bluuebunny/crossref_metadata_2025 huggingface dataset:
The MU Study of Seropositivity and Risk for SARS-CoV-2 and COVID-19: Crucial Behavioral and Immunological Data from Midwestern College Students
Authors: Myroniuk Tyler W. , Hermsen Joan M. , Hamilton Christal , David Ifeolu , Teti Michelle , Ranjit Yerina S. , Woodrey Shannen N. , Stilley Julie A.W. , Teixeiro Emma , Guan Yue , Daniels Mark , Schatz Enid
Published: January 2022

Objective

We describe our Fall 2020 study of college students’ COVID-19 related behaviors, attitudes, and antibody test results.

Participants

The study included 1,446 randomly selected and self-enrolled undergraduate and graduate students from a midwestern university.

Methods

An online survey was distributed to a sample of students, between September and December 2020. A sub-group also participated in a SARS-CoV-2 antibody blood draw.

Results

Nearly half of students reported a prior COVID-19 test with 22% indicating a positive test, which represents an 11% positivity rate across all student participants. Of those who participated in antibody testing, 15.1% tested positive for SARS-CoV-2 antibodies. Seventy-seven percent of participants said they would get vaccinated. One-third of students reported moderate to severe generalized anxiety disorder and 13% reported moderate to severe depression.

Conclusions

This study informed campus decisions in Fall 2020. The importance of effective public health messaging on campus should continue in the future.
Childhood vaccination coverage by socioeconomic, geographic, maternal, child, and healthcare characteristics in Nigeria: equity impact analysis
Authors: Williams Sarah V , Akande Tanimola , Abbas Kaja
Published: January 2022

Background

Nigeria has a high proportion of the world’s underimmunised children. We estimated the inequities in childhood immunisation coverage associated with socioeconomic, geographic, maternal, child, and healthcare characteristics among children aged 12-23 months in Nigeria using a social determinants of health perspective.

Methods

We first conducted a systematic review focused on inequities in childhood immunisation in low- and middle-income countries to identify the social determinants of childhood immunisation. To identify inequities in basic vaccination coverage in Nigeria (1-dose BCG, 3-dose DTP-HepB-Hib (diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B), 3-dose polio, and 1-dose measles) of 6,059 children aged 12-23 months using the 2018 Nigeria Demographic and Health Survey, we conducted multiple logistic regression to analyse the association of basic vaccination with these determinants.

Results

We identified social determinants of immunisation: household wealth, religion, and ethnicity (socioeconomic characteristics); region and place of residence (geographic characteristics); maternal age at birth, maternal education, and maternal household head status (maternal characteristics); sex of child, and birth order (child characteristics); antenatal care and birth setting (healthcare characteristics). While basic vaccination coverage was 31% (95% CI: 29–33), 19% (95% CI:18–21) of children aged 12-23 months had received none of the basic vaccines. After controlling for background characteristics, there was a significant increase in the odds of basic vaccination by household wealth, antenatal care, delivery in a health facility, maternal age and maternal education. Children of Fulani ethnicity in comparison to children of Igbo ethnicity had lower odds of receiving basic vaccinations.

Conclusions

Children from the poorest households, of Fulani ethnicity, who were born in home settings, and with young mothers with no formal education nor antenatal care, were associated with lower odds of basic vaccination in Nigeria. Basic vaccination coverage is below target levels for all groups and we recommend a proportionate universalism approach for addressing the immunisation barriers.
Massive covidization of research citations and the citation elite
Authors: Ioannidis John P.A. , Bendavid Eran , Salholz-Hillel Maia , Boyack Kevin W. , Baas Jeroen
Published: January 2022

Massive scientific productivity accompanied the COVID-19 pandemic. We evaluated the citation impact of COVID-19 publications relative to all scientific work published in 2020-2021 and assessed the impact on scientist citation profiles. Using Scopus data until August 1, 2021, COVID-19 items accounted for 4% of papers published, 20% of citations received to papers published in 2020-2021 and >30% of citations received in 36 of the 174 disciplines of science (up to 79.3% in General and Internal Medicine). Across science, 98 of the 100 most-cited papers published in 2020-2021 were related to COVID-19. 110 scientists received >=10,000 citations for COVID-19 work, but none received >=10,000 citations for non-COVID-19 work published in 2020-2021. For many scientists, citations to their COVID-19 work already accounted for more than half of their total career citation count. Overall, these data show a strong covidization of research citations across science with major impact on shaping the citation elite.
Observing non-covalent interactions in experimental electron density for macromolecular systems: A novel perspective for protein–ligand interaction research
Authors: Ding Kang , Yin Shiqiu , Li Zhongwei , Jiang Shiju , Yang Yang , Zhou Wenbiao , Zhang Yingsheng , Huang Bo
Published: January 2022

