bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19 vaccine effectiveness against laboratory confirmed symptomatic SARS-CoV-2 infection, COVID-19 related hospitalizations and deaths, among individuals aged 65 years or more in Portugal: a cohort study based on data-linkage of national registries February-September 2021
Authors: Machado Ausenda , Kislaya Irina , Rodrigues Ana Paula , Sequeira Duarte , Lima João , Cruz Camila , Leite Pedro Pinto , Matias-Dias Carlos , Nunes Baltazar
Published: December 2021

Background

Using data from electronic health registries, this study intended to estimate the COVID-19 vaccine effectiveness in the population aged 65 years and more, against symptomatic infection, COVID-19 related hospitalizations and deaths, overall and by time since complete vaccination.

Methods

We stablished a cohort of individuals aged 65 and more years old, resident in Portugal mainland, using the National Health Service unique identifier User number to link eight electronic health registries. Outcomes included were symptomatic SARS-CoV-2 infections, COVID-19 related hospitalizations or deaths. The exposures of interest were the mRNA vaccines (Cominarty or Spikevax) and the viral vector Vaxzevria vaccine. Complete scheme vaccine effectiveness (VE) was estimated as one minus the confounder adjusted hazard ratio, for each outcome, estimated by time-dependent Cox regression with time dependent vaccine exposure.

Results

For the cohort of individuals aged 65-79 years, complete scheme VE against symptomatic infection varied between 43% (Vaxzevria) and 65% (mRNA vaccines). This estimate was slightly lower in the ≥80 year cohort (53% for mRNA vaccines. VE against COVID-19 hospitalization varied between 89% (95%CI: 52-94) for Vaxzevria and 95% (95%CI: 93-97) for mRNA vaccines for the cohort aged 65-79 years and was 76% (95%CI: 67-83) for mRNA vaccines in the ≥80 year cohort. High VE against COVID-19 related deaths were estimated, for both vaccine types, 95% and 81% for the 65-79 years and the ≥80 year cohort, respectively.

We observed a significant waning of VE against symptomatic infection, with VE estimates reaching approximately 34% for both vaccine types and cohorts. Significant waning was observed for the COVID-19 hospitalizations in the ≥80 year cohort (decay from 83% 14-41 days to 63% 124 days after mRNA second dose). No significant waning effect was observed for COVID-19 related deaths in the period of follow-up of either cohorts.

Conclusions

In a population with a high risk of SARS-CoV-2 complications, we observed higher overall VE estimates against more severe outcomes for both age cohorts when compared to symptomatic infections. Considering the analysis of VE according to time since complete vaccination, the results showed a waning effect for both age cohorts in symptomatic infection and COVID-19 hospitalization for the 80 and more yo cohort.
SMER28 attenuates PI3K/mTOR signaling by direct inhibition of PI3K p110 delta
Authors: Kirchenwitz Marco , Stahnke Stephanie , Prettin Silvia , Borowiak Malgorzata , Birchmeier Carmen , Rottner Klemens , Stradal Theresia E.B. , Steffen Anika
Published: December 2021

SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and consequently growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction of phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by interference of SMER28 with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor typrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited.
Sex-dependent effects ofSetd1ahaploinsufficiency on development and adult behaviour
Authors: Bosworth Matthew L. , Isles Anthony R. , Wilkinson Lawrence S. , Humby Trevor
Published: December 2021

Loss of function (LoF) mutations affecting the histone methyl transferaseSETD1Aare implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model ofSetd1ahaploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, maleSetd1a+/-mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young maleSetd1a+/-mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes inSetd1a+/samples. In adulthood, we found enhanced acoustic startle responding in maleSetd1a+/-mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and femaleSetd1a+/-mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety,Setd1ahaplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use ofSetd1ahaploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes.
A New Gene Set Identifies Senescent Cells and Predicts Senescence-Associated Pathways Across Tissues
Authors: Saul Dominik , Kosinsky Robyn Laura , Atkinson Elizabeth J , Doolittle Madison L. , Zhang Xu , LeBrasseur Nathan K. , Pignolo Robert J. , Robbins Paul D. , Niedernhofer Laura J. , Ikeno Yuji , Jurk Diana , Passos João F. , Hickson LaTonya J. , Xue Ailing , Monroe David G. , Tchkonia Tamara , Kirkland James L. , Farr Joshua N. , Khosla Sundeep
Published: December 2021

