were made to test the hypotheses that (1) P-Die vehicle mice will have significant deterioration compared with P-Live mice targeting the kidney and (2) HAT will correct these deleterious changes in P-Die mice. Compared with P-Live, P-Die mice had a significant decline in all measured physiologic parameters (HR, cardiac output, breath rate, and temperature), which were corrected with HAT therapy (P < 0.05 for all parameters). The P-Die mice had declines in the ascorbic acid within the blood, peritoneal lavage, and kidney homogenate compared with P-Live mice indicating consumption, and the decline was corrected with HAT. Elevated IL-6, KC, Macrophage Inflammatory Protein-2, and IL-1RA were found in P-Die mice and decreased with HAT. Markers of endothelial cell injury (glypican 1 and glypican 4) were elevated in the P-Die mice, and these values were decreased with HAT therapy. Low oxygen levels with subsequent oxidative stress (OS) in the kidney were visualized in histologic sections using hypoxyprobe and also with carbonyl proteins and 8-iso-prostaglandin F2α in kidney homogenates. The P-Die mice had significant elevations of renal OSs, which was ameliorated with HAT. Kidney injury was evident in the P-Die mice compared with P-Live mice with elevations in blood urea nitrogen and cystatin C, which were significantly reduced with HAT. There was no evidence of global hypoxia or organ injury because hepatic parameters remained normal. Conclusions: Our data show that in CLP-induced sepsis, P-Die mice have increased inflammation, OS, and kidney injury. Hydrocortisone, ascorbic acid, and thiamine therapy decreased renal OS and injury in the P-Die group when given after the onset of sepsis-induced physiologic changes.
POTENTIAL CARDIOPROTECTIVE EFFECT OF GENIPIN VIA CYCLOOXIDASE 2 SUPPRESSION AND P53 SIGNAL PATHWAY ATTENUATION IN INDUCED MYOCARDIAL INFARCTION IN RATS
Authors: Zhao Liang , Sun Lulu , Li Xiafei , Lu Tian , Pan Yuxue , Du Pengchong
Published: November 2022

Background and aims: Genipin, an iridoid derived from geniposide by β-glucosidase hydrolysis, has shown potential benefit in the treatment of heart function insufficiency despite its unclear therapeutic mechanism. This study aimed to investigate the primary cardioprotective mechanism of genipin. We hypothesized that genipin demonstrated the antiapoptosis and anti-inflammation for cardiac protection by inhibiting the cyclooxidase 2 (COX2)–prostaglandin D2 (PGD2) and murine double minute 2 (MDM2)–p53 pathways. Methods: The normal Sprague-Dawley rats were made into myocardial infarction models by conventional methods. Animals were treated with genipin for 5 weeks after myocardial infarction (MI). Morphometric and hemodynamic measurements were performed 5 weeks post-MI. Biological and molecular experiments were performed after the termination. Results: Both morphometry and hemodynamics in systole and diastole were significantly impaired in the model group but restored close to basal level after treatment with genipin. Genipin also restored the post-MI upregulated expressions of cytochrome c, p53, COX2, and PGD2 and downregulated expression of MDM2 to the approximate baseline. Genipin inhibited apoptotic and inflammatory pathways to prevent post-MI structure-function remodeling. Conclusions: This study showed the cardioprotective mechanism of genipin and implied its potential clinical application for the treatment of ischemic heart failure.
Liver Paired Exchange: Programmatic Hopes and Fears
Authors: Khan Afshin A. , Hashimoto Koji , Kwon Choon H. David , Fujiki Masato , Ahmad Mahwish , Esfeh Jamak Modaresi
Published: November 2022

The dearth of deceased liver donors has created a supply demand gap, necessitating creation of living donor liver transplantation. However, living donor liver transplantation has relied on directed donation, whereby many potential directed donors are rejected based on ABO blood group incompatibility, hepatic size incompatibility, or the need for biliary or arterial reconstruction during transplant surgery. Much like kidney paired exchange, liver paired exchange (LPE) circumvents these incompatibility issues by relying on anonymous, nondirected, or bridge donors that are better anatomical or histological matches for recipients. Although Asia has taken the lead in LPE, the process has only recently been adopted in North America, with the first successful surgery done in the United States in 2019. Our review article sheds light on the process of LPE and the success of LPE in the United States thus far and, additionally, highlights the several logistical and ethical challenges that must be considered as transplant centers adopt and scale up LPE across the United States to address the increased demand for liver allografts.
Immunosuppression in Uterus Transplantation: Experience From the Dallas Uterus Transplant Study
Authors: Wilson Nicole K. , Schulz Philipp , Wall Anji , Parrott Megan , Testa Giuliano , Johannesson Liza , Sam Teena
Published: November 2022

Background.

Uterus transplantation is a temporary transplant allowing women with absolute uterine factor infertility to experience pregnancy and childbirth. The degree of immunosuppression (IS) required to prevent rejection while minimizing toxicity to the recipient and fetus remains an area of investigation.

Methods.

In this article, we describe immunosuppressive therapy, rejection episodes, infections, and adverse events in 14 uterus transplant recipients. Induction consisted of antithymocyte globulin and methylprednisolone. Ten recipients (71%) received no steroids postoperatively, and 4 (29%) had steroids tapered off at 42 d. All received oral tacrolimus, either immediate release (n = 2, 14%) or extended release (n = 12, 86%). Mycophenolate was used in 4 cases (29%), de novo azathioprine in 9 (64%), and de novo everolimus in 1 (7%).