We report for the first time the use of experimental electron density (ED) in the Protein Data Bank for modeling non-covalent interactions (NCIs) for protein–ligand complexes. Our methodology is based on the reduced electron density gradient (RDG) theory describing intermolecular NCI by ED and its first derivative. We established a database called the Experimental NCI Database (ExptNCI;http://ncidatabase.stonewise.cn/#/nci) containing ED saddle points, indicating ~200,000 NCIs from over 12,000 protein–ligand complexes. We also demonstrated the use of the database for depicting amide–π interactions in a protein–ligand binding system. In summary, the database provides details on experimentally observed NCIs for protein–ligand complexes and can support future studies, including studies on rarely documented NCIs and the development of artificial intelligent models for protein–ligand binding prediction.
Close relatives of MERS-CoV in bats use ACE2 as their functional receptors
Authors: Xiong Qing , Cao Lei , Ma Chengbao , Liu Chen , Si Junyu , Liu Peng , Gu Mengxue , Wang Chunli , Shi Lulu , Tong Fei , Huang Meiling , Li Jing , Zhao Chufeng , Shen Chao , Chen Yu , Zhao Huabin , Lan Ke , Wang Xiangxi , Yan Huan
Published: January 2022

Middle East Respiratory Syndrome coronavirus (MERS-CoV) and several bat coronaviruses employ Dipeptidyl peptidase-4 (DPP4) as their functional receptors1–4. However, the receptor for NeoCoV, the closest MERS-CoV relative yet discovered in bats, remains enigmatic5. In this study, we unexpectedly found that NeoCoV and its close relative, PDF-2180-CoV, can efficiently use some types of bat Angiotensin-converting enzyme 2 (ACE2) and, less favorably, human ACE2 for entry. The two viruses use their spikes’ S1 subunit carboxyl-terminal domains (S1-CTD) for high-affinity and species-specific ACE2 binding. Cryo-electron microscopy analysis revealed a novel coronavirus-ACE2 binding interface and a protein-glycan interaction, distinct from other known ACE2-using viruses. We identified a molecular determinant close to the viral binding interface that restricts human ACE2 from supporting NeoCoV infection, especially around residue Asp338. Conversely, NeoCoV efficiently infects human ACE2 expressing cells after a T510F mutation on the receptor-binding motif (RBM). Notably, the infection could not be cross-neutralized by antibodies targeting SARS-CoV-2 or MERS-CoV. Our study demonstrates the first case of ACE2 usage in MERS-related viruses, shedding light on a potential bio-safety threat of the human emergence of an ACE2 using “MERS-CoV-2” with both high fatality and transmission rate.
Lesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype
Authors: O’Shea T.M. , Ao Y. , Wang S. , Wollenberg A.L. , Kim J.H. , Ramos Espinoza R.A. , Czechanski A. , Reinholdt L.G , Deming T.J. , Sofroniew M.V.
Published: January 2022

Neural progenitor cells (NPC) represent potential cell transplantation therapies for CNS injuries. To understand how lesion environments influence transplanted NPC fate in vivo, we derived NPC expressing a ribosomal protein-hemagglutinin tag (RiboTag) for transcriptional profiling of transplanted NPC. Here, we show that NPC grafted into uninjured CNS generate cells that are transcriptionally similar to healthy astrocytes and oligodendrocyte lineages. In striking contrast, NPC transplanted into serum-exposed CNS lesions after stroke or spinal cord injury generate cells that share transcriptional, morphological and functional features with newly proliferated host astroglia that restrict inflammation and fibrosis and thereby protect adjacent neural tissue. Our findings reveal overlapping differentiation potentials of grafted NPC and proliferating host astrocytes; and show that in the absence of other interventions, non-cell autonomous cues in CNS lesions direct the differentiation of grafted NPC predominantly towards a naturally occurring neuroprotective wound repair astroglial phenotype.
Cytotoxic T lymphocytes targeting a conserved SARS-CoV-2 spike epitope are efficient serial killers
Authors: Fathi Mohsen , Charley Lindsey , Cooper Laurence J.N. , Varadarajan Navin , Meyer Daniel
Published: January 2022

Understanding the cellular immune response to infections, cancers and vaccines lags behind the investigation of humoral responses. While neutralizing antibody responses wane over time, the ability of T cells to recognize viruses including SARS-CoV-2 is instrumental to providing long-term immunity. Although T-cell receptor (TCR) repertoire screening can provide insights into the skewing of a T-cell response elicited upon vaccination or infection, they unfortunately provide no assessment into the functional capacity of T cells or their ability to eliminate virally infected targets. We have used time-lapse imaging microscopy in nanowell grids (TIMING) to integrate the migration of individual T cells with analysis of effector functions including cytokine secretion and cytotoxicity. Machine learning is then applied to study thousands of videos of dynamic interactions as T cells with specificity for SARS-CoV-2 eliminate targets bearing spike protein as a surrogate for viral infection. Our data provide the first direct evidence that cytotoxic T lymphocytes from a convalescent patient targeting an epitope conserved across all known variants of concern (VoC) are serial killers capable of eliminating multiple infected targets. These data have implications for development of vaccines to provide broad and sustained cellular immunity and for the recovery and monitoring of individuals who have been exposed to SARS-CoV-2.

Multidisciplinary abstract

We present an imaging platform that uses artificial intelligence (AI) to track thousands of individual cell-cell interactions within nanowell arrays. We apply this platform to quantify how the T cell component of adaptive immunity responds to infections. Our results show that T cells specific for a conserved epitope within the SARS-CoV-2 spike protein are serial killers that can rapidly eliminate virally infected targets. The ability to map the functional capacity of T cells and their ability to kill infected cells provides fundamental insights into the immunology of vaccines and recovery from infections.

