bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporary hold of mycophenolate boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients
Authors: Schrezenmeier Eva , Rincon-Arevalo Hector , Jens Annika , Stefanski Ana-Luisa , Hammett Charlotte , Osmanodja Bilgin , Koch Nadine , Zukunft Bianca , Beck Julia , Oellerich Michael , Pross Vanessa , Stahl Carolin , Choi Mira , Bachmann Friederike , Liefeldt Lutz , Glander Petra , Schütz Ekkehard , Bornemann-Kolatzki Kirsten , López del Moral Covadonga , Schrezenmeier Hubert , Ludwig Carolin , Jahrsdörfer Bernd , Eckardt Kai-Uwe , Lachmann Nils , Kotsch Katja , Dörner Thomas , Halleck Fabian , Sattler Arne , Budde Klemens
Published: January 2022

Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression. Recent data from autoimmune patients suggest that temporary MPA hold might significantly improve booster vaccination outcomes. We applied a fourth dose of SARS-CoV-2 vaccine during temporary (5 weeks) MPA hold to 29 kidney transplant recipients, who had not mounted a humoral immune-response to previous vaccinations. Seroconversion until day 32 after vaccination was observed in 76% of patients, associated with acquisition of virus neutralizing capacity. Interestingly, 21/25 (84%) CNI-treated patients responded, but only 1/4 Belatacept-treated patients. In line with humoral responses, counts and relative frequencies of spike receptor binding domain (RBD) specific B cells were significantly increased on day 7 after vaccination, with an increase in RBD specific CD27++CD38+ plasmablasts. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, frequencies were positively correlated with specific IgG levels. Importantly, antigen-specific proliferating Ki67+ and in vivo activated PD1+ T cells significantly increased after re-vaccination during MPA hold, whereas cytokine production and memory differentiation remained unaffected. In summary, MPA hold was safe and augmented all arms of immunity during booster vaccination, suggesting its implementation in vaccination protocols for clinically stable transplant recipients.
Effect of Ozone on Allergic Airway Inflammation
Authors: Arjomandi Mehrdad , Wong Hofer , Tenney Rachel , Holland Nina , Balmes John R.
Published: January 2022

Background

Exposure to O3 has been associated with increased risk of exacerbations of asthma, but the underlying mechanisms are not well studied. We hypothesized that O3 exposure would enhance airway inflammatory responses to allergen and the GSTM1 null genotype would modulate this enhancement.

Procedures

In a cross-over design, 10 asthmatic subjects (50% with GSTM1 null genotype) who had specific sensitization to Dermatophagoides pteronyssinus (DP) were exposed to 160 ppb O3 or filtered air (FA) control for 4 h with intermittent exercise on two separate days at least three weeks apart. 20 h post-exposure, endobronchial challenge with DP allergen, and sham normal saline (NS) instillation, were performed in two separate lung lobes. Six h later, a second bronchoscopy was performed to collect bronchoalveolar lavage (BAL) fluid from the DP- and NS-challenged lobes for analyses of cellular and biochemical markers of inflammation. Multiple variable regression was used to compare cell and cytokine responses across the four exposure groups (FA-NS, O3-NS, FA-DP, O3-DP). Effect modification by GSTM1 genotype was assessed in stratified regressions.

Main Findings

BAL eosinophil and lymphocyte counts were increased in segments challenged with DP compared to segments that received sham challenges (p<0.01). DP challenge compared to sham challenge also caused a significant increase in BAL concentrations of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 (p<0.03 for all comparisons). O3 exposure did not significantly affect BAL cells or cytokine levels although BAL neutrophil count with DP challenge was non-significantly higher after O3 compared to after FA exposure (p<0.11). Compared to GSTM1-present subjects, GSTM1-null subjects had significantly reduced inflammatory responses including lower eosinophil (p<0.041) and IL-4 (p<0.014) responses to DP challenge after O3 exposure.

Conclusions

O3 appears to have mixed effects on allergen-induced airway inflammation. While O3 did not cause a clear differential effect on airway cellular or cytokine responses to allergen challenge, those responses did appear to be modulated by the antioxidant enzyme, GSTM1, as evident by the attenuation of airway inflammatory responses to allergen after O3 exposure in the absence of the gene.

HIGHLIGHTS

Ozone may increase risk of asthma exacerbation but the exact mechanisms are not clear.

Susceptibility to ozone-induced airway inflammation may be associated with GSTM1 genotype.

Ozone may enhance allergen-induced airway recruitment of neutrophils.