Results.

Sixteen clinically silent, treatment-responsive rejection episodes occurred in 10 recipients. Five recipients (36%) experienced acute kidney injury. In 3 recipients, IS was discontinued due to renal dysfunction. Eleven infection episodes were noted in 7 recipients. No babies had congenital abnormalities.

Conclusions.

Our experience demonstrates that safe IS regimens can be used for uterus transplant recipients before and during pregnancy.
Draft genomes, phylogenomic reconstruction and comparative genome analysis of three Xenorhabdus strains isolated from soil dwelling nematodes in Kenya
Authors: Awori Ryan Musumba , Waturu Charles N. , Pidot Sacha J. , Amugune Nelson O. , Bode Helge B.
Published: November 2022

As a proven source of potent and selective antimicrobials, Xenorhabdus bacteria are important to an age plagued with difficult-to-treat microbial infections. Yet, only twenty-seven species have been described to date. In this study, a new Xenorhabdus species was discovered through genomic studies on three isolates from Kenyan soils. Soils in Western Kenya were surveyed for steinernematids and Steinernema isolates VH1 and BG5 were recovered from red volcanic loam soils from cultivated land in Vihiga and clay soils from riverine land in Bungoma respectively. From the two nematode isolates, Xenorhabdus sp. strain BG5 and Xenorhabdus sp. strain VH1 were isolated. The genomes of these two, plus that of X. griffiniae XN45 —this was previously isolated from Steinernema sp. scarpo that also originated from Kenyan soils— were sequenced and assembled. Nascent genome assemblies of the three isolates were of good quality with over 70% of their proteome having known functions. These three isolates formed the X. griffiniae clade in a phylogenomic reconstruction of the genus. Their species were delineated using three overall genome relatedness indices: Xenorhabdus sp. nov. BG5, X. griffiniae VH1, and X. griffiniae XN45. A pangenome analysis of this clade revealed that over 70% of species-specific genes encoded unknown functions. Transposases were linked to genomic islands in Xenorhabdus sp. nov. BG5. Thus, overall genome-related indices sufficiently delineated species of two new Xenorhabdus isolates from Kenya, both of which were closely related to X. griffiniae. Most genes that drove speciation in the X. griffiniae clade encoded unknown functions.
Assessment of potential transthyretin amyloid cardiomyopathy cases in the Brazilian public health system using a Machine Learning Model
Authors: Zuppo Laper Isabella , Camacho-Hubner Cecilia , Vansan Ferreira Rafaela , Leite Bertoli de Souza Claudenice , Simões Marcus Vinícius , Fernandes Fabio , de Barros Correia Edileide , de Jesus Lopes de Abreu Ariane , Silva Julian Guilherme
Published: November 2022

Objectives

To identify and describe the profile of potential transthyretin cardiac amyloidosis (ATTR-CM) cases in the Brazilian public health system (SUS), using a predictive machine learning (ML) model.

Methods

This was a retrospective descriptive database study that aimed to estimate the frequency of potential ATTR-CM cases in the Brazilian public health system using a supervised ML model, from January 2015 to December 2021. To build the model, a list of ICD-10 codes and procedures potentially related with ATTR-CM was created based on literature review and validated by experts.

Results

From 2015 to 2021, the ML model classified 262 hereditary ATTR-CM (hATTR-CM) and 1,581 wild-type ATTR-CM (wtATTR-CM) potential cases. Overall, the median age of hATTR-CM and wtATTR-CM patients was 66.8 and 59.9 years, respectively. The ICD-10 codes most presented as hATTR-CM and wtATTR-CM were related to heart failure and arrythmias. Regarding the therapeutic itinerary, 13% and 5% of hATTR-CM and wtATTR-CM received treatment with tafamidis meglumine, respectively, while 0% and 29% of hATTR-CM and wtATTR-CM were referred to heart transplant.

Conclusion

Our findings may be useful to support the development of health guidelines and policies to improve diagnosis, treatment, and to cover unmet medical needs of patients with ATTR-CM in Brazil.
A life-history perspective on the evolutionary interplay of sex ratios and parental sex roles
Authors: Long Xiaoyan , Székely Tamas , Komdeur Jan , Weissing Franz J.
Published: November 2022

Parental care is one of the most diverse social behaviours, and caring by the male, female or both parents is essential for successful reproduction of many organisms. Theoretical and empirical studies suggest that parental sex roles are associated with biased sex ratios. However, there is considerable debate on the causal relationship between parental sex roles and sex ratio biases and on the relative importance of the operational sex ratio (OSR), the adult sex ratio (ASR), and the maturation sex ratio (MSR). Here we use individual-based evolutionary simulations to investigate the joint evolution of sex-specific parental behaviour and the various sex ratios in several life history scenarios. We show that sex differences in maturation time or mortality rates at various life-history stages predict the evolution of parental sex roles relatively well: typically, but not always, parental care is biased toward the sex with the lower mortality or the faster maturation. The association of parental sex roles with the various sex ratios is more intricate. In our simulations, the operational sex ratio at evolutionary equilibrium was typically biased toward the less-caring sex. However, the direction and strength of OSR biases often changed drastically in the course of evolution, implying that, rather than being a driver of parental sex roles, OSR biases emerge as a consequence of sex-biases in parental care. When the MSR or the ASR is biased, this bias is generally associated with a bias in parental care: the overrepresented sex does most of the caring. However, the opposite pattern (that the underrepresented sex did most of the caring) also occurs in some scenarios. Moreover, pronounced parental sex roles may also evolve in the absence of an MSR or ASR bias. Taken together, we conclude that none of the sex ratios can be viewed as drivers of a parental care bias; they rather co-evolve with parental care bias in a subtle manner.
Large depth differences between target and flankers can increase crowding: Evidence from a multi-depth plane display
Authors: Smithers Samuel P. , Shao Yulong , Altham James , Bex Peter J.
Published: November 2022