Graphical Abstract
Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope
Authors: Hochmair Janine , Exner Christian , Franck Maximilian , Dominguez-Baquero Alvaro , Diez Lisa , Brognaro Hévila , Kraushar Matthew , Mielke Thorsten , Radbruch Helena , Kaniyappan Senthil , Falke Sven , Mandelkow Eckhard , Betzel Christian , Wegmann Susanne
Published: January 2022

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, this synergy enhances bundling and spatially arranges microtubules. We further show that different Tau condensates efficiently induce pathological Tau in cells, including small accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations, and a condensate-like density for nuclear envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.
Songbird parents coordinate offspring provisioning at fine spatio-temporal scales
Authors: Baldan Davide , Van Loon E. Emiel
Published: January 2022

For parents, rearing offspring together is far from a purely cooperative exercise, as a conflict of interest (‘sexual conflict’) exists over their optimum level of care. Recent theory emphasises that sexual conflict can be evolutionarily resolved, and complete parental cooperation can occur if parents directly respond (‘negotiate’) to each other and coordinate their level of care. Despite numerous experiments show that parents are responsive to each other, we still lack empirical evidence of the behavioural mechanisms by which this negotiation occurs. In this study, we investigated the spatio-temporal coordination of parental provisioning behaviour as a possible mechanism of negotiation over parental care. We deployed an automated radio-tracking technology to track the provisioning activity of wild great tit (Parus major) pairs during chick rearing. Our analyses represent the first detailed spatial and temporal description of foraging coordination in songbird parents in a natural context. We demonstrate that the foraging behaviour of the two parents is highly coordinated in space and time, with parents changing their foraging locations in conjunction with their partners’ movements. Therefore, foraging coordination could be a mechanism by which parents directly monitor and respond to each other’s level of investment.
HNRNPK is retained in the cytoplasm by Keratin 19 to stabilize target mRNAs
Authors: Fallatah Arwa , Anastasakis Dimitrios G. , Manzourolajdad Amirhossein , Sharma Pooja , Wang Xiantao , Jacob Alexis , Alsharif Sarah , Elgerbi Ahmed , Coulombe Pierre A. , Hafner Markus , Chung Byung Min
Published: January 2022

Heterogeneous nuclear ribonucleoprotein K (HNRNPK) regulates pre-mRNA processing and long non-coding RNA localization in the nucleus. It was previously shown that shuttling of HNRNPK to the cytoplasm promotes cell proliferation and cancer metastasis. However, the mechanism of HNRNPK cytoplasmic localization, its cytoplasmic RNA ligands, and impact on posttranscriptional gene regulation remain uncharacterized. Here we show that the intermediate filament protein Keratin 19 (K19) directly interacts with HNRNPK and sequesters it in the cytoplasm. Correspondingly, in K19 knockout breast cancer cells, HNRNPK does not localize in the cytoplasm, resulting in reduced cell proliferation. We mapped cytoplasmic HNRNPK target mRNAs using PAR-CLIP where transcriptome data to show that, in the cytoplasm, HNRNPK stabilizes target mRNAs bound to the 3’ untranslated region at the expected C-rich sequence elements. Furthermore, these mRNAs are typically involved in cancer progression and include the p53 signaling pathway that is dysregulated upon HNRNPK knockdown or K19 knockout. This study identifies how a cytoskeletal protein can directly regulate gene expression by controlling subcellular localization of RNA binding proteins to support pathways involved in cancer progression.
CGRP Administration into the Cerebellum Evokes Migraine-like Behaviors Predominately in Female Mice
Authors: Wang Mengya , Duong Thomas L. , Rea Brandon J. , Waite Jayme S. , Huebner Michael W. , Flinn Harold C. , Russo Andrew F. , Sowers Levi P.
Published: January 2022

The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous preclinical studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like behaviors in mice, but the sites of action in the brain remain unidentified. The cerebellum has the most CGRP binding sites in the central nervous system and is increasingly recognized as both a sensory and motor integration center. The objective of this study was to test whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. In this study, CGRP was directly injected into the right MN of C57BL/6J mice via a cannula. A battery of behavioral tests was done to assess migraine-like behaviors. CGRP caused light aversion measured as decreased time in the light zone even with dim light. The mice also spent more time resting in the dark zone, but not the light, along with decreased rearing and transitions between zones. These behaviors were similar for both sexes. In contrast, significant responses to CGRP were seen only with female mice in the open field assay, von Frey test, and automated squint assay, indicating anxiety, tactile hypersensitivity, and spontaneous pain, respectively. In male mice, the responses had the same trend as females but did not reach statistical significance. No detectable effect of CGRP on gait was observed in either sex. These results suggest that CGRP in the MN causes light aversion in males, while in females, light aversion is accompanied by increased anxiety, tactile hypersensitivity, and spontaneous pain. A caveat is that we cannot exclude contributions from other cerebellar regions in addition to the MN due to diffusion of the injected peptide. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine pathophysiology and possibly its prevalence in females.
Repressing ABCB7 Potentiates Cisplatin Response in Pediatric Group 3 Medulloblastoma by Triggering Ferroptosis
Authors: Kanchan Ranjana K. , Perumal Naveenkumar , Khan Parvez , Doss David , Gopalakrishnan Prakadeeshwari , Venkata Ramakanth Chirravuri , Thapa Ishwor , Vengoji Raghupathy , Kaushal Jyoti B. , Siddiqui Jawed A. , Nasser Mohd Wasim , Batra Surinder K. , Mahapatra Sidharth
Published: January 2022