The GSTM1 null mutation may decrease both eosinophil and cytokine allergic airway responses after O3 exposure.
Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses
Authors: Dosil Sara G. , López-Cobo Sheila , Rodríguez-Galán Ana , Fernández-Delgado Irene , Ramirez-Huesca Marta , Milán-Rois Paula , Castellanos Milagros , Somoza Álvaro , Gómez Manuel José , Reyburn Hugh T. , Valés-Gómez Mar , Sánchez-Madrid Francisco , Fernández-Messina Lola
Published: January 2022

Natural killer (NK) cells recognise and kill target cells undergoing different types of stress. NK cells are also capable of modulating immune responses. In particular, they regulate T cell functions. Small RNA next-generation sequencing of resting and activated NK cells and their secreted EVs led to the identification of a specific repertoire of NK-EV-associated microRNAs and their post-transcriptional modifications signature. Several microRNAs of NK-EVs, namely miR-10b-5p, miR-92a-3p and miR-155-5p, specifically target molecules involved in Th1 responses. NK-EVs promote the downregulation of GATA-3 mRNA in CD4+T cells and subsequent T-bet de-repression that leads to Th1 polarization and IFN-γ and IL-2 production. NK-EVs also have an effect on monocyte and moDCs function, driving their activation and increased presentation and co-stimulatory functions. Nanoparticle-delivered NK-EV microRNAs partially recapitulate NK-EV effectsin vivo. Our results provide new insights on the immunomodulatory roles of NK-EVs that may help to improve their use as immunotherapeutic tools.
Consensus on COVID-19 vaccination in pediatric oncohematological patients, on behalf of infectious working group of Italian Association of Pediatric Hematology Oncology
Authors: Cesaro Simone , Muggeo Paola , Zama Daniele , Cellini Monica , Perruccio Katia , Colombini Antonella , Carraro Francesca , Petris Mariagrazia , Petroni Valeria , Mascarin Maurizio , Baccelli Francesco , Soncini Elena , Mura Rosamaria , Laspina Milena , Decembrino Nunzia , Burnelli Roberta , Frenos Stefano , Castagnola Elio , Faraci Maura , Meazza Cristina , Barzaghi Federica , D’Amico Maria Rosaria , Capasso Maria , Calore Elisabetta , Ziino Ottavio , Barone Angelica , Compagno Francesca , Luti Laura , Galaverna Federica , De Santis Raffaella , Brescia Letizia , Meneghello Linda , Petrone Angelamaria , Giurici Nagua , Schumacher Fabian , Mercolini Federico
Published: January 2022

Vaccines represent the best tool to prevent the severity course and fatal consequences of pandemic by new Coronavirus 2019 infection (SARS-CoV-2). Considering the limited data on vaccination of pediatric oncohematological patients, we develop a Consensus document to support the Italian pediatric hematological oncological (AIEOP) centers in a scientifically correct communication with families and patients and to promote vaccination. The topics of the Consensus were: SARS-CoV-2 infection and disease (COVID-19) in the pediatric subjects; COVID-19 vaccines (type, schedule); which and when to vaccinate; contraindications and risk of serious adverse events; rare adverse events; third dose and vaccination after COVID-19; and other general prevention measures. Using the Delphi methodology for Consensus, 21 statements and their corresponding rationale were elaborated and discussed with the representatives of 31 centers, followed by voting. AIEOP Centers showed an overall agreement on all the statements that were therefore approved.

This consensus document highlights that children and adolescents affected by hematological and oncological diseases are a fragile category. Vaccination plays an important role to prevent COVID-19, to permit the regular administration of chemotherapy or other treatments, to perform control visits and hospital admissions, and to prevent treatment delays.
Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissues
Authors: Nelson Christine E. , Namasivayam Sivaranjani , Foreman Taylor W. , Kauffman Keith D. , Sakai Shunsuke , Dorosky Danielle E. , Lora Nickiana E. ,   NIAID/DIR Tuberculosis Imaging Program, Brooks Kelsie , Potter E. Lake , Roederer Mario , Sher Alan , Weiskopf Daniela , Sette Alessandro , de Wit Emmie , Hickman Heather D. , Brenchley Jason M. , Via Laura E. , Barber Daniel L.
Published: January 2022

SARS-CoV-2 primarily replicates in mucosal sites, and more information is needed about immune responses in infected tissues. We used rhesus macaques to model protective primary immune responses in tissues during mild COVID-19. Viral RNA levels were highest on days 1-2 post-infection and fell precipitously thereafter. 18F-fluorodeoxyglucose (FDG)-avid lung abnormalities and interferon (IFN)-activated myeloid cells in the bronchoalveolar lavage (BAL) were found on days ∼3-4. Virus-specific effector CD8 and CD4 T cells were detectable in the BAL and lung tissue on days ∼7-10, after viral RNA, lung inflammation, and IFN-activated myeloid cells had declined. Notably, SARS-CoV-2-specific T cells were not detectable in the nasal turbinates, salivary glands, and tonsils on day 10 post-infection. Thus, SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19.