Crowding occurs when the presence of nearby features causes highly visible objects to become unrecognizable. Although crowding has implications for many everyday tasks and the tremendous amounts of research reflect its importance, surprisingly little is known about how depth affects crowding. Most available studies show that stereoscopic disparity reduces crowding, indicating that crowding may be relatively unimportant in three-dimensional environments. However, most previous studies tested only small stereoscopic differences in depth in which disparity, defocus blur, and accommodation are inconsistent with the real world. Using a novel multi-depth plane display, this study investigated how large (0.54 - 2.25 diopters), real differences in target-flanker depth, representative of those experienced between many objects in the real world, affect crowding. Our findings show that large differences in target-flanker depth increased crowding in the majority of observers, contrary to previous work showing reduced crowding in the presence of small depth differences. Furthermore, when the target was at fixation depth, crowding was generally more pronounced when the flankers were behind the target as opposed to in front of it. However, when the flankers were at fixation depth, crowding was generally more pronounced when the target was behind the flankers. These findings suggest that crowding from clutter outside the limits of binocular fusion can still have a significant impact on object recognition and visual perception in the peripheral field.
Signatures of electrical stimulation driven network interactions in the human limbic system
Authors: Valencia Gabriela Ojeda , Gregg Nicholas M. , Worrell Gregory A. , Huang Harvey , Lundstrom Brian N. , Brinkmann Benjamin H. , Attia Tal Pal , Van Gompel Jamie J. , Bernstein Matt A. , In Myung-Ho , Huston John III , Miller Kai J. , Hermes Dora
Published: November 2022

Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain stimulation therapy, is involved in emotion and memory processing. Previous anatomical, neurophysiological and functional studies suggest distinct subsystems within the limbic network (Rolls, 2015). Previous studies using intracranial electrical stimulation, however, have emphasized the similarities of the evoked waveforms across the limbic network. We test whether these subsystems have distinct stimulation-driven signatures. In seven patients with drug-resistant epilepsy we stimulated the limbic system with single pulse electrical stimulation (SPES). Reliable cortico-cortical evoked potentials (CCEPs) were measured between hippocampus and the posterior cingulate cortex (PCC) and between the amygdala and the anterior cingulate cortex (ACC). However, the CCEP waveform in the PCC after hippocampal stimulation showed a unique and reliable morphology, which we term the limbic H-wave. This limbic H-wave was visually distinct and separately decoded from the amygdala to ACC waveform. Diffusion MRI data show that the measured endpoints in the PCC overlap with the endpoints of the parolfactory cingulum bundle rather than the parahippocampal cingulum, suggesting that the limbic H-wave may travel through fornix, mammillary bodies and the anterior nucleus of the thalamus (ANT). This was further confirmed by stimulating the ANT, which evoked the same limbic H-wave but with a shorter latency. Limbic subsystems have unique stimulation evoked signatures that may be used in the future to help develop stimulation therapies.

Significance Statement

The limbic system is often compromised in diverse clinical conditions, such as epilepsy or Alzheimer’s disease, and it is important to characterize its typical circuit responses. Stimulation evoked waveforms have been used in the motor system to diagnose circuit pathology. We translate this framework to limbic subsystems using human intracranial stereo EEG (sEEG) recordings that measure deeper brain areas. Our sEEG recordings describe a stimulation evoked waveform characteristic to the memory and spatial subsystem of the limbic network that we term the limbic H-wave. The limbic H-wave follows anatomical white matter pathways from hippocampus to thalamus to the posterior cingulum and shows promise as a distinct biomarker of signaling in the human brain memory and spatial limbic network.
Auditory deprivation during development alters efferent neural feedback and perception
Authors: Mishra Srikanta K , Moore David R.
Published: November 2022

Auditory experience plays a critical role in hearing development. Developmental auditory deprivation due to otitis media, a common childhood disease, produces long-standing changes in the central auditory nervous system, even after the middle ear pathology is resolved. The effects of sound deprivation due to otitis media have been mostly studied in the ascending neural system but remain to be examined in the descending pathway that runs from the auditory cortex to the cochlea via the brainstem. Alterations in the efferent neural system could be important because the descending olivocochlear pathway influences the neural representation of transient sounds in noise in the afferent auditory system and is thought to be involved in auditory relearning following injury. The main objectives of the present study were to (1) investigate whether degraded auditory input due to otitis media during childhood is associated with weakened medial olivocochlear efferent neural responses, even after the resolution of the middle ear pathology, and (2) to examine the involvement of the efferent neural feedback in perceptual masking deficits associated with auditory deprivation due to otitis media.