Although cellular senescence is increasingly recognized as driving multiple age-related co-morbidities through the senescence-associated secretory phenotype (SASP), in vivo senescent cell identification, particularly in bulk or single cell RNA-sequencing (scRNA-seq) data remains challenging. Here, we generated a novel gene set (SenMayo) and first validated its enrichment in bone biopsies from two aged human cohorts. SenMayo also identified senescent cells in aged murine brain tissue, demonstrating applicability across tissues and species. For direct validation, we demonstrated significant reductions in SenMayo in bone following genetic clearance of senescent cells in mice, with similar findings in adipose tissue from humans in a pilot study of pharmacological senescent cell clearance. In direct comparisons, SenMayo outperformed all six existing senescence/SASP gene sets in identifying senescent cells across tissues and in demonstrating responses to senescent cell clearance. We next used SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from publicly available human and murine bone marrow/bone scRNA-seq data and identified monocytic and osteolineage cells, respectively, as showing the highest levels of senescence/SASP genes. Using pseudotime and cellular communication patterns, we found senescent hematopoietic and mesenchymal cells communicated with other cells through common pathways, including the Macrophage Migration Inhibitory Factor (MIF) pathway, which has been implicated not only in inflammation but also in immune evasion, an important property of senescent cells. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Moreover, using this senescence panel, we were able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways associated with these cells, which may be particularly useful for evolving efforts to map senescent cells (e.g., SenNet). In addition, SenMayo represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.
SARS-CoV2 variant-specific replicating RNA vaccines protect from disease and pathology and reduce viral shedding following challenge with heterologous SARS-CoV2 variants of concern
Authors: Hawman David W. , Meade-White Kimberly , Archer Jacob , Leventhal Shanna , Wilson Drew , Shaia Carl , Randall Samantha , Khandhar Amit P. , Hsiang Tien-Ying , Gale Michael , Berglund Peter , Fuller Deborah Heydenburg , Feldmann Heinz , Erasmus Jesse H.
Published: December 2021

Despite mass public health efforts, the SARS-CoV2 pandemic continues as of late-2021 with resurgent case numbers in many parts of the world. The emergence of SARS-CoV2 variants of concern (VoC) and evidence that existing vaccines that were designed to protect from the original strains of SARS-CoV-2 may have reduced potency for protection from infection against these VoC is driving continued development of second generation vaccines that can protect against multiple VoC. In this report, we evaluated an alphavirus-based replicating RNA vaccine expressing Spike proteins from the original SARS-CoV-2 Alpha strain and recent VoCs delivered in vivo via a lipid inorganic nanoparticle. Vaccination of both mice and Syrian Golden hamsters showed that vaccination induced potent neutralizing titers against each homologous VoC but reduced neutralization against heterologous challenges. Vaccinated hamsters challenged with homologous SARS-CoV2 variants exhibited complete protection from infection. In addition, vaccinated hamsters challenged with heterologous SARS-CoV-2 variants exhibited significantly reduced shedding of infectious virus. Our data demonstrate that this vaccine platform elicits significant protective immunity against SARS-CoV2 variants and supports continued development of this platform.
Active neural coordination of motor behaviors with internal states
Authors: Zhang Yisi S. , Takahashi Daniel Y. , El Hady Ahmed , Liao Diana A. , Ghazanfar Asif A.
Published: December 2021

The brain continuously coordinates skeletomuscular movements with internal physiological states like arousal, but how is this coordination achieved? One possibility is that brain simply reacts to changes in external and/or internal signals. Another possibility is that it is actively coordinating both external and internal activities. We used functional ultrasound imaging to capture a large medial section of the brain, including multiple cortical and subcortical areas, in marmoset monkeys while monitoring their spontaneous movements and cardiac activity. By analyzing the causal ordering of these different time-series, we found that information flowing from the brain to movements and heart rate fluctuations were significantly greater than in the opposite direction. The brain areas involved in this external versus internal coordination were spatially distinct but also extensively interconnected. Temporally, the brain alternated between network states for this regulation. These findings suggest that the brain’s dynamics actively and efficiently coordinate motor behavior with internal physiology.
3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib
Authors: Meraz Ismail M. , Majidi Mourad , Fang Bingliang , Meng Feng , Gao Lihui , Shao RuPing , Song Renduo , Li Feng , Ha Min Jin , Wang Qi , Wang Jing , Shpall Elizabeth , Jung Sung Yun , Haderk Franziska , Gui Philippe , Riess Jonathan Wesley , Olivas Victor , Bivona Trever G , Roth Jack A.
Published: December 2021

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones were used to model osimertinib acquired resistance in humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation were found in resistant clones. Resistant tumors in humanized mice were initially partially responsive to osimertinib, then aggressive tumor regrowth occurred accompanied by an immunosuppressive tumor microenvironment. 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitized resistant clones and a patient derived xenograft (PDX) with acquired resistance to osimertinib. PDK1 knock-out dysregulated PI3K/Akt/mTOR signaling, promoted cell cycle arrest at the G1 phase, and inhibited nuclear translocation of yes-associated protein (YAP). Higher expression of PDK1 was found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.
Proteome Microarray Screening Identifies Human Polyphosphate-Binding Proteins in the Phosphatidylinositol Signaling Pathway
Authors: Krenzlin Viola , Roewe Julian , Strueve Marcel , Martínez-Negro María , Reinhardt Christoph , Morsbach Svenja , Bosmann Markus
Published: December 2021