ONE SENTENCE SUMMARY

SARS-CoV-2 infection leads to mild, focal lung inflammation, and type I IFN activated myeloid cells that mostly resolve prior to the influx of virus-specific effector T cells or antibody responses in rhesus macaques.
Differential Peripheral Blood Glycoprotein Profiles in Symptomatic and Asymptomatic COVID-19
Authors: Pickering Chad , Zhou Bo , Xu Gege , Rice Rachel , Ramachandran Prasanna , Huang Hector , Pham Tho D. , Schapiro Jeffrey M. , Cong Xin , Chakraborty Saborni , Edwards Karlie , Reddy Srinivasa T. , Guirgis Faheem , Wang Taia T. , Serie Daniel , Lindpaintner Klaus
Published: January 2022

Glycosylation is the most common form of post-translational modification of proteins, critically affecting their structure and function. Using liquid chromatography and mass spectrometry for high-resolution site-specific quantification of glycopeptides coupled with high-throughput artificial intelligence-powered data processing, we analyzed differential protein glyco-isoform distributions of 597 abundant serum glycopeptides and non-glycosylated peptides in 50 individuals who had been seriously ill with COVID-19 and in 22 individuals who had recovered after an asymptomatic course of COVID-19. As additional comparison reference phenotypes, we included 12 individuals with a history of infection with a common cold coronavirus, 16 patients with bacterial sepsis, and 15 healthy subjects without history of coronavirus exposure. We found statistically significant differences, at FDR<0.05, for normalized abundances of 374 of the 597 peptides and glycopeptides interrogated, between symptomatic and asymptomatic COVID-19 patients. Similar statistically significant differences were seen when comparing symptomatic COVID-19 patients to healthy controls (350 differentially abundant peptides and glycopeptides) and common cold coronavirus seropositive subjects (353 differentially abundant peptides and glycopeptides). Among healthy controls and sepsis patients, 326 peptides and glycopeptides were found to be differentially abundant, of which 277 overlapped with biomarkers that showed differential expression between symptomatic COVID-19 cases and healthy controls. Among symptomatic COVID-19 cases and sepsis patients, 101 glycopeptide and peptide biomarkers were found to be statistically significantly abundant. Using both supervised and unsupervised machine learning techniques, we found specific glycoprotein profiles to be strongly predictive of symptomatic COVID-19 infection. LASSO-regularized multivariable logistic regression and K-means clustering yielded accuracies of 100% in an independent test set and of 96% overall, respectively. Our findings are consistent with the interpretation that a majority of glycoprotein modifications observed which are shared among symptomatic COVID-19 and sepsis patients likely represent a generic consequence of a severe systemic immune and inflammatory state. However, there are glyco-isoform changes that are specific and particular to severe COVID-19 infection. These may be representative of either COVID-19-specific consequences or of susceptibility to or predisposition for a severe course of the disease. Our findings support the potential value of glycoproteomic biomarkers in the biomedical understanding, and, potentially, the clinical management of serious acute infectious conditions.
Innate and adaptive immune defects associated with lower SARS-CoV-2 BNT162b2 mRNA vaccine response in elderly people
Authors: Vitallé Joana , Pérez-Gómez Alberto , Ostos Francisco José , Gasca-Capote Carmen , Jiménez-León María Reyes , Bachiller Sara , Rivas-Jeremías Inmaculada , del Mar Silva-Sánchez Maria , Ruiz-Mateos Anabel , López-Cortes Luis Fernando , Rafii-El-Idrissi Benhnia Mohammed , Ruiz-Mateos Ezequiel
Published: January 2022

The immune factors associated with impaired SARS-CoV-2 vaccine response in the elderly are mostly unknown. We studied old and young people vaccinated with SARS-CoV-2 BNT162b2 mRNA before and after the first and second dose. Aging was associated with a lower anti-RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2 specific T cell response. The dramatic decrease in thymic function in the elderly, which fueled alteration in T cell homeostasis, and lower CD161+ T cell levels were associated with decreased T cell response two months after vaccination. Additionally, a deficient dendritic cell (DC) homing, activation and Toll like receptor (TLR)-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the elderly, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.
Genome-wide Association Study of Pulmonary Function in Europeans and Africans from the UK Biobank Identifies Distinct Variants
Authors: Sinkala Musalula , Elsheikh Samar S. M. , Mbiyavanga Mamana , Cullinan Joshua , Mulder Nicola J.
Published: January 2022

Pulmonary function is an indicator of well-being, and pulmonary pathologies are the third major cause of death worldwide. FEV1, FVC, and PEF are quantitively used to assess pulmonary function. We conducted a genome-wide association analysis of pulmonary function in 383,471 individuals of European and 5,978 African descent represented in the UK Biobank. Here, we report 817 variants in Europeans and 3 in Africans associated (p-values < 5 × 10−8) with three pulmonary function parameters; FEV1, FVC and PEF. In addition to 377 variants in Europeans previously reported to be associated with phenotypes related to pulmonary function, we identified 330 novel loci, including an ISX intergenic variant rs369476290 on chromosome 22 in Africans and a KDM2A intron variant rs12790261 on chromosome 11 in Europeans. Remarkably, we find no shared variants among Africans and Europeans. Enrichment analyses of variants separately for each ancestry background revealed significant enrichment for terms related to pulmonary phenotypes in Europeans but not Africans. Further analysis of studies of pulmonary phenotypes revealed individuals of European background are disproportionally overrepresented in datasets compared to Africans, with the gap widening over the past five years. Our findings offer a better understanding of the different variants that modify pulmonary function in Africans and Europeans, a significant finding for future GWAS studies and medicine.
BNT162b2 post-exposure-prophylaxis against COVID-19
Authors: Shmuelian Zohar , Warszawer Yehuda , Or Omri , Arbel-Alon Sagit , Giladi Hilla , Tsadok Meytal Avgil , Cohen Roy , Shefer Galit , Maruotti Antonello , Lasinio Giovanna Jona , Galun Eithan
Published: January 2022