We measured contralateral inhibition of otoacoustic emissions—a biomarker for medial efferent activity—and speech-in-noise recognition in children with a medical history of otitis media (N=76) and age-matched controls (N=99). All children had normal auditory function at the time of experimentation.

We found that the inhibitory strength of the medial olivocochlear efferents is weaker in children with a documented history of otitis media relative to controls. In addition, children with otitis media history required a more advantageous signal-to-noise ratio than controls to achieve the same criterion performance level. Importantly, the deficits in perceptual masking were related to efferent inhibition, and these effects could not be attributed to the middle ear or cochlear mechanics.

These findings raise the possibility that perceptual masking deficits—a hallmark of impaired (central) auditory processing—resulting from otitis media can arise from the altered brainstem efferent feedback. To date, it was known that degraded auditory experience reorganizes the ascending neural pathways; here, we show that the lack of optimal auditory input to the afferent system during development could have a long-standing impact on the functioning of the descending neural pathways.
Comparative effectiveness of heterologous booster schedules with AZD1222, BNT162b2, or mRNA-1273 vaccines against COVID-19 during omicron predominance in the Nordic countries
Authors: Andersson Niklas Worm , Thiesson Emilia Myrup , Baum Ulrike , Pihlström Nicklas , Starrfelt Jostein , Faksová Kristýna , Poukka Eero , Lund Lars Christian , Hansen Christian Holm , Aakjær Mia , Kjær Jesper , Cohet Catherine , Goossens Mathijs , Andersen Morten , Hallas Jesper , Meijerink Hinta , Ljung Rickard , Hviid Anders
Published: November 2022

Objective

To investigate the effectiveness of heterologous booster schedules with AZD1222 (Oxford-AstraZeneca, referred to as AZD), BNT162b2 (Pfizer-BioNTech, BNT), and mRNA-1273 (Moderna, MOD) vaccines compared with primary schedules and with homologous mRNA-vaccine booster schedules during a period of omicron predominance.

Design

Population-based cohort analyses.

Setting

Denmark, Finland, Norway, and Sweden, 27 December 2020 to 28 February 2022.

Participants

Adults that had received at least a primary vaccination schedule (ie, two doses) of the AZD, BNT, and/or MOD vaccines during the study period.

Main outcome measures

Using the Kaplan-Meier estimator, we compared country-specific risks of SARS-CoV-2 infection and severe COVID-19 outcomes in heterologous booster vaccinated with primary schedule vaccinated (matched analyses) and homologous booster vaccinated (weighted analyses) since emergence of omicron.

Results

Heterologous booster schedules improved protection against all outcomes compared with primary schedules, with the largest and most robust effects observed for severe COVID-19. Risk differences for documented infection ranged from -22.4% to -3.1% (comparative vaccine effectiveness [CVE] 9.7% to 60.9%; >63.2% for COVID-19 hospitalisation) across countries for AZD1BNT2BNT3 (AZD as primary dose followed by two doses of BNT) vs AZD1BNT2 and -22.2% to -3.2% (CVE 37.4% to 67.8%; >34.6% for hospitalisation) for BNT1BNT2MOD3 vs BNT1BNT2, the two most common heterologous booster schedules. Heterologous- and homologous booster schedules had comparable effectiveness. Risk differences of documented infection ranged from -0.4% to 4.4% (CVE -20.0% to 2.4%) for AZD1BNT2BNT3 vs BNT1BNT2BNT3 and -19.8% to 1.7% (CVE -14.6% to 53.8%) for BNT1BNT2MOD3 vs BNT1BNT2BNT3; for most comparisons, risk differences for severe COVID-19 outcomes were smaller than 1 per 1000 vaccinated. Previous infection followed by a booster dose conferred the greatest protection.

Conclusion

Heterologous booster vaccine schedules are associated with an increased protection against omicron-related COVID-19 outcomes that is comparable to that afforded by homologous booster schedules.
Interpretable Detection of Epiretinal Membrane from Optical Coherence Tomography with Deep Neural Networks
Authors: Ayhan Murat Seçkin , Neubauer Jonas , Uzel Mehmet Murat , Gelisken Faik , Berens Philipp
Published: November 2022

Purpose

To automatically detect epiretinal membranes (ERMs) of different sizes in various OCT scans of the central and paracentral macula region and classify them by size using deep neural networks (DNNs).

Methods

11,061 OCT-images of 624 volume OCT scans (624 eyes of 461 patients) were included and graded according to the presence of an ERM and its size (small 100-1000µm, large >1000 µm). The data set was divided into training, validation and test sets (comprising of 75%, 10%, 15% of the data, respectively). An ensemble of DNNs was trained and saliency maps were generated using Guided Backprob. OCT-scans were also transformed into a one-dimensional value using t-SNE analysis.

Results

The DNNs’ receiver-operating-characteristics on the test set showed a high performance for no ERM, small ERM and large ERM cases (AUC: 0.99, 0.92, 0.99, respectively; 3-way accuracy: 89%), with small ERMs being the most difficult ones to detect. t-SNE analysis sorted cases by size and, in particular, revealed increased classification uncertainty at the transitions between groups. Saliency maps reliably highlighted ERMs, regardless of the presence of other OCT features (i.e. retinal thickening, intraretinal pseudocysts, epiretinal proliferation) and entities such as ERM-retinoschisis, macular pseudohole and lamellar macular hole.