Polyphosphates are linear chains of orthophosphate residues that are present in all living cells. Polyphosphates are released from platelet d-granules and are also produced in bacteria. Polyphosphates are procoagulant in mammalian species and in bacteria are required for energy and phosphate storage, stress resistance, chelation of metal ions and escaping host immunity. Despite these pleiotropic effects, sparse information is available on molecular binding partners of polyphosphates. Here, we used a slide-based human proteome microarray screen for the search of polyphosphate-binding proteins. This approach suggested several novel proteins with relation to the phosphatidylinositol signaling pathway. The highest signals were obtained for Disabled-1 (DAB1) and phosphatidylinositol-5-phosphate 4-kinase 2B (PIP4K2B). Isothermal titration calorimetry was used for confirmation of DAB1 interactions with long-chain polyphosphates. These results offer new rationale to further investigate the interference of polyphosphates with intracellular signaling pathways.
Constructing synthetic-protein assemblies from de novo designed 310 helices
Authors: Kumar Prasun , Paterson Neil G. , Clayden Jonathan , Woolfson Derek N.
Published: December 2021

Compared with the iconic α helix, 310 helices occur much less frequently in protein structures. The different 310-helical parameters lead to energetically less favourable internal energies, and a reduced tendency to pack into defined higher-order structures. Consequently, in natural proteins, 310 helices rarely extend past 6 residues, and do not form regular supersecondary, tertiary, or quaternary interactions. Here, we show that despite their absence in nature, synthetic protein-like assemblies can be built from 310 helices. We report the rational design, solution-phase characterisation, and an X-ray crystal structure for water-soluble bundles of 310 helices with consolidated hydrophobic cores. The design uses 6-residue repeats informed by analysing natural 310 helices, and incorporates aminoisobutyric acid residues. Design iterations reveal a tipping point between α-helical and 310-helical folding, and identify features required for stabilising assemblies in this unexplored region of protein-structure space.
Combined Pan-, Population-, and Phylo-Genomic Analysis of Aspergillus fumigatus Reveals Population Structure and Lineage-Specific Diversity
Authors: Lofgren Lotus A. , Ross Brandon S. , Cramer Robert A. , Stajich Jason E.
Published: December 2021

Aspergillus fumigatus is a deadly agent of human fungal disease, where virulence heterogeneity is thought to be at least partially structured by genetic variation between strains. While population genomic analyses based on reference genome alignments offer valuable insights into how gene variants are distributed across populations, these approaches fail to capture intraspecific variation in genes absent from the reference genome. Pan-genomic analyses based on de novo assemblies offer a promising alternative to reference-based genomics, with the potential to address the full genetic repertoire of a species. Here, we use a combination of population genomics, phylogenomics, and pan-genomics to assess population structure and recombination frequency, phylogenetically structured gene presence-absence variation, evidence for metabolic specificity, and the distribution of putative antifungal resistance genes in A. fumigatus. We provide evidence for three primary populations of A. fumigatus, structured by both gene variation (SNPs and indels) and distinct gene presence-absence variation with unique suites of accessory genes present exclusively in each clade. Accessory genes displayed functional enrichment for nitrogen and carbohydrate metabolism, suggesting that populations may be stratified by environmental niche specialization. Similarly, the distribution of antifungal resistance genes and resistance alleles were often structured by phylogeny. A. fumigatus demonstrated exceptionally high levels of recombination and one of the largest fungal pan-genomes reported to date including many genes unrepresented in the Af293 reference genome. These results highlight the inadequacy of relying on a single-reference genome-based approach for evaluating intraspecific variation, and the power of combined genomic approaches to elucidate population structure, genetic diversity, and putative ecological drivers of clinically relevant fungi.
Improved neutralisation of the SARS-CoV-2 Omicron variant after Pfizer-BioNTech (BNT162b2) COVID-19 vaccine boosting with a third dose
Authors: Basile Kerri , Rockett Rebecca J , McPhie Kenneth , Fennell Michael , Johnson-Mackinnon Jessica , Agius Jessica E , Fong Winkie , Rahman Hossinur , Ko Danny , Donavan Linda , Hueston Linda , Lam Connie , Arnott Alicia , Chen Sharon C-A , Maddocks Susan , O’Sullivan Matthew V , Dwyer Dominic E , Sintchenko Vitali , Kok Jen
Published: December 2021

In late November 2021, the World Health Organization declared the SARS-CoV-2 lineage B.1.1.529 the fifth variant of concern, Omicron. This variant has acquired 15 mutations in the receptor binding domain of the spike protein, raising concerns that Omicron could evade naturally acquired and vaccine-derived immunity. We utilized an authentic virus, multicycle neutralisation assay to demonstrate that sera collected one, three and six months post-two doses of Pfizer-BioNTech BNT162b2 has a limited ability to neutralise SARS-CoV-2. However, four weeks after a third dose, neutralising antibody titres are boosted. Despite this increase, neutralising antibody titres are reduced four-fold for Omicron compared to lineage A.2.2 SARS-CoV-2.
Impaired dynamics of prefrontal beta-band networks during cognitive action control in Parkinson’s disease
Authors: Duprez Joan , Tabbal Judie , Hassan Mahmoud , Modolo Julien , Kabbara Aya , Mheich Ahmad , Drapier Sophie , Vérin Marc , Sauleau Paul , Wendling Fabrice , Benquet Pascal , Houvenaghel Jean-François
Published: December 2021