Background

During the COVID-19 pandemic, post-exposure-prophylaxis is not a practice. Following exposure, only patient isolation is imposed. Moreover, no therapeutic prevention approach is applied. We asked whether evidence exists for reduced mortality rate following post-exposure-prophylaxis.

Methods

To estimate the effectiveness of post-exposure-prophylaxis, we obtained data from the Israeli Ministry of Health (MoH) registry. The study population consisted of Israeli residents aged 12 years and older, identified for the first time as PCR-positive for SARS-CoV-2, between December 20th, 2020 (the beginning of the vaccination campaign) and October 7th, 2021. We compared “recently injected” patients - that proved PCR-positive on the same day or on one of the five consecutive days after first vaccination (representing an unintended post-exposure-prophylaxis), to unvaccinated control group.

Results

Among Israeli residents identified PCR-positive for SARS-CoV-2, 11,690 were found positive on the day they received their first vaccine injection (BNT162b2) or on one of the 5 days thereafter. In patients over 65 years, 143 deaths occurred among 1413 recently injected (10.12%) compared to 280 deaths among the 1413 unvaccinated (19.82%), odd ratio (OR) 0.46 (95% confidence interval (CI), 0.36 to 0.57; P<0.001). The most significant reduction in the death toll was observed among the 55 to 64 age group, with 8 deaths occurring among the 1322 recently injected (0.61%) compared to 43 deaths among the 1322 unvaccinated control (3.25%), OR 0.18 (95% CI, 0.07 to 0.39; P<0.001).

Conclusion

Post-exposure-prophylaxis is effective against death in COVID-19 infection.

Israeli MoH Registry Number

HMO-0372-20
Multi-omics reveals principles of gene regulation and pervasive non-productive transcription in the human cytomegalovirus genome
Authors: Jürges Christopher Sebastian , Lodha Manivel , Khanh Le-Trilling Vu Thuy , Bhandare Pranjali , Wolf Elmar , Zimmermann Albert , Trilling Mirko , Prusty Bhupesh , Dölken Lars , Erhard Florian
Published: January 2022

For decades, human cytomegalovirus (HCMV) was thought to express ≈200 viral proteins during lytic infection. In recent years, systems biology approaches uncovered hundreds of additional viral gene products and suggested thousands of viral sites of transcription initiation. Despite all available data, the molecular mechanisms of HCMV gene regulation remain poorly understood. Here, we provide a unifying model of productive HCMV gene expression employing transcription start site profiling combined with metabolic RNA labeling as well as integrative computational analysis of previously published big data. This approach defined the expression of >2,600 high confidence viral transcripts and explained the complex kinetics of viral protein expression by cumulative effects of translation of incoming virion-associated RNA, multiple transcription start sites with distinct kinetics per viral open reading frame, and differences in viral protein stability. Most importantly, we identify pervasive transcription of transient RNAs as a common feature of this large DNA virus with its human host.
Heparin-derived theranostic nanoprobes overcome the blood brain barrier and target glioma in murine model
Authors: Samanta Sumanta , Joncour Vadim Le , Wegrzyniak Olivia , Rangasami Vignesh Kumar , Ali-Löytty Harri , Hong Taehun , Selvaraju Ram Kumar , Aberg Ola , Hilborn Jons , Laakkonen Pirjo , Varghese Oommen P. , Eriksson Olof , Cabral Horacio , Oommen Oommen P.
Published: January 2022

The poor permeability of theranostic agents across the blood-brain-barrier (BBB) significantly hampers the development of new treatment modalities for neurological diseases. We have discovered a new biomimetic nanocarrier using heparin (HP) that effectively passes the BBB and targets glioblastoma. Specifically, we designed HP coated gold nanoparticles (HP-AuNPs) that were labeled with three different imaging modalities namely, fluorescein (FITC-HP-AuNP), radioisotope 68Gallium (68Ga-HP-AuNPs), and MRI active gadolinium (Gd-HP-AuNPs). The systemic infusion of FITC-HP-AuNPs in three different mouse strains (C57BL/6JRj, FVB, and NMRI-nude) displayed excellent penetration and revealed uniform distribution of fluorescent particles in the brain parenchyma (69-86%) with some accumulation in neurons (8-18%) and microglia (4-10%). Tail-vein administration of radiolabeled 68Ga-HP-AuNPs in healthy rats also showed 68Ga-HP-AuNP inside the brain parenchyma and in areas containing cerebrospinal fluid, such as the lateral ventricles, the cerebellum, and brain stem. Finally, tail-vein administration of Gd-HP-AuNPs (that display ∼3 fold higher relaxivity than that of commercial Gd-DTPA) in an orthotopic glioblastoma (U87MG xenograft) model in nude mice demonstrated enrichment of T1-contrast at the intracranial tumor with a gradual increase in the contrast in the tumor region between 1h-3h. We believe, our finding offers the untapped potential of HP-derived-NPs to deliver cargo molecules for treating neurological disorders.
Chaining for Accurate Alignment of Erroneous Long Reads to Acyclic Variation Graphs*
Authors: Ma Jun , Cáceres Manuel , Salmela Leena , Mäkinen Veli , Tomescu Alexandru I.
Published: January 2022