Conclusion

DNNs can reliably detect and grade ERMs according to their size not only in the fovea but also in the paracentral region. This is also achieved in cases of hard-to-detect, small ERMs. In addition, the generated saliency maps can be used effectively to highlight small ERMs that might otherwise be missed. The proposed model could be used for screening programs or decision support systems in the future.
Human neutralizing antibodies to cold linear epitopes and to subdomain 1 of SARS-CoV-2
Authors: Bianchini Filippo , Crivelli Virginia , Abernathy Morgan E. , Guerra Concetta , Palus Martin , Muri Jonathan , Marcotte Harold , Piralla Antonio , Pedotti Mattia , Gasparo Raoul De , Simonelli Luca , Matkovic Milos , Toscano Chiara , Biggiogero Maira , Calvaruso Veronica , Svoboda Pavel , Rincón Tomás Cervantes , Fava Tommaso , Podešvová Lucie , Shanbhag Akanksha A. , Celoria Andrea , Sgrignani Jacopo , Stefanik Michal , Hönig Vaclav , Pranclova Veronika , Michalcikova Tereza , Prochazka Jan , Guerrini Giuditta , Mehn Dora , Ciabattini Annalisa , Abolhassani Hassan , Jarrossay David , Uguccioni Mariagrazia , Medaglini Donata , Pan-Hammarström Qiang , Calzolai Luigi , Fernandez Daniel , Baldanti Fausto , Franzetti-Pellanda Alessandra , Garzoni Christian , Sedlacek Radislav , Ruzek Daniel , Varani Luca , Cavalli Andrea , Barnes Christopher O. , Robbiani Davide F.
Published: November 2022

Emergence of SARS-CoV-2 variants diminishes the efficacy of vaccines and antiviral monoclonal antibodies. Continued development of immunotherapies and vaccine immunogens resilient to viral evolution is therefore necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. Antibody fp.006 binds the fusion peptide and cross-reacts against coronaviruses of the fourgenera, including the nine human coronaviruses, through recognition of a conserved motif that includes the S2’ site of proteolytic cleavage. Antibody hr2.016 targets the stem helix and neutralizes SARS-CoV-2 variants. Antibody sd1.040 binds to subdomain 1, synergizes with antibody rbd.042 for neutralization and, like fp.006 and hr2.016, protects mice when present as bispecific antibody. Thus, coldspot-guided antibody discovery reveals donor-derived neutralizing antibodies that are cross-reactive withOrthocoronavirinae, including SARS-CoV-2 variants.

One sentence summary

Broadly cross-reactive antibodies that protect from SARS-CoV-2 variants are revealed by virus coldspot-driven discovery.
Polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant lipid nanoparticles in rats
Authors: Wang Haiyang , Wang Yisha , Yuan Changzheng , Xu Xiao , Zhou Wenbin , Huang Yuhui , Lu Huan , Zheng Yue , Luo Gan , Shang Jia , Sui Meihua
Published: November 2022

With the large-scale vaccination of lipid nanoparticles (LNP)-based COVID-19 mRNA vaccines, elucidating the potential polyethylene glycol (PEG)-associated immune responses triggered by clinically relevant LNP has become imminent. However, inconsistent findings were observed across very limited population-based studies. Herein we initiated a study using LNP carrier of Comirnaty®as a representative, and simulated real-world clinical practice covering a series of time points and various doses correlated with approved LNP-delivered drugs in a rat model. We demonstrated the time- and dose-dependency of LNP-induced anti-PEG antibodies in rats. As a thymus-independent antigen, LNP unexpectedly induced isotype switch and immune memory, leading to rapid enhancement and longer lasting time of anti-PEG IgM and IgG upon re-injection in rats. Importantly, initial LNP injection accelerated the blood clearance of subsequent dosing in rats. These findings refine our understandings on LNP and possibly other PEG derivatives, and may promote optimization of related premarket guidelines and clinical protocols.
A single-dose MCMV-based vaccine elicits long-lasting immune protection in mice against distinct SARS-CoV-2 variants
Authors: Metzdorf Kristin , Jacobsen Henning , Kim Yeonsu , Teixeira Alves Luiz Gustavo , Kulkarni Upasana , Eschke Kathrin , Chaudhry M. Zeeshan , Hoffmann Markus , Bertoglio Federico , Ruschig Maximilian , Hust Michael , Brdovčak Maja Cokarić , Materljan Jelena , Šustić Marko , Krmpotić Astrid , Jonjić Stipan , Widera Marek , Ciesek Sandra , Pöhlmann Stefan , Landthaler Markus , Čičin-Šain Luka
Published: November 2022