Among the cognitive symptoms that are associated with Parkinson’s disease (PD), alterations in cognitive action control (CAC) are commonly reported in patients. CAC enables the suppression of an automatic action, in favor of a goal-directed one. The implementation of CAC is time-resolved and arguably associated with dynamic changes in functional brain networks. However, the electrophysiological functional networks involved, their dynamic changes, and how these changes are affected by PD, still remain unknown. In this study, to address this gap of knowledge, 21 PD patients and 10 healthy controls (HC) underwent a Simon task while high-density electroencephalography (HD-EEG) was recorded. Source-level dynamic connectivity matrices were estimated using the phase-locking value in the beta (12-25 Hz) and gamma (30-45 Hz) frequency bands. Temporal independent component analyses were used as a dimension reduction tool to isolate the group-specific brain network states that were dominant during the task. Typical microstate metrics were quantified to investigate the presence of these states at the subject-level. Our results first confirmed that PD patients experienced difficulties in inhibiting automatic responses during the task. At the group-level, HC displayed a significant functional network state that involved typical CAC-related prefrontal and cingulate nodes (e.g., inferior frontal cortex). Both group- and subject-level analyses showed that this network was less present in PD to the benefit of other networks involving lateralized temporal and insular components. The presence of this prefrontal network was associated with decreased reaction time. In the gamma band, two networks (fronto-cingulate and fronto-temporal) followed one another in HC, while 3 partially overlapping networks that included fronto-temporal, fronto-occipital and cross-hemispheric temporal connections were found in PD. At the subject-level, differences between PD and HC were less marked. Altogether, this study showed that the functional brain networks observed during CAC and their temporal changes were different in PD patients as compared to HC, and that these differences partially relate to behavioral changes. This study also highlights that task-based dynamic functional connectivity is a promising approach in understanding the cognitive dysfunctions observed in PD and beyond.

Highlights

Cognitive action control is associated with dynamic functional networks

Prefrontal and cingulate beta connectivity are prominent in healthy controls

PD patients have different dynamic networks in which prefrontal nodes are absent

The occurrence of prefrontal beta networks was associated with a decreased reaction time

Functional networks in the gamma band were temporally organized in HC, but overlapping in PD patients
Adaptive discrimination of antigen risk by predictive coding in immune system
Authors: Yoshido Kana , Naoki Honda
Published: December 2021

The immune system discriminates between harmful and harmless antigens based on past experiences; however, the underlying mechanism is largely unknown. From the viewpoint of machine learning, the learning system predicts the observation and updates the prediction based on prediction error, a process known as ‘predictive coding’. Here, we modeled the population dynamics of T cells by adopting the concept of predictive coding; helper and regulatory T cells predict the antigen amount and excessive immune response, respectively. Their prediction error signals, possibly via cytokines, induce their differentiation to memory T cells. Through numerical simulations, we found that the immune system identifies antigen risks depending on the concentration and input rapidness of the antigen. Further, our model reproduced history-dependent discrimination, as in allergy onset and subsequent therapy. Together, this study provided a novel framework to improve our understanding of how the immune system adaptively learns the risks of diverse antigens.
Personalized models of breast cancer desmoplasia reveal biomechanical determinants of drug penetration
Authors: Offeddu Giovanni S. , Cambria Elena , Shelton Sarah E. , Wan Zhengpeng , Haase Kristina , Possenti Luca , Nguyen Huu Tuan , Gillrie Mark R. , Hickman Dean , Knutson Charles G. , Kamm Roger D.
Published: December 2021

Breast cancer desmoplasia heterogeneity contributes to high disease mortality due to discrepancies in treatment efficacy between patients. Personalizedin vitrobreast cancer models can be used for high throughput testing and ranking of therapeutic strategies to normalize the aberrant microenvironment in a patient-specific manner. Here, tumoroids assembled from patient-derived cells cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction. Increased hyaluronic acid and collagen deposition, loss of vascular glycocalyx and reduced perfusion, and elevated interstitial fluid pressure in the models result in impaired drug distribution to tumor cells. We demonstrate the application of these personalized models as tools to rank molecular therapies for the normalization of the tumoroid microenvironment and to discover new therapeutic targets such as IL8 and CD44, which may ultimately improve drug efficacy in breast cancer patients.
Dehalobium species implicated in 2,3,7,8-tetrachloro-p-dioxin dechlorination in the contaminated sediments of Sydney Harbour Estuary
Authors: Lee Matthew , Liang Gan , Holland Sophie I. , O’Farrell Casey , Osbourne Keith , Manefield Michael J.
Published: December 2021