Aligning reads to a variation graph is a standard task in pangenomics, with downstream applications such as improving variant calling. While thevgtoolkit (Garrison et al.,Nature Biotechnology, 2018) is a popular aligner of short reads,GraphAligner(Rautiainen and Marschall,Genome Biology, 2020) is the state-of-the-art aligner of erroneous long reads.GraphAlignerworks by finding candidate read occurrences based onindividuallyextending the best seeds of the read in the variation graph. However, a more principled approach recognized in the community is to co-linearly chainmultipleseeds.

We present a new algorithm to co-linearly chain a set of seeds in a string labeled acyclic graph, together with the first efficient implementation of such a co-linear chaining algorithm into a new aligner of erroneous long reads to acyclic variation graphs,GraphChainer. Compared toGraphAligner,GraphChaineraligns 12% to 17% more reads, and 21% to 28% more total read length, on real PacBio reads from human chromosomes 1, 22 and the whole human pangenome. On both simulated and real data,GraphChaineraligns between 95% and 99% of all reads, and of total read length. We also show thatminigraph(Li et al.,Genome Biology, 2020) andminichain(Chandra and Jain,RECOMB, 2023) obtain an accuracy of less than 60% on this setting.

GraphChaineris freely available athttps://github.com/algbio/GraphChainer. The datasets and evaluation pipeline can be reached from the previous address.
In vitro and in vivo venom-inhibition assays identify metalloproteinase-inhibiting drugs as potential treatments for snakebite envenoming by Dispholidus typus
Authors: Menzies Stefanie K. , Clare Rachel H. , Xie Chunfang , Westhorpe Adam , Hall Steven R. , Edge Rebecca J. , Alsolaiss Jaffer , Crittenden Edouard , Harrison Robert A , Kool Jeroen , Casewell Nicholas R.
Published: January 2022

Snakebite envenoming affects more than 250,000 people annually in sub-Saharan Africa. Envenoming by Dispholidus typus (boomslang) results in venom induced consumption coagulopathy, whereby highly abundant prothrombin-activating snake venom metalloproteinases (SVMPs) consume clotting factors and deplete fibrinogen. The only available treatment for D. typus envenoming is the monovalent SAIMR Boomslang antivenom. Treatment options are urgently required because this antivenom is often difficult to source and, at $6,000/vial, typically unaffordable for most snakebite patients. We therefore investigated the in vitro and in vivo preclinical efficacy of four SVMP inhibitors to neutralise the effects of D. typus venom; the matrix metalloproteinase inhibitors marimastat and prinomastat, and the metal chelators dimercaprol and DMPS. The venom of D. typus exhibited an SVMP-driven procoagulant phenotype in vitro. Marimastat and prinomastat demonstrated equipotent inhibition of the SVMP-mediated procoagulant activity of the venom in vitro, whereas dimercaprol and DMPS showed considerably lower potency. However, when tested in preclinical murine models of envenomation, DMPS and marimastat demonstrated partial protection against venom lethality, demonstrated by prolonged survival times of experimental animals, whereas dimercaprol and prinomastat failed to confer any protection at the doses tested. The results presented here demonstrate that DMPS and marimastat show potential as novel small molecule-based therapeutics for D. typus snakebite envenomation. These two drugs have been previously shown to be effective against Echis ocellatus venom induced consumption coagulopathy (VICC) in preclinical models, and thus we conclude that marimastat and DMPS may be valuable early intervention therapeutics to broadly treat VICC following snakebite envenoming in sub-Saharan Africa.
Wnt/PCP signaling mediates breast cancer metastasis by promoting pro-invasive protrusion formation in collectively motile leader cells
Authors: VanderVorst Kacey , Dreyer Courtney A. , Hatakeyama Jason , Bell George R. R. , Berg Anastasia L. , Hernandez Maria , Lee Hyun , Collins Sean R. , Carraway Kermit L.
Published: January 2022