Current vaccines against COVID-19 elicit immune responses that are overall strong but wane rapidly. As a consequence, the necessary booster shots have led to vaccine fatigue. Hence, vaccines that would provide lasting protection against COVID-19 are needed, but are still unavailable. Cytomegaloviruses (CMV) elicit lasting and uniquely strong immune responses. Used as vaccine vectors, they may be attractive tools that obviate the need for boosters. Therefore, we tested the murine CMV (MCMV) as a vaccine vector against COVID-19 in relevant preclinical models of immunization and challenge. We have previously developed a recombinant murine CMV (MCMV) vaccine vector expressing the spike protein of the ancestral SARS-CoV-2 (MCMVS). In this study, we show that the MCMVSelicits a robust and lasting protection in young and aged mice. Notably, S-specific humoral and cellular immunity was not only maintained but even increased over a period of at least 6 months. During that time, antibody avidity continuously increased and expanded in breadth, resulting in neutralization of genetically distant variants, like Omicron BA.1. A single dose of MCMVSconferred rapid virus clearance upon challenge. Moreover, MCMVSvaccination controlled two immune-evading variants of concern (VoCs), the Beta (B.1.135) and the Omicron (BA.1) variants. Thus, CMV vectors provide unique advantages over other vaccine technologies, eliciting broadly reactive and long-lasting immune responses against COVID-19.

Authors Summary

While widespread vaccination has substantially reduced risks of severe COVID presentations and morbidity, immune waning and continuous immune escape of novel SARS-CoV-2 variants have resulted in a need for numerous vaccine boosters and a continuous adaptation of vaccines to new SARS-CoV-2 variants. We show in proof of principle experiments with a recombinant murine cytomegalovirus expressing the SARS-CoV-2 spike protein (MCMVS) that one immunization with a CMV vaccine vector drives enduring protection in both young and aged mice, with long-term maturation of immune responses that broaden the antiviral effects over time. Hence, this approach resolves issues of immune waning and mitigates the effects of COVID-19 evolution and immune escape, reducing the need for additional immunizations and potentially improving vaccine compliance.
Plasma after both SARS-CoV-2 boosted vaccination and COVID-19 potently neutralizes BQ.1.1 and XBB.1
Authors: Sullivan David J , Franchini Massimo , Senefeld Jonathon W. , Joyner Michael J. , Casadevall Arturo , Focosi Daniele
Published: November 2022

Objectives

Recent 2022 SARS-CoV-2 Omicron variants, have acquired resistance to most neutralizing anti-Spike monoclonal antibodies authorized, and the BQ.1.* sublineages are notably resistant to all authorized monoclonal antibodies. Polyclonal antibodies from individuals both vaccinated and recently recovered from Omicron COVID-19 (VaxCCP) could retain new Omicron neutralizing activity.

Methods

Here we reviewed BQ.1.* virus neutralization data from 920 individual patient samples from 43 separate cohorts defined by boosted vaccinations with or without recent Omicron COVID-19, as well as infection without vaccination.

Results

More than 90% of the plasma samples from individuals in the recently (within 6 months) boosted VaxCCP study cohorts neutralized BQ.1.1, and BF.7 with 100% neutralization of WA-1, BA.4/5, BA.4.6 and BA.2.75. The geometric mean of the geometric mean 50% neutralizing titers (GM (GMT50) were 314, 78 and 204 for BQ.1.1, XBB.1 and BF.7, respectively. Compared to VaxCCP, plasma sampled from COVID-19 naïve subjects who also recently within 6 months received at least a third vaccine dose had about half of the GM (GMT50) for all viral variants.

Conclusions

Boosted VaxCCP characterized by either recent vaccine dose or infection event within 6 months represents a robust, variant-resilient, passive immunotherapy against the new Omicron BQ.1.1, XBB.1 and BF.7 variants.
Comparative genomic analysis betweenLeonurus japonicusandLeonurus sibiricus
Authors: Yang Dan-Jie , Yan Meng-Xiao , Li Peng , Liu Pan , Gao Yun , Jiang Yan , He Ze-Kun , Kong Yu , Zhong Xin , Wu Sheng , Yang Jun , Wang Hong-Xia , Huang Yan-Bo , Wang Le , Chen Xiao-Ya , Hu Yong-Hong , Zhao Qing , Xu Ping
Published: November 2022

Leonurus japonicusHoutt. is an important medicinal plant in East Asia and is now widely recognized for its role in treating cerebral apoplexy and lowering blood lipids. Here, we report two sets of chromosome-level genome sequences for leonurine-producingLeonurus japonicusand for its closely related species leonurine-freeLeonurus sibiricus, where 99.78% of 518.19 Mb ofL. japonicuswas assembled into ten pseudochromosomes with a contig N50 of 17.62 Mb and 99.33% of 472.29 Mb ofL. sibiricuswas assembled into nine pseudochromosomes with a contig N50 of 13.29 MB. The reference genomes ofLeonuruswill accelerate the decoding of novel bioactive molecules in medicinal plants, especially in the Lamiaceae family.
Retention of visuo-proprioceptive recalibration in estimating hand position
Authors: Wali Manasi , Lee-Miller Trevor , Babu Reshma , Block Hannah J.
Published: November 2022