Polychlorinated dibenzo-p-dioxins and furans (PCDD/F) are some of the most environmentally recalcitrant and toxic compounds. They are naturally occurring and by-products of anthropogenic activity. Sydney Harbour Estuary (Sydney, Australia), is heavily contaminated with PCDD/F. Analysis of sediment cores revealed that the contamination source in Homebush Bay continues to have one of the highest levels of PCDD/F contamination in the world (5207 pg WHO-TEQ g-1) with >50% of the toxicity attributed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) the most toxic and concerning of the PCDD/F congeners. Comparison of congener profiles at the contamination source with surrounding bays and historical data provided evidence for the attenuation of 2,3,7,8-TCDD and other congeners at the source. This finding was supported by the detection of di-, mono- and unchlorinated dibenzo-p-dioxin. Microbial community analysis of sediments by 16S amplicon sequencing revealed an abundance of lineages from the class Dehalococcoidia (up to 15% of the community), including the genus Dehalobium (up to 0.5%). Anaerobic seawater enrichment cultures using perchloroethene as a more amenable growth substrate enriched only the Dehalobium population by more than six-fold. The enrichment culture then proved capable of reductively dechlorinating 2,3,7,8-TCDD to 2,3,7-TCDD and octachlorodibenzo-p-dibenzodioxin to hepta and hexa congeners. This work is the first to show microbial reductive dehalogenation of 2,3,7,8-TCDD with a bacterium from outside the Dehalococcoides genus, and one of only a few that demonstrates PCDD/F degradation in a marine environment.
In vitro validation of neoantigen prediction algorithm for developing personalized cancer vaccine therapy
Authors: Choe Yun-jeong , Kim Eunyoung , Oh Jooyeon , Jang Miran , Fu Weixan , Lee Hanna , Chung Minho , Pyo Kyung-Ho , Synn Chung-Bong , Kim Sora , Yang Yohan , Kim Ahyeon , Cho Byung Chul , Kim Han Sang , Kim Sangwoo , Carreno Beatriz , Kim Jee Ye , Paik Soonmyung
Published: December 2021

Background

The development of personalized neoantigen-based therapeutic cancer vaccines relies on computational algorithm-based pipelines. One of the critical issues in the pipeline is obtaining higher positive predictive value (PPV) performance, i.e., how many are immunogenic when selecting the top 5 to 20 candidate neoepitopes for the vaccination. We attempted to test the PPV of a neoepitope prediction algorithm Neopepsee.

Methods

Six breast cancer patients and patient-derived xenografts from three lung cancer patients and their paired peripheral blood samples were subjected to whole-exome and RNA sequencing. Neoantigen was predicted using two different algorithms (Neopepsee and pVACseq). Response of induced memory T cells to neopeptide candidates was evaluated by IFN-γ Enzyme-linked immune absorbent spot (ELISpot) assays of peripheral blood mononuclear cell (PBMC) from three HLA-matched donors. Positive ELISpot response to a candidate peptide in at least 2 of 3 donor PBMC was regarded as an immunogenic response.

Results

Neopepsee predicted 159 HLA-A matched neoepitope candidates out of 898 somatic mutations in nine patients (six breast and three lung cancer patients), whereas pVACseq predicted 84 HLA-A matched candidates. A total of 26 neopeptide candidates overlapped between the two predicted candidate pools. Among the candidates, 28 (20%, 28/ 137) and 15 (20%, 15/ 75) were positive by ELISpot assay, respectively. Among 26 overlapped candidates, 20 could be tested, and 7 of them (35%) were validated by ELISpot. Neopepsee identified at least one neoepitope in 7 of 9 patients (range 0-6), compared to 6 by pVACseq (range 0-5).

Conclusion

As suggested by Tumor Neoantigen Selection Alliance (TESLA), our results demonstrate low PPV of individual prediction models as well as the complementary nature of the Neopepsee and pVACseq and may help design neoepitope targeted cancer vaccines. Our data contribute a significant addition to the database of tested neoepitope candidates that can be utilized to further train and improve the prediction algorithms.
Proteomics analysis in urinary bladder cancer patients identifies urinary SOD2 as a predictive marker of recurrence
Authors: Kumari Nitu , Bishwal Subasa Chandra , Chaudhary Shweta , Malalkar Deepankar , Dubey Uma S. , Vasudeva Pawan , Kumar Anup , Saxena Sunita , Nanda Ranjan Kumar , Agrawal Usha
Published: December 2021

Early non-invasive detection of tumor is an urgent clinical need for managing urothelial bladder cancer. Cystoscopy and cytology are the current standards for diagnosis of recurrence, but are limited by low sensitivity. Quantitative proteomics tool was employed to identify important deregulated molecules in bladder cancer tissues and validated using Western blot and immunohistochemistry analysis. A set of 1137 proteins were identified in four paired bladder cancer patients. Among these, 64 proteins were deregulated in all cases among which 9 were commonly up-regulated. The Ingenuity Pathway Analysis (IPA) generated top 11 Networks in which three commonly upregulated (SERPING1, SOD2 and HSPB6) proteins were involved and selected for further validation. Tissue expression of SOD2, SERPING1 and HSPB6 monitored in an independent sample set (n=18) by immuno-histochemical analysis showed similar profile. Western blot analysis of these proteins in urine of bladder cancer (n=26) and healthy subjects (n=10) showed a specificity and sensitivity of >80% for SOD2 and so was selected for further validation in a separate set (n=150) by ELISA. Significant elevation in urinary SOD2 level was found in urothelial bladder cancer patients compared to healthy controls and in recurrent cases compared to primary (p-value<0.001). Kaplan Meier survival analysis showed urinary SOD2 concentration >2,100 pg/ml was significantly associated with poorer survival.Cumulative survival of patient with low SOD2 concentration was 34.4% compared to 18.9% in patient with high SOD2 at 24 months (p=0.025). The study identifies SOD2 as a non-invasive biomarker which may help to extend the period between cystoscopies during follow-up.