As evidence supporting essential roles for collective cell migration in carcinoma metastasis continues to accumulate, a better understanding of the underlying cellular and molecular mechanisms will be critical to translating these findings to the treatment of advanced cancers. Here we report that Wnt/PCP, a non-canonical Wnt signaling pathway, mediates breast cancer collective migration and metastasis. We observe that mammary gland-specific knockout of Vangl2, a tetraspanin-like scaffolding protein required for Wnt5a-induced signaling and motility in cultured breast cancer cell lines, results in a striking decrease in metastatic efficiency but not primary tumor growth in the MMTV-NDL transgenic mouse model of HER2-positive breast cancer. We also observe that expression levels of core Wnt/PCP components Wnt5a, Vangl1 and Vangl2 are selectively elevated in K14-positive leader cells relative to follower cells within a collectively migrating cohort, and that Vangl2 expression selectively promotes RhoA activation in leading edge cells. Moreover, Vangl expression drives collective migration in three-dimensional ex vivo tumor organoids, and Vangl protein specifically accumulates within pro-migratory filamentous actin-rich protrusions of leader cells. Together, our observations point to a model whereby Wnt/PCP upregulation facilitates breast tumor collective cell motility by selectively augmenting the formation pro-migratory protrusions within leader cells.
Differences in pathways contributing to thyroid hormone effects on postnatal cartilage calcification versus secondary ossification center development
Authors: Gomez Gustavo A. , Aghajanian Patrick , Pourteymoor Sheila , Larkin Destiney , Mohan Subburaman
Published: January 2022

The proximal and distal femur epiphysis of mice are both weight bearing structures derived from chondrocytes but differ in development. Mineralization at the distal epiphysis occurs in an osteoblast rich secondary ossification center (SOC), while the chondrocytes of the proximal femur head (FH) in particular, are directly mineralized. Thyroid hormone (TH) plays important roles in distal knee SOC formation, but whether TH also affects proximal FH development remains unexplored. Here, we found that TH controls chondrocyte maturation and mineralization at the FH in vivo through studies in Thyroid stimulating hormone receptor (Tshr-/-) hypothyroid mice by X-ray, histology, transcriptional profiling, and immunofluorescence staining. Both in vivo, and in vitro studies conducted in ATDC5 chondrocyte progenitors concur that TH regulates expression of genes that modulate mineralization (Bsp, Ocn, Dmp1, Opn, and Alp). Our work also delineates differences in prominent transcription factor regulation of genes involved in the different mechanisms leading to proximal FH cartilage calcification and endochondral ossification at the distal femur. The information on the molecular pathways contributing to postnatal cartilage calcification can provide insights on therapeutic strategies to treat pathological calcification that occurs in soft tissues such as aorta, kidney, and articular cartilage.
Busy and confused? High risk of missed alerts in the cockpit: an electrophysiological study
Authors: Causse Mickael , Parmentier Fabrice B. R. , Mouratille Damien , Thibaut Dorothée , Kisselenko Marie , Fabre Eve
Published: January 2022

Of evolutionary importance, the ability to react to unexpected auditory stimuli remains critical today, especially in settings such as aircraft cockpits or air traffic control towers, characterized by high mental and auditory loads. Evidences show that both factors can negatively impact auditory attention and prevent appropriate reactions in hazardous situations. In the present study, sixty participants performed a simulated aviation task, varying in terms of mental load (no, low, high mental load), that was embedded with a concurrent tone detection paradigm, in which auditory load was manipulated by the number of different tones (1, 2 or 3). We measured both detection performance (miss, false alarm) and brain activity (event-related potentials) related to the target tone. Our results showed that both mental and auditory loads affected tone detection performance. Importantly, their combined effects had a massive impact on the percentage of missed target tones. While, in the no mental load condition, miss rate was very low with 1 (0.53%) and 2 tones (1.11%), it increased drastically with 3 tones (24.44%), and this effect was accentuated as mental load increased, yielding to the higher miss rate in the 3-tone paradigm under high mental load conditions (68.64%). Increased mental load, auditory load, and miss rate, were all associated with disrupted brain response to the target tone as showed by reductions of the P3b amplitude. In sum, our results highlight the importance of balancing mental and auditory loads to maintain or improve efficient reactions to alarms in complex environment.
Integrating Cell Morphology with Gene Expression and Chemical Structure to Aid Mitochondrial Toxicity Detection
Authors: Seal Srijit , Carreras-Puigvert Jordi , Trapotsi Maria-Anna , Yang Hongbin , Spjuth Ola , Bender Andreas
Published: January 2022

Mitochondrial toxicity is an important safety endpoint in drug discovery. Models based solely on chemical structure for predicting mitochondrial toxicity are currently limited in accuracy and applicability domain to the chemical space of the training compounds. In this work, we aimed to utilize both -omics and chemical data to push beyond the state-of-the-art. We combined Cell Painting and Gene Expression data with chemical structural information from Morgan fingerprints for 382 chemical perturbants tested in the Tox21 mitochondrial membrane depolarization assay. We observed that mitochondrial toxicants differ from non-toxic compounds in morphological space and identified compound clusters having similar mechanisms of mitochondrial toxicity, thereby indicating that morphological space provides biological insights related to mechanisms of action of this endpoint. We further showed that models combining Cell Painting, Gene Expression features and Morgan fingerprints improved model performance on an external test set of 244 compounds by 60% (in terms of F1 score) and improved extrapolation to new chemical space. The performance of our combined models was comparable with dedicated in vitro assays for mitochondrial toxicity. Our results suggest that combining chemical descriptors with biological readouts enhances the detection of mitochondrial toxicants, with practical implications in drug discovery.