Medulloblastomas (MB) are the most common malignant pediatric brain tumor and a leading cause of childhood mortality. Aggressive tumors belonging to group 3 (G3MB) are distinguished by a marked reduction in programmed cell death by ferroptosis. These aggressive tumors also enrich iron transport and glutathione metabolism. A highly enriched pathway in these tumors is iron-sulfur (Fe-S) cluster binding corresponding to significant upregulation of ABCB7, a poor prognostic feature linked with accelerated mortality. This study elucidated whether repressing ABCB7 activates ferroptosis to mitigate G3MB aggressiveness and whether this pathway is pharmacologically targetable.In silicoandin vitroanalyses confirmed upregulation of ABCB7 and GPX4, the central regulator of ferroptosis, in G3MB cell lines and tumors. Repressing ABCB7 (miR-1253OE, siABCB7, sh-ABCB7) induced iron overload, elicited oxidative stress, and triggered lipid peroxidation, leading to an abrogation of medullosphere formation and cell death by ferroptosis. Intriguingly, fractionation studies revealed that ABCB7 repression abrogated GPX4 expression, most likely by GSH depletion. Repressing ABCB7 induced mitochondrial dysfunction and reduced oxidative phosphorylation. Cisplatin, a chemotherapeutic mainstay of G3MB, induces cell death by DNA crosslinking. In ABCB7 repressed cell lines, the IC50of cisplatin was halved, resulting in augmented oxidative stress and lipid peroxidation, culminating in a higher index of ferroptosis. Artesunate, an anti-malarial drug capable of triggering ferroptosis, was shown to synergize with cisplatin, reducing tumor burden and significantly prolonging survival. Taken together, the current study illustrates how targeting iron transport can augment ferroptosis in G3MBs. It further identifies an FDA-approved drug capable of recapitulating these effects and potentiating mainstay chemotherapy.
Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses
Authors: Mao Tianyang , Israelow Benjamin , Suberi Alexandra , Zhou Liqun , Reschke Melanie , Peña-Hernández Mario A , Dong Huiping , Homer Robert J. , Saltzman W. Mark , Iwasaki Akiko
Published: January 2022

As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin.

One-sentence summary

Broad sarbecovirus protective mucosal immunity is generated by unadjuvanted intranasal spike boost in preclinical model.
Converting non-neutralizing SARS-CoV-2 antibodies targeting conserved epitopes into broad-spectrum inhibitors through receptor blockade
Authors: Weidenbacher Payton A.-B. , Waltari Eric , de los Rios Kobara Izumi , Bell Benjamin N. , Pak John E. , Kim Peter S.
Published: January 2022

All but one of the authorized monoclonal antibody-based treatments for SARS-CoV-2 are largely ineffective against Omicron, highlighting the critical need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective therapeutic antibodies target epitopes that are not highly conserved. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to antibodies that are known to be non-neutralizing, but which target highly conserved epitopes in the viral spike protein. These inhibitors, called Receptor-blocking conserved non-neutralizing Antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOC), including Omicron. Neutralization potency is dependent on both the binding and inhibitory ReconnAb components as activity is lost when the linker joining the two is severed. In addition, a bifunctional ReconnAb, made by linking ACE2 to a bispecific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad- spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.
Patients’ satisfaction and quality of clinical laboratory services provision at public health facilities in northeast Ethiopia
Authors: Abebe Daniel Dagne , Temesgen Minwuyelet Maru , Abozin Addisu Tesfie , Zeleke Abebe Eyasu , Hassen Seid Legesse , Gebremichael Hailay Berhe
Published: January 2022

Patient satisfaction is a key element of quality measures that has increasingly become acknowledged as an important tool for service improvement. This study aimed to assess the level of patients’ satisfaction and associated factors with clinical laboratory services provided at public health facilities. A cross-sectional study was conducted from May-June 2019 among clients attending 24 health centers and 8 hospitals, northeast Ethiopia. A total of 502 patients were selected using systematic random sampling. Patient’s satisfaction towards multiple aspects of laboratory services was assessed using structured exit interview questionnaire, on a rating scale of 1 (very dissatisfied) to 5 points (very satisfied). We assessed test availability and laboratory practices using facility inventory, stepwise accreditation audit checklist and blinded slide rechecking. Data were entered and analyzed using EpiData ver3.1 and STATA ver14.1. Multivariable logistic regression analysis was used to determine the association of factors with overall satisfaction. Overall, majority of the respondents (73.5%) were found to be satisfied. Lowest mean ratings were obtained for waiting area (3.3), and information provided on specimen collection (3.5) and on how and when to receive results (3.7). Patients were more likely to be satisfied in health centers (75.2%) than in hospitals (68.6%) (AOR=1.9, 95%CI: 1.0-3.6, p=0.036). Patients’ timely receipt of results (p=0.005) and laboratories’ accuracy of results (p< 0.025) also showed significant positive associations with satisfaction. In conclusion, there were specific areas of deficiency that were driving dissatisfaction, particularly in the larger hospital laboratories. Therefore, more and balanced emphasis should be given to the patients’ experiences, alongside technical quality improvements, to reduce the disparities and enhance the overall quality of care.
Functional proteomic profiling links deficient DNA clearance to mortality in patients with severe COVID-19 pneumonia
Authors: Aramburu Iker Valle , Hoving Dennis , Vernardis Spyros I. , Tin Martha , Demichev Vadim , Helbig Elisa Theresa , Lippert Lena , Stahl Klaus , Ioannou Marianna , Temkin Mia I. , White Matthew , Radbruch Helena , Ihlow Jana , Horst David , Chiesa Scott T. , Deanfield John E. , David Sascha , Bode Christian , Kurth Florian , Ralser Markus , Papayannopoulos Venizelos
Published: January 2022