Significance

Cystoscopy is an invasive and painful method commonly used for diagnosis of urothelial bladder cancer. Non-invasive methods having high specificity and sensitivity to monitor the patients for recurrence are unavailable. Our study reveals significantly higher SOD2 level in drug naive and reoccurring bladder cancer tissues, and similar profile was observed in the parallel urine samples. Hence, SOD2 seems to be a useful biomarker of recurrent urothelial bladder cancer and predict the survival of patients.
Broad anti-SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 prime-boost vaccination
Authors: Kaku Chengzi I. , Champney Elizabeth R. , Normark Johan , Johnson Carl E. , Ahlm Clas , Sakharkar Mrunal , Ackerman Margaret E. , Forsell Mattias N. E. , Walker Laura M.
Published: December 2021

Heterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy and address ongoing vaccine supply challenges. Here, we longitudinally profiled SARS-CoV-2 spike (S)-specific serological and memory B cell (MBC) responses in individuals receiving either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous mRNA booster immunization induced significantly higher serum neutralizing antibody and MBC responses compared to homologous ChAdOx1 boosting. Specificity mapping of circulating S-specific B cells revealed that mRNA-1273 booster immunization dramatically immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273-boosted participants displayed higher binding affinities and increased breadth of reactivity against variants of concern (VOCs) relative to those isolated from ChAdOx1-boosted participants. Overall, the results provide fundamental insights into the B cell response induced by ChAdOx1 and a molecular basis for the enhanced immunogenicity observed following heterologous mRNA booster vaccination.
Durability of mRNA-1273 against COVID-19 in the time of Delta: Interim results from an observational cohort study
Authors: Florea Ana , Sy Lina S. , Luo Yi , Qian Lei , Bruxvoort Katia J. , Ackerson Bradley K. , Lee Gina S. , Ku Jennifer H. , Tubert Julia E. , Tian Yun , Talarico Carla A. , Tseng Hung Fu
Published: December 2021

Background

We conducted a prospective cohort study at Kaiser Permanente Southern California to study the vaccine effectiveness (VE) of mRNA-1273 over time and during the emergence of the Delta variant.

Methods

The cohort for this planned interim analysis consisted of individuals aged ≥18 years receiving 2 doses of mRNA-1273 through June 2021, matched 1:1 to randomly selected unvaccinated individuals by age, sex, and race/ethnicity, with follow-up through September 2021. Outcomes were SARS-CoV-2 infection, and COVID-19 hospitalization and hospital death. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) comparing outcomes in the vaccinated and unvaccinated groups. Adjusted VE (%) was calculated as (1-aHR)x100. HRs and VEs were also estimated for SARS-CoV-2 infection by age, sex, race/ethnicity, and during the Delta period (June-September 2021). VE against SARS-CoV-2 infection and COVID-19 hospitalization was estimated at 0-<2, 2-<4, 4-<6, and 6-<8 months post-vaccination.

Results

927,004 recipients of 2 doses of mRNA-1273 were matched to 927,004 unvaccinated individuals. VE (95% CI) was 82.8% (82.2-83.3%) against SARS-CoV-2 infection, 96.1% (95.5-96.6%) against COVID-19 hospitalization, and 97.2% (94.8-98.4%) against COVID-19 hospital death. VE against SARS-CoV-2 infection was similar by age, sex, and race/ethnicity, and was 86.5% (84.8-88.0%) during the Delta period. VE against SARS-CoV-2 infection decreased from 88.0% at 0-<2 months to 75.5% at 6-<8 months.

Conclusions

These interim results provide continued evidence for protection of 2 doses of mRNA-1273 against SARS-CoV-2 infection over 8 months post-vaccination and during the Delta period, and against COVID-19 hospitalization and hospital death.

This prospective cohort study provides evidence for continued protection of 2 doses of mRNA-1273 against SARS-CoV-2 infection over 8 months post-vaccination and during the Delta period. VE against COVID-19 hospitalization remained robust and stable over the same period.
Harmonization of SARS CoV-2 antibodies determination. Is it really possible?
Authors: Dittadi Ruggero
Published: December 2021

The WHO standard was prepared with the aim of harmonizing assays detecting antibodies against SARS CoV-2. The aspect of the harmonization of the assays is to date under debate. We re-evaluated a previously studied set of cases (108 specimens of 48 patients and 60 specimens of 20 vaccinated subjects, collected after 14 days from the first dose, 14 days and 3 months after a second dose of the Comirnaty BNT162b2 vaccine), calculating the ratios between the results of two methods (SARS-CoV-2 IgG anti-RBD, SNIBE and anti-SARS-CoV-2 QuantiVac ELISA IgG, Euroimmun).