Abstract Figure

Graphical Abstract
Comparing transmission reconstruction models with Mycobacterium tuberculosis whole genome sequence data
Authors: Sobkowiak Benjamin , Romanowski Kamila , Sekirov Inna , Gardy Jennifer L , Johnston James
Published: January 2022

Pathogen genomic epidemiology is now routinely used worldwide to interrogate infectious disease dynamics. Multiple computational tools that reconstruct transmission networks by coupling genomic data with epidemiological modelling have been developed. The resulting inferences are often used to inform outbreak investigations, yet to date, the performance of these transmission reconstruction tools has not been compared specifically for tuberculosis, a disease process with complex epidemiology that includes variable latency periods and within-host heterogeneity. Here, we carried out a systematic comparison of seven publicly available transmission reconstruction tools, evaluating their accuracy in predicting transmission events in both simulated and real-world Mycobacterium tuberculosis outbreaks. No tool was able to fully resolve transmission networks, though both the single-tree and multi-tree input implementations of TransPhylo identified the most epidemiologically supported transmission events and the fewest false positive links. We observed a high degree of variability in the transmission networks inferred by each approach. Our findings may inform an end-user’s choice of tools in future tuberculosis transmission analyses and underscore the need for caution when interpreting transmission networks produced using probabilistic approaches.
Raman Signal Denoising using Fully Convolutional Encoder Decoder Network
Authors: Loc Irem , Kecoglu Ibrahim , Unlu Mehmet Burcin , Parlatan Ugur
Published: January 2022

Raman spectroscopy is a vibrational method that gives molecular information rapidly and non-invasively. Despite its advantages, the weak intensity of Raman spectroscopy leads to low-quality signals, particularly with tissue samples. The requirement of high exposure times makes Raman a time-consuming process and diminishes its non-invasive property while studying living tissues. Novel denoising techniques using convolutional neural networks (CNN) have achieved remarkable results in image processing. Here, we propose a similar approach for noise reduction for the Raman spectra acquired with 10x lower exposure times. In this work, we developed fully convolutional encoder-decoder architecture (FCED) and trained them with noisy Raman signals. The results demonstrate that our model is superior (p-value < 0.0001) to the conventional denoising techniques such as the Savitzky-Golay filter and wavelet denoising. Improvement in the signal-to-noise ratio values ranges from 20% to 80%, depending on the initial signal-to-noise ratio. Thus, we proved that tissue analysis could be done in a shorter time without any need for instrumental enhancement.
Delayed processing of blood samples impairs the accuracy of mRNA-based biomarkers
Authors: Wilson Chace , Dias Nicolas W. , Pancini Stefania , Mercadante Vitor , Biase Fernando H.
Published: January 2022

Background

The transcriptome of peripheral white blood cells (PWBCs) contains valuable physiological information, thus making them a prime biological sample for investigating mRNA-based biomarkers. However, prolonged storage of whole blood samples can alter gene transcript abundance in PWBCs, compromising the results of biomarker discovery. Here, we designed an experiment to interrogate the impacts of delayed processing of whole blood samples on gene transcript abundance in PWBCs. We hypothesized that storing blood samples for 24 hours at 4°C would cause RNA degradation resulting in altered transcriptome profiles.

Results

We produced RNA-sequencing data for 30 samples collected from five estrus synchronized heifers (Bos taurus). We quantified transcript abundance for 12,414 protein-coding genes in PWBCs. Analysis of parameters of RNA quality revealed no statistically significant differences (P>0.05) between samples collected from the jugular vein and coccygeal vein, as well as among samples processed after one, three, six, or eight hours. However, samples processed after 24 hours of storage had a lower RNA integrity number value (P=0.03) in comparison to those processed after one hour of storage. Next, we analyzed RNA-sequencing data between samples using those processed after one hour of storage as the baseline for comparison. Interestingly, evaluation of 3’/5’ bias revealed no differences between genes with lower transcript abundance in samples stored for 24 hours relative to one hour. In addition, sequencing coverage of transcripts was similar between samples from the 24-hour and one-hour groups. We identified four and 515 genes with differential transcript abundance in samples processed after storage for eight and 24 hours, respectively, relative to samples processed after one hour.