Hyperinflammation, coagulopathy and immune dysfunction are prominent in patients with severe infections. Extracellular chromatin clearance by plasma DNases suppresses such pathologies in mice but whether severe infection interferes with these pathways is unclear. Here, we show that patients with severe SARS-CoV-2 infection or microbial sepsis exhibit low extracellular DNA clearance capacity associated with the release of the DNase inhibitor actin. Unlike naked DNA degradation (DNase), neutrophil extracellular trap degradation (NETase) was insensitive to G-actin, indicating distinct underlying mechanisms. Activity-based proteomic profiling of severely ill SARS-CoV-2 patient plasma revealed that patients with high NETase and DNase activities exhibited 18-fold higher survival compared to patients with low activity proteomic profiles. Remarkably, low DNA clearance capacity was also prominent in healthy individuals with chronic inflammation, suggesting that pre-existing inflammatory conditions may increase the risk for mortality upon infection. Hence, functional proteomic profiling illustrates that non-redundant DNA clearance activities protect critically ill patients from mortality, uncovering protein combinations that can accurately predict mortality in critically ill patients.
Acquired neutralizing breadth against SARS-CoV-2 variants including Omicron after three doses of mRNA COVID-19 vaccination and the vaccine efficacy
Authors: Furukawa Koichi , Tjan Lidya Handayani , Kurahashi Yukiya , Sutandhio Silvia , Nishimura Mitsuhiro , Arii Jun , Mori Yasuko
Published: January 2022

To investigate the induction of neutralizing antibodies against Omicron after two and three vaccine doses in recipients of different ages. Physicians at Kobe University Hospital who had received the second dose of the BNT162b2 mRNA vaccine. At 2 months after the second vaccinations, the positive rate of neutralizing antibody against Omicron was 28%, and the titer was significantly lower than those against other variants, 11.8-fold and 3.6-fold lower than those against D614G and Delta, respectively. Unlike Delta, that positive rates of neutralizing antibody against Omicron were low in all age groups, and there was no significant difference in titers among age groups. Seven months after the 2nd dose, the positive rate of neutralizing antibody against Omicron decreased to 6%, but after the booster,3rd vaccination, it increased to 100%, and the titer was much higher than those at 2 and 7 months post-vaccination, 32-fold and 39-fold respectively. The booster vaccination effect was also observed in the younger at 41-fold, middle-aged at 43-fold, and older at 27-fold groups compared to the 7-month titers. Surprisingly, higher-than-predicted titers of the neutralizing antibodies against Omicron were induced after the booster vaccination regardless of recipient age, while this effect was not observed after two doses, indicating the induction of antibodies against common epitopes by the booster vaccination. Three doses can be confidently recommended to suppress the pandemic.
Historical records of plant-insect interactions in subarctic Finland
Authors: Zoller Leana , Knight Tiffany M.
Published: January 2022

Historical ecological records document the diversity and composition of communities decades or centuries ago and provide a valuable benchmark for modern comparisons. Historical datasets on plant-animal interactions allow for modern comparisons that examine the stability of species and interaction networks over long periods of time and in response to anthropogenic change. Here we present a curated dataset of interactions between plants and insects in subarctic Finland, generated from digitizing a historical document from the late 19th century and updating the taxonomy using currently accepted nomenclature. The resulting dataset contains 654 records of plant-insect interactions observed during the years 1895-1900, and includes 498 unique interactions between 86 plant species and 173 insect taxa. Syrphidae, Apidae and Muscidae were the insect families involved in most interactions, and interactions were most observed with the plant species Angelica archangelica, Salix caprea, and Chaerophyllum prescottii. Interaction data are available as csv-file and provide a valuable resource on plant-insect interactions over 120 years ago in a high latitude ecosystem that is undergoing rapid climate change.
The scotopic band: primate detailed scotopic vision and perceptual uncertainty
Authors: Barash Shabtai , Spivak Oleg , Thier Peter
Published: January 2022