The brain estimates hand position using visual and proprioceptive cues, which are combined to give an integrated multisensory estimate. Spatial mismatches between cues elicit recalibration, a compensatory process where each unimodal estimate is shifted closer to the other. It is unclear how well visuo-proprioceptive recalibration is retained after mismatch exposure. Here we asked whether direct vision and/or active movement of the hand can undo visuo-proprioceptive recalibration, and whether recalibration is still evident 24 hours later. 75 participants performed two blocks of visual, proprioceptive, and combination trials, with no feedback or direct vision of the hand. In Block 1, a 70 mm visuo-proprioceptive mismatch was gradually imposed, and recalibration assessed. Block 2 tested retention. Between blocks, Groups 1-4 rested or made active movements with their directly visible or unseen hand for several minutes. Group 5 had a 24-hour gap between blocks. All five groups recalibrated both vision and proprioception in Block 1, and Groups 1-4 retained most of this recalibration in Block 2. Interestingly, Group 5 showed an offline increase in proprioceptive recalibration, but retained little visual recalibration. Our results suggested that visuo-proprioceptive recalibration is robustly retained in the short-term. In the longer term, contextual factors may affect retention.
Whole genome sequencing reveals fine-scale climate associated adaptive divergence near the range limits of a temperate reef fish
Authors: Nugent Cameron M. , Kess Tony , Brachmann Matthew K. , Langille Barbara L. , Duffy Steven J. , Lehnert Sarah J. , Wringe Brendan F. , Bentzen Paul , Bradbury Ian R.
Published: November 2022

Adaptation to ocean climate is increasingly recognized as an important driver of diversity in marine species despite the lack of physical barriers to dispersal and the presence of pelagic stages in many taxa. A robust understanding of the genomic and ecological processes involved in structuring populations is lacking for most marine species, often hindering management and conservation action. Cunner (Tautogolabrus adspersus), is a temperate reef fish that displays both pelagic early life history stages and strong site-associated homing as adults; the species is also presently of interest for use as a cleaner fish in salmonid aquaculture in Atlantic Canada. Here we produce a chromosome-level genome assembly for cunner and characterize spatial population structure throughout Atlantic Canada using whole genome resequencing. The genome assembly spanned 0.72 Gbp and resolved 24 chromosomes; whole genome resequencing of 803 individuals from 20 locations spanning from Newfoundland to New Jersey identified approximately 11 million genetic variants. Principal component analysis revealed four distinct regional groups in Atlantic Canada, including three near the range edge in Newfoundland. PairwiseFSTand selection scans revealed consistent signals of differentiation and selection at discrete genomic regions including adjacent peaks on chromosome 10 recurring across multiple pairwise comparisons (i.e.,FST0.5-0.75). Redundancy analysis suggested significant association of environmental variables related to benthic temperature and oxygen range with genomic structure, again highlighting the previously identified region on chromosome 10. Our results suggest that climate associated adaptation in this temperate reef fish drives regional diversity despite high early life history dispersal potential.
Population-level integration of single-cell datasets enables multi-scale analysis across samples
Authors: De Donno Carlo , Hediyeh-Zadeh Soroor , Wagenstetter Marco , Moinfar Amir Ali , Zappia Luke , Lotfollahi Mohammad , Theis Fabian J.
Published: November 2022

The increasing generation of population-level single-cell atlases with hundreds or thousands of samples has the potential to link demographic and technical metadata with high-resolution cellular and tissue data in homeostasis and disease. Constructing such comprehensive references requires large-scale integration of heterogeneous cohorts with varying metadata capturing demographic and technical information. Here, we presentsingle-cell population level integration (scPoli), a semi-supervised conditional deep generative model for data integration, label transfer and query-to-reference mapping. Unlike other models, scPoli learns both sample and cell representations, is aware of cell-type annotations and can integrate and annotate newly generated query datasets while providing an uncertainty mechanism to identify unknown populations. We extensively evaluated the method and showed its advantages over existing approaches. We applied scPoli to two population-level atlases of lung and peripheral blood mononuclear cells (PBMCs), the latter consisting of roughly 8 million cells across 2,375 samples. We demonstrate that scPoli allows atlas-level integration and automatic reference mapping with label transfer. It can explain sample-level biological and technical variations such as disease, anatomical location and assay by means of its novel sample embeddings. We use these embeddings to explore sample-level metadata, enable automatic sample classification and guide a data integration workflow. scPoli also enables simultaneous sample-level and cell-level analysis of gene expression patterns, revealing genes associated with batch effects and the main axes of between-sample variation. We envision scPoli becoming an important tool for population-level single-cell data integration facilitating atlas use but also interpretation by means of multi-scale analyses.
The human sperm head spins with a conserved direction during swimming in 3D
Authors: Corkidi G. , Montoya F. , González-Cota A.L. , Hernández-Herrera P. , Bruce N.C. , Bloomfield-Gadêlha H. , Darszon A.
Published: November 2022

In human sperm, head spinning is essential for sperm swimming and critical for fertilization. Measurement of head spinning has not been straightforward due to its symmetric head morphology, its translucent nature and fast 3D motion driven by its helical flagellum movement. Microscope image acquisition has been mostly restricted to 2D single focal plane images limited to head position tracing, in absence of head orientation and rotation in 3D. To date, human sperm spinning has been reported to be mono or bidirectional, and even intermittently changing direction. This variety in head spinning direction, however, appears to contradict observations of conserved helical beating of the human sperm flagellum. Here, we reconcile these observations by directly measuring the head spinning movement of freely swimming human sperm with multi-plane 4D microscopy. We show that 2D microscopy is unable to distinguish the spinning direction in human sperm. We evaluated the head spinning of 409 spermatozoa in four different conditions: in non-capacitating and capacitating solutions, for both aqueous and viscous media. All spinning spermatozoa, regardless of the experimental conditions spun counterclockwise (CCW) as seen from head-to-tail. Head spinning was suppressed in 57% of spermatozoa swimming in non-capacitating viscous media, though, interestingly, they recovered the CCW spinning after incubation in capacitating conditions within the same viscous medium. Our observations show that the spinning direction in human sperm is conserved, even when recovered from non-spin, indicating the presence of a robust and persistent helical driving mechanism powering the human sperm flagellum, thus of critical importance in future sperm motility assessments, human reproduction research and microorganism self-organised swimming.
A macrophage subpopulation promotes airineme-mediated intercellular communication in a Matrix Metalloproteinase-9 dependent manner
Authors: Bowman Raquel Lynn , Wang Daoqin , Eom Dae Seok
Published: November 2022