In the vaccinated subjects the ratios of the results between methods according to the WHO standard were relatively dispersed, but the harmonization results good. On the other hand, in patient samples the variability between tests was very high and the harmonization was unsatisfactory (median ratios between methods 2.23, 10th-90th percentile: 1.1-5.6).

Interestingly, in patient samples the harmonization depends on the time from the onset of symptoms, and greatly improves after 6 months from the diagnosis. 40 patient specimens and 31 of vaccinated subjects after the second dose were evaluated also with a third method (Access SARS-CoV-2 IgG (1st IS), Beckman Coulter), obtaining a similar trend.

We can conclude that the actual effectiveness of harmonization between methods may vary depending on the scenario in which they will be used.
Both Prey and Predator Features Determine Predation Risk and Survival of Schooling Prey
Authors: Jolles Jolle W. , Sosna Matthew M. G. , Mazué Geoffrey P. F. , Twomey Colin R. , Bak-Coleman Joseph , Rubenstein Daniel I. , Couzin Iain D.
Published: December 2021

Predation is one of the main evolutionary drivers of social grouping. While it is well appreciated that predation risk is likely not shared equally among individuals within groups, its detailed quantification has remained difficult due to the speed of attacks and the highly-dynamic nature of collective prey response. Here, using high-resolution tracking of solitary predators (Northern pike) hunting schooling fish (golden shiners), we not only provide detailed insights into predator decision-making but show which key spatial and kinematic features of predator and prey influence individual’s risk to be targeted and survive attacks. Pike tended to stealthily approach the largest groups, and were often already inside the school when launching their attack, making prey in this frontal “strike zone” the most vulnerable to be targeted. From the prey’s perspective, those fish in central locations, but relatively far from, and less aligned with, neighbours, were most likely to be targeted. While the majority of attacks (70%) were successful, targeted individuals that did manage to avoid capture exhibited a higher maximum acceleration response just before the attack and were further away from the pike‘s head. Our results highlight the crucial interplay between predators’ attack strategy and response of prey in determining predation risk in mobile animal groups.
Mucosal and systemic responses to SARS-CoV-2 vaccination in infection naïve and experienced individuals
Authors: Sajadi Mohammad M. , Myers Amber , Logue James , Saadat Saman , Shokatpour Narjes , Quinn James , Newman Michelle , Deming Megan , Tehrani Zahra Rikhtegaran , Karimi Maryam , Abbasi Abdolrahim , Shlyak Mike , Frieman Matthew B. , Crotty Shane , Harris Anthony D.
Published: December 2021

With much of the world infected with or vaccinated against SARS-CoV-2, understanding the immune responses to the SARS-CoV-2 spike (S) protein in different situations is crucial to controlling the pandemic. We studied the clinical, systemic, mucosal, and cellular responses to two doses of SARS-CoV-2 mRNA vaccines in 62 individuals with and without prior SARS-CoV-2 exposure that were divided into three groups based on serostatus and/or degree of symptoms: Antibody negative, Asymptomatic, and Symptomatic. In the previously SARS-CoV-2-infected (SARS2-infected) Asymptomatic and Symptomatic groups, symptoms related to a recall response were elicited after the first vaccination. Anti-S trimer IgA and IgG levels peaked after 1st vaccination in the SARS2-infected groups, and were higher that the in the SARS2-naive group in the plasma and nasal samples at all time points. Neutralizing antibodies titers were also higher against the WA-1 and B.1.617.2 (Delta) variants of SARS-CoV-2 in the SARS2-infected compared to SARS2-naïve vaccinees. After the first vaccination, differences in cellular immunity were not evident between groups, but the AIM+ CD4+ cell response correlated with durability of humoral immunity against the SARS-CoV-2 S protein. In those SARS2-infected, the number of vaccinations needed for protection, the durability, and need for boosters are unknown. However, the lingering differences between the SARS2-infected and SARS2-naïve up to 10 months post-vaccination could explain the decreased reinfection rates in the SARS2-infected vaccinees recently reported and suggests that additional strategies (such as boosting of the SARS2-naïve vaccinees) are needed to narrow the differences observed between these groups.
Unexpected short- and long-term effects of chronic adolescent HU-210 exposure on emotional behavior
Authors: Farinha-Ferreira Miguel , Rei Nádia , Fonseca-Gomes João , Miranda-Lourenço Catarina , Serrão Paula , Vaz Sandra H. , Gomes Joana I. , Martins Valéria , de Alves Pereira Beatriz , Sebastião Ana M.
Published: December 2021