Primates perceive detailed images in photopic (daylight) vision via a preferred-processing, high-acuity pathway, made up of a small photopic center (the fovea), and dedicated eye movements, whose function is to shift images of target objects to the fovea and keep them while foveal cones sense the image. Thus, the preferred processing pathway processes images serially, not in parallel. No such pathway is known for scotopic (night-light) vision or mesopic (twilight) vision – though details are informative in dim light, even vital; it remains unclear whether and how scotopic vision of details is accomplished. Here we show that primates do have a scotopic preferred-processing pathway. It consists of a ‘scotopic center’, located on a ‘scotopic band’, and eye movements that shift target images not to the fovea but directly to the scotopic center. In contrast to the stationary fovea, the scotopic center can relocate over the scotopic band. The scotopic center relocates to match changing visual conditions and contextual needs. Ambient light intensity is mapped monotonically onto the scotopic band, with mesopic vision at one end. The dimmer the light is, the more dorsal the scotopic center relocates on the scotopic band. Importantly, the scotopic center relocates (or ‘set’) not only in passive response to ambient light but also actively, driven by internal factors. In near-threshold conditions the scotopic center relocates to a more dorsal band location than in salient conditions. That the same relocation of the scotopic center can be instigated both by dimming the ambient light and by reducing the detectability of targets indicates that, at the core, the longitudinal axis of the scotopic band encodes the level of perceptual uncertainty.
Inference and Uncertainty Quantification of Stochastic Gene Expression via Synthetic Models
Authors: Öcal Kaan , Gutmann Michael U. , Sanguinetti Guido , Grima Ramon
Published: January 2022

Abstract

Estimating uncertainty in model predictions is a central task in quantitative biology. Biological models at the single-cell level are intrinsically stochastic and nonlinear, creating formidable challenges for their statistical estimation which inevitably has to rely on approximations that trade accuracy for tractability. Despite intensive interest, a sweet spot in this trade off has not been found yet. We propose a flexible procedure for uncertainty quantification in a wide class of reaction networks describing stochastic gene expression including those with feedback. The method is based on creating a tractable coarse-graining of the model that is learned from simulations, asynthetic model, to approximate the likelihood function. We demonstrate that synthetic models can substantially outperform state-of-the-art approaches on a number of nontrivial systems and datasets, yielding an accurate and computationally viable solution to uncertainty quantification in stochastic models of gene expression.
Prior exposure to speech rapidly modulates cortical processing of high-level linguistic structure
Authors: Meng Qingqing , Li Hegner Yiwen , Giblin Iain , McMahon Catherine , Johnson Blake W
Published: January 2022

Neural activity has been shown to track hierarchical linguistic units in connected speech and these responses can be directly modulated by changes in speech intelligibility caused by spectral degradation. In the current study, we manipulate prior knowledge to increase the intelligibility of physically identical speech sentences and test the hypothesis that the tracking responses can be enhanced by this intelligibility improvement. Cortical magnetoencephalography (MEG) responses to intelligible speech followed by either the same (matched) or different (unmatched) unintelligible speech were measured in twenty-three normal hearing participants. Driven by prior knowledge, cortical coherence to “abstract” linguistic units with no accompanying acoustic cues (phrases and sentences) was enhanced relative to the unmatched condition, and was lateralized to the left hemisphere. In contrast, cortical responses coherent to word units, aligned with acoustic onsets, were bilateral and insensitive to contextual information changes. No such coherence changes were observed when prior experience was not available (unintelligible speech before intelligible speech). This dissociation suggests that cerebral responses to linguistic information are directly affected by intelligibility, which in turn are powerfully shaped by physical cues in speech. These results provide an objective and sensitive neural index of speech intelligibility, and explain why previous studies have reported no effect of prior knowledge on cortical entrainment.
PPMO-mediated exon skipping induces uniform sarcolemmal dystrophin rescue with dose-dependent restoration of circulating microRNA biomarkers and muscle biophysical properties
Authors: Chwalenia Katarzyna , Oieni Jacopo , Zemła Joanna , Lekka Małgorzata , Ahlskog Nina , Coenen-Stass Anna M.L. , McClorey Graham , Wood Matthew J.A. , Lomonosova Yulia , Roberts Thomas C.
Published: January 2022

Duchenne muscular dystrophy (DMD) is a paediatric muscle-wasting disorder caused by genetic loss of the gene encoding the dystrophin protein. Therapies that restore dystrophin expression are presumed to correct the disease, with antisense-mediated exon skipping being the leading approach. In this study, we aimed to determine whether exon skipping using a peptide-phosphorodiamidate morpholino oligonucleotide (PPMO) conjugate results in dose-dependent restoration of uniform dystrophin localization, together with correction of putative DMD serum and muscle biomarkers. To this end, dystrophin-deficient mdx mice were treated with a PPMO (Pip9b2-PMO) designed to induce Dmd exon 23 skipping and dystrophin rescue at single, ascending intravenous doses (3, 6, or 12 mg/kg) and sacrificed two weeks later. Dose-dependent exon skipping and dystrophin protein restoration were observed. Importantly, dystrophin expression was uniformly distributed at the sarcolemma of corrected myofibers at all doses. The abundance of serum microRNA biomarkers (i.e. miR-1a-3p, miR-133a-3p, miR-206-3p, miR-483-3p) and creatinine kinase were restored towards wild-type levels after treatment in a dose-dependent manner. All biomarkers were strongly anti-correlated with both exon skipping level and dystrophin expression. Dystrophin rescue was also strongly positively correlated with muscle stiffness (i.e. Young’s modulus) as determined by atomic force microscopy (AFM) nanoindentation assay. These data demonstrate that PPMO-mediated exon skipping generates myofibers with uniform dystrophin expression, and that both serum miRNA biomarkers and muscle AFM have potential utility as pharmacodynamic biomarkers of dystrophin restoration therapy in the context of DMD.
Non-uniform dystrophin re-expression after CRISPR-mediated exon excision in the dystrophin/utrophin double-knockout mouse model of DMD
Authors: Hanson Britt , Stenler Sofia , Ahlskog Nina , Chwalenia Katarzyna , Svrzikapa Nenad , Coenen-Stass Anna M. L. , Weinberg Marc S. , Wood Matthew J. A. , Roberts Thomas C.
Published: January 2022