Tissue-resident macrophages are highly heterogenous and perform various dedicated functions depending on their locations. In particular, skin resident macrophages have intriguing roles in long-distance intercellular signaling by mediating cellular protrusions called ‘airinemes’ in zebrafish. During pigment pattern formation, macrophages relay signaling molecules containing ‘airineme vesicles’ from one pigment cell to another. Without macrophages, airineme-mediated signaling is abolished, disrupting pigment pattern formation. It remains unknown, however, if the same macrophage population controls both these signaling roles and typical immune functions or if a separate macrophage subpopulation functions in intercellular communication. In this study, with high-resolution confocal live-imaging and cell type-specific genetic ablation approachesin vivo, we have identified a macrophage subpopulation responsible for airineme-mediated signaling. These cells appear distinct from conventional skin resident macrophages by their amoeboid morphology and faster/expansive migratory behaviors. Instead, we show that they resemble ectoderm-derived macrophages termed metaphocytes. Metaphocyte ablation dramatically reduces airineme extension and signaling. In addition, these amoeboid/metaphocytes require high levels of MMP9 expression for their migration and airineme-mediated signaling. These results reveal a novel macrophage subpopulation with specialized functions in airineme-mediated signaling, which may play roles in many other aspects of intercellular communication.
Development and Evolution of Drosophila Chromatin Landscape in a 3D genome context
Authors: Ali Mujahid , Younas Lubna , Liu Jing , Zhou Qi
Published: November 2022

Chromatin states of genes and transposable elements (TEs) dictated by combinations of various histone modifications comprise key information for understanding the mechanisms of genome organization and regulation. However, little is known about the principles of their dynamic changes during development and evolution in a three-dimensional genome context. To address this, we studyDrosophila pseudoobscura, a Drosophila model species that diverged fromD. melanogasterabout 25 million years ago. We collected 71 epigenomic datasets targeting 11 histone modification marks and 4 Hi-C datasets, and projected 15 chromatin states across four different developmental stages and two adult tissues. We estimate that before zygotic genome activation, 41% of the genome has already been deposited with histone modifications, while 20% of the rest genome switches from a ‘null’ state to an active/inactive chromatin state after the zygotic genome activation. Over two thirds of the genomic region exhibit at least one transition between different chromatin states during development. And such transitions oncis-regulatory regions are associated with tissue- or stage-specific formation of chromatin loops or topologically associated domain borders (TABs), as well as specific activation of gene expression. We further demonstrate that while evolutionarily young TEs are preferentially targeted by silencing histone modifications, old TEs are more frequently domesticated as TABs or specific enhancers that further contribute to the genome organization or local gene regulation. Interestingly, this trend is reversed on the newly evolved X chromosome inD. pseudoobscura, due to the acquisition of dosage compensation mechanism. Overall we characterize the developmental and evolutionary dynamics of Drosophila epigenomic states, and highlight the roles of certain TEs of different evolutionary ages in genome organization and regulation.
Soft and stretchable organic bioelectronics for continuous intra-operative neurophysiological monitoring during microsurgery
Authors: Zhou Wenjianlong , Jiang Yuanwen , Xu Qin , Chen Liangpeng , Qiao Hui , Wang Yixuan , Lai Jiancheng , Zhong Donglai , Zhang Yuan , Li Weining , Du Yanru , Wang Xuecheng , Lei Jiaxin , Dong Gehong , Guan Xiudong , Ma Shunchang , Kang Peng , Yuan Linhao , Zhang Milin , Tok Jeffrey B.-H. , Li Deling , Bao Zhenan , Jia Wang
Published: November 2022

Continuous intra-operative neurophysiological monitoring (CINM) that provides precise mapping of neural anatomy through the entire microsurgery process is essential to preserve the structural and functional integrity of the nerve. However, bulky and rigid electrodes used currently in clinics are usually unable to reliably maintain continuous and stable contacts with the vulnerable and complex nerve networks, thus often resulting in detrimental post-operative complications, such as hemiplegia and sensory disturbances. Here, we describe a biomechanically compatible, suture-free, and individually reconfigurable CINM based on soft and stretchable organic electronic materials. Due to both low impedance and modulus of our conducting polymer electrodes, we achievedfor the first timecontinuous recording of near-field action potential with high signal-to-noise ratio and minimal invasiveness during microsurgeries. Utilizing this unprecedented CINM modality, in conjunction with localized neurostimulation, we further demonstrated our approach in enabling optimal post-operative prognosis in preclinical animal models by preserving normal neural functions after a variety of tumor resection surgeries.