Chronic adolescent cannabinoid receptor agonist exposure has been shown to lead to persistent increases in depressive-like behaviors. This has been a key obstacle to the development of cannabinoid-based therapeutics. However, most of the published work has been performed with only three compounds, namely Δ9-tetrahydrocannabinol, CP55,940 and WIN55,212-2. Hypothesizing that different compounds may lead to distinct outcomes, we herein used the highly potent CB1R/CB2R full agonist HU-210, and first aimed at replicating cannabinoid-induced long-lasting effects, by exposing adolescent female Sprague-Dawley rats to increasing doses of HU-210, for 11 days and testing them at adulthood, after a 30-day drug washout. Surprisingly, HU-210 did not significantly impact adult anxious- or depressive-like behaviors. We then tested whether chronic adolescent HU-210 treatment resulted in short-term (24h) alterations in depressive-like behavior. Remarkably, HU-210 treatment simultaneously induced marked antidepressant- and prodepressant-like responses, in the modified forced swim (mFST) and sucrose preference tests (SPT), respectively. Hypothesizing that mFST results were a misleading artifact of HU-210-induced behavioral hyperreactivity to stress, we assessed plasmatic noradrenaline and corticosterone levels, under basal conditions and following an acute swim-stress episode. Notably, we found that while HU-210 did not alter basal noradrenaline or corticosterone levels, it greatly augmented the stress-induced increase in both.

Our results show that, contrary to previously studied cannabinoid receptor agonists, HU-210 does not induce persisting depressive-like alterations, despite inducing marked short-term increases in stress-induced reactivity. By showing that not all cannabinoid receptor agonists may induce long-term negative effects, these results hold significant relevance for the development of cannabinoid-based therapeutics.
The anti-angiogenic compound dimethyl fumarate inhibits the serine synthesis pathway and increases glycolysis in endothelial cells
Authors: Ocaña Maria Carmen , Yang Chendong , Bernal Manuel , Martínez-Poveda Beatriz , Vu Hieu S. , Cárdenas Casimiro , DeBerardinis Ralph J. , Quesada Ana R. , Medina Miguel Ángel
Published: December 2021

A pathological and persistent angiogenesis is observed in several diseases like retinopathies, diabetes, psoriasis and cancer. Dimethyl fumarate, an ester from the Krebs cycle intermediate fumarate, is approved as a drug for the treatment of psoriasis and multiple sclerosis, and its anti-angiogenic activity has been reported in vitro and in vivo. However, it is not known whether dimethyl fumarate is able to modulate endothelial cell metabolism, considered an essential feature for the angiogenic switch. By means of different experimental approximations, including proteomics, isotope tracing and metabolomics experimental approaches, in this work we studied the possible role of dimethyl fumarate in endothelial cell energetic metabolism. We demonstrate for the first time that dimethyl fumarate promotes glycolysis and diminishes cell respiration, which could be a consequence of a down-regulation of serine and glycine synthesis through inhibition of PHGDH activity in endothelial cells. This new target can open a new field of study regarding the mechanism of action of dimethyl fumarate.
Modeling Synaptic Effects of Anesthesia and its Cortical Cholinergic Reversal
Authors: Eniwaye Bolaji P. , Booth Victoria , Hudetz Anthony G. , Zochowski Michal
Published: December 2021

General anesthetics work through a variety of molecular mechanisms while resulting in the common end point of sedation and loss of consciousness. Generally, the administration of common inhalation anesthetics induces decreases in synaptic excitation while promoting synaptic inhibition. Animal studies have shown that, during anesthesia, exogenously induced increases in acetylcholine-mediated effects in the brain can elicit wakeful-like behavior despite the continued presence of the anesthetic. Less investigated, however, is the question of whether the brain’s electrophysiological activity is also restored to pre-anesthetic levels and quality by such interventions. Here we apply a computational model of a network composed of excitatory and inhibitory neurons to simulate the network effects of changes in synaptic inhibition and excitation due to anesthesia and its reversal by muscarinic receptor-mediated cholinergic effects. We use a differential evolution algorithm to fit model parameters to match measures of spiking activity, neuronal connectivity, and network dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that facilitating muscarinic receptor effects of acetylcholine on top of anesthetic-induced synaptic changes predicts reversal of the neurons’ spiking activity, functional connectivity, as well as pairwise and population interactions. Thus, our model results predict a possible neuronal mechanism for the induced reversal of the effects of anesthesia on post synaptic potentials, consistent with experimental behavioral observations.

Author Summary

Here, we apply a computational model of a network composed of excitatory and inhibitory neurons to simulate the network effects of changes in synaptic inhibition and excitation due to anesthesia and we investigate the possibility of its reversal by muscarinic receptor-mediated cholinergic effects. Specifically, we use a differential evolution algorithm to fit model parameters to match dynamics recorded in the visual cortex of rodents during anesthesia with desflurane in vivo. We find that changes of the fitted synaptic parameters in response to the increasing desflurane concentration matched those established by neurophysiology. Further, our results demonstrate that the cellular effects induced by anesthesia can be mitigated by the changes in cellular excitability due to acetylcholine.