Duchenne muscular dystrophy (DMD) is the most prevalent inherited myopathy affecting children, caused by genetic loss of the gene encoding the dystrophin protein. There are currently four FDA-approved drugs for DMD that aim to restore expression of dystrophin by exon skipping using splice switching oligonucleotides. While these therapies require lifelong repeat administration, recent advancements in gene editing technologies have raised the possibility of achieving ‘permanent exon skipping’, and thereby curing the disease with a single treatment. Here we have investigated the use of the Staphylococcus aureus CRISPR/Cas9 system and a double-cut strategy, delivered using a pair of AAV9 vectors, for dystrophin restoration in the severely-affected dystrophin/utrophin double knock-out (dKO) mouse. Single guide RNAs were designed to induce double-strand DNA breaks on either side of Dmd exon 23, such that the intervening exon 23 sequence is excised when the flanking intronic regions are joined via the non-homologous end joining repair pathway. Exon 23 deletion was confirmed at the DNA level by PCR and Sanger sequencing, and at the RNA level by RT-qPCR. Restoration of dystrophin protein expression was demonstrated by western blot and immunofluorescence staining in mice treated via either intraperitoneal or intravenous routes of delivery. Dystrophin restoration was most effective in the diaphragm, where a maximum of 5.7% of wild-type dystrophin expression was observed. CRISPR treatment was insufficient to extend lifespan in the dKO mouse, and dystrophin was expressed in a within-fiber patchy manner in skeletal muscle tissues. Further analysis revealed a plethora of non-productive DNA repair events, including AAV genome integration at the CRISPR cut sites. This study highlights potential challenges for the successful development of CRISPR therapies in the context of DMD.
Mouse Nuclear RNAi-defective 2 Promotes Splicing of Weak 5’ Splice Sites
Authors: Flemr Matyas , Schwaiger Michaela , Hess Daniel , Iesmantavicius Vytautas , Tuck Alex Charles , Mohn Fabio , Bühler Marc
Published: January 2022

Removal of introns during pre-mRNA splicing, which is central to gene expression, initiates by base pairing of U1 snRNA with a 5’ splice site (5’SS). In mammals, many introns contain weak 5’SSs that are not efficiently recognized by the canonical U1 snRNP, suggesting alternative mechanisms exist. Here, we develop a cross-linking immunoprecipitation coupled to a high-throughput sequencing method, BCLIP-seq, to identify NRDE2 (Nuclear RNAi defective-2) and CCDC174 (Coiled-Coil Domain-Containing 174) as novel RNA-binding proteins in mouse ES cells that associate with U1 snRNA and unspliced 5’SSs. Both proteins bind directly to U1 snRNA independently of canonical U1 snRNP specific proteins, and they are required for the selection and effective processing of weak 5’SSs. Our results reveal that mammalian cells use non-canonical splicing factors bound directly to U1 snRNA to effectively select suboptimal 5’SS sequences in hundreds of genes, promoting proper splice site choice and accurate pre-mRNA splicing.
LET-dependence of radiation-induced makers of Immunogenic Cell Death in human cancer cell lines
Authors: Ponnaiya Brian , LoMastro Anthony , Grabham Peter W. , Garty Guy , Harken Andrew D. , Amundson Sally A. , Hillman Elizabeth M.C. , Brenner David J.
Published: January 2022

Purpose

It has been suggested that heavy-ion radiation therapy may contribute to the control of distal metastases. These distant responses may include immune cell activation. Immunostimulation resulting from radiation-induced immunogenic cell death (ICD) of cancer cells, leads to the recruitment of anti-tumor T cells. Specific markers of ICD include translocation of calreticulin (CRT) and extracellular release of high mobility group box 1 protein (HMGB1), and ATP. However, the LET dependence of these effects remains unknown.

Materials and Methods

Expression of the molecular indicators described above were tested in a panel of human cancer cell lines, that included pancreatic cancer (Panc1 and Paca2), glioblastoma (U87 and LN18) and melanoma (HTB129 and SK-Mel5). Cells were irradiated with 5 Gy of particles spanning a range of LETs, from 10 KeV/μm to 150 KeV/μm and assayed for relocalization of calreticulin and release of HMGB1 and ATP were assayed 24 hours later.

Results

In the pancreatic cancer cell lines (Panc1 and Paca2) there was a continued increase in the membrane relocalization of calreticulin as a function of increasing LET up to 150 KeV/μm. The melanoma cell lines, HTB129 and Sk-Mel5 showed similar patterns. In contrast, calreticulin levels were higher, but not LET-dependent, in irradiated U87 and LN18 (glioblastoma) lines. With the exception of the response in Paca2, increases in LET correlated with increases in HMGB1 that seemed to peak at 100 KeV/μm and then either remain unchanged or decrease at 150 KeV/μm. while the ATP levels were elevated in media from some of the irradiated groups, there were no clear patterns either by cell type or LET.

Conclusions

Our results indicate that at equal doses, although there is an overall trend of increases in the responses to increasing LETs, there are significant cell line-specific differences in the patterns of expression of these key ICD markers.
Polymorphism, polytypism and modular aspect of compounds with the general formula A
2
M
3(TO4)4 (A = Na, Rb, Cs, Ca; M = Mg, Mn, Fe3+, Cu2+; T = S6+, P5+): order–disorder, topological description and DFT calculations
Authors: Aksenov Sergey , Antonov Andrey , Deyneko Dina , Krivovichev Sergey , Merlino Stefano
Published: January 2022

The crystal structure of Na2Mn3(SO4)4 [unit-cell parameters a = 14.8307 (18), b = 9.9107 (18), c = 8.6845 (12) Å, space group Cmc21] displays order–disorder (OD) character and can be described using the OD groupoid family, more precisely a family of OD structures built up by two types of non-polar layers, with layer symmetry P(m)c21 (L
2n+1 type) and P(b)cm (L
2n
type) (category IV). A new hypothetical MDO2 polytype has been proposed and the geometry optimization demonstrates its reasonability as another possible stable polytype. Compounds Na2Mn3–x
Mg
x
(SO4)4 with the unit-cell parameters a ∼ 29.2–29.7 Å, b ∼ 9.5–9.9 Å, c ∼ 8.7 Å and space group Pbca can be described in terms of modularity as a sequence of A, S
1 and S
2 modules:…|AS
1
AS
2
AS
1
AS
2|… or (AS
1
AS
2), together with MDO1 (AS
1
AS
1) and MDO2 (AS
2
AS
2). The crystal structures of itelmenite, NaCaFe3+
3(PO4)4, and Ca2MgFe3+
2(PO4)4 are crystal-chemical isotypic to Na2Mn3–x
Mg
x
(SO4)4 and should be considered as (A*S
1
A*S
2) derivatives of the (AS
1
AS
2)-type structure.
Short‐term pain trajectories in patients with knee osteoarthritis
Authors: Atukorala Inoshi , Downie Aron , Pathmeswaran Arunasalam , Deveza Leticia Miranda Alle , Chang Thashi , Zhang Yuqing , Hunter David John
Published: January 2022

Aim

It is unknown if pain in knee osteoarthritis (KOA) follows distinct patterns over the short term. Therefore, the aim of this study was to identify whether persons with a previous history of KOA pain fluctuations have distinct trajectories of pain over 90 days and to examine associations between baseline characteristics and pain trajectories.

Method

People with a previous history of KOA were selected from a web‐based longitudinal study. Baseline variables were sex, age, being obese/overweight, years of KOA, knee injury, knee buckling, satisfactory Lubben Social Support Score, pain and stress scales, Intermittent Constant Osteoarthritis Pain Score (ICOAP), medication use, and physical activity. Participants completed a Knee Injury and Osteoarthritis Outcomes Score (KOOS) pain subscale (KOOS‐p, rated 0 = extreme to 100 = no knee problems) at 10‐day intervals for 90 days. Short‐term KOOS‐p trajectories were identified using latent growth mixture modeling and the baseline risk factors for these pain trajectories were examined.

Results

Participants (n = 313) had a mean age of 62.2 (SD ± 8.1) years and and a body mass index of 29.8 (SD ± 6.6) kg/m2. The three‐class latent growth mixture modeling quadratic model with best fit indices was chosen (based on lowest sample‐size‐adjusted Bayesian Information Criterion, high probability of belonging, interpretability). Three distinct pain trajectory clusters (over 90 days) were identified: low‐moderate pain at baseline with large improvement (n = 11), minimal change in pain over 90 days (n = 248), and moderate‐high pain with worsening (n = 46). Higher ICOAP (intermittent scale), perceived stress, negative affect score, and knee buckling at baseline were associated with a worse knee pain trajectory (P < 0.05).

Conclusions

Persons with KOA showed unique short‐term pain trajectories over 90 days, with distinct characteristics at baseline associated with each trajectory.
Update on feline alphaherpesvirus‐1 seroprevalence in Victorian feral and owned cats
Authors: Cottingham E , Johnstone T , Hartley CA , Devlin JM
Published: January 2022

The seroprevalence of feline alphaherpesvirus‐1 (FHV‐1) in feral cats in Victoria, Australia, was last assessed in 1981 when serum‐virus‐neutralising antibodies (VNAb) against FHV‐1 were detected in 11% of the sampled population from two Victorian locations. In this current study, VNAb were assessed in serum from feral cats located in Phillip Island, Point Cook and Hattah in the Mallee region in Northern Victoria. In feral cats, the seroprevalence of VNAb to FHV‐1 was highest in Point Cook at 24.6% (17/69), followed by Phillip Island at 16.7% (11/66) and Hattah where no feral cats had detectable VNAb to FHV‐1 (0/12). In contrast, virus‐neutralising antibodies were observed in 84.1% (37/44) of Victorian‐owned cats. This higher seroprevalence in owned cats is likely due to the use of FHV‐1 vaccines; however, the vaccination history of the cats was not known and the development of neutralising antibodies after infection or vaccination can vary. The results are useful for understanding FHV‐1 exposure in feral and owned cats and are important background information in the context of any potential future use of FHV‐1‐vectored vaccines.