Conclusions

The PWBCs respond to prolonged cold storage by increasing genes related to active chromatin compaction which in turn reduces gene transcription. This alteration in transcriptome profiles can impair the accuracy of mRNA-based biomarkers. Therefore, blood samples collected for mRNA-based biomarker discovery should be refrigerated immediately and processed within six hours post sampling.
Regulation of Chromatin Accessibility by hypoxia and HIF
Authors: Batie Michael , Frost Julianty , Shakir Dilem , Rocha Sonia
Published: January 2022

Reduced oxygen availability (hypoxia) can act as a signalling cue in physiological processes such as development, but also in pathological conditions such as cancer or ischaemic disease. As such, understanding how cells and organisms respond to hypoxia is of great importance. The family of transcription factors called Hypoxia Inducible Factors (HIFs) coordinate a transcriptional programme required for survival and adaptation to hypoxia. The effects of hypoxia and HIF on the chromatin accessibility landscape are still unclear. Here, using genome wide mapping of chromatin accessibility via ATAC-seq, we find hypoxia induces loci specific changes in chromatin accessibility enriched at hypoxia transcriptionally responsive genes. These changes are predominantly HIF dependent, reversible upon reoxygenation and partially mimicked by chemical HIF stabilisation independent of molecular dioxygenase inhibition. This work demonstrates that indeed, HIF stabilisation is necessary and sufficient to alter chromatin accessibility in hypoxia, with implications for our understanding of gene expression regulation by hypoxia and HIF.
Corrosion behavior of 2205 duplex stainless steel in acidizing stimulation solution for oil and gas wells at 200°C
Authors: Du Juan , Yu Mengyao , Liu Pingli , Fu Yongqiang , Xiong Gang , Liu Jinming , Chen Xiang
Published: January 2022

Purpose

This paper aims to analyze the high temperature (200°C) corrosion behavior of 2205 duplex stainless steel in acidizing stimulation solution containing hydrochloric acid (HCl) and acetic acid.

Design/methodology/approach

The corrosion rate of 2205 duplex stainless steel in all kinds of acid solutions was calculated through immersion tests and electrochemical test. The corrosion product composition is analyzed by X-ray diffraction analysis. The element composition and element distribution before and after corrosion were analyzed by an X-ray energy spectrometer. The corrosion morphology of the steel surface was observed by a scanning electron microscope. Both static and dynamic corrosion experiments were carried out at 200°C.

Findings

The results show that 2205 duplex stainless steel has excellent corrosion resistance in low to high concentration acetic acid solutions, but increasing the concentration of Cl− in acetic acid solution will accelerate the corrosion rate. Low concentration HCl solution can cause serious corrosion to 2205 duplex stainless steel. The system of HCl and acetic acid will produce a synergistic effect on corrosion of 2205 duplex stainless steel and accelerate the corrosion. Sb2O3 is a good corrosion inhibitor synergist for high-temperature acidizing stimulation solution.

Originality/value

The amount of HCl that is used in acidizing stimulation is usually determined by the dissolution effect of the acid on the rocks, but for ultra-high-temperature reservoirs, the amount of HCl should be based on reducing the corrosion of oil and gas wells.
Review on critical technology development of avian radar system
Authors: Chen Weishi , Huang Yifeng , Lu Xianfeng , Zhang Jie
Published: January 2022

Purpose

This paper aims to review the critical technology development of avian radar system at airports.

Design/methodology/approach

After the origin of avian radar technology is discussed, the target characteristics of flying birds are analyzed, including the target echo amplitude, flight speed, flight height, trajectory and micro-Doppler. Four typical airport avian radar systems of Merlin, Accipiter, Robin and CAST are introduced. The performance of different modules such as antenna, target detection and tracking, target recognition and classification, analysis of bird information together determines the detection ability of avian radar. The performances and key technologies of the ubiquitous avian radar are summarized and compared with other systems, and their applications, deployment modes, as well as their advantages and disadvantages are introduced and analyzed.

Findings

The ubiquitous avian radar achieves the long-time integration of target echoes, which greatly improves detection and classification ability of the targets of birds or drones, even under strong background clutter at airport. In addition, based on the big data of bird situation accumulated by avian radar, the rules of bird activity around the airport can be mined to guide the bird avoidance work.

Originality/value

This paper presented a novel avian radar system based on ubiquitous digital radar technology. The authors’ experience has confirmed that this system can be effective for airport bird strike prevention and management. In the future, the avian radar system will see continued improvement in both software and hardware, as the system is designed to be easily extensible.
Beginning farmers' entry and exit: evidence from county level data
Authors: Hartarska Valentina , Nadolnyak Denis , Sehrawat Nisha
Published: January 2022

Purpose

This paper identifies factors that affect entry and exit of beginning, young and women farmers and ranchers.

Design/methodology/approach

The empirical framework is fixed effects regression analysis that uses county level data to evaluate how barriers to entry, access to and use of credit, local economic environment, and climate affect entry and exit of Beginning Farmers and Ranchers (BFRs). The dataset is assembled from several sources matching the Census of Agriculture years for the period of 1997–2017.

Findings

Results show that new farmers are more likely to enter in counties with more and smaller farms and with lower farm productivity, indicating that BFRs have the potential to improve the overall productivity in such counties if able to grow and succeed. The results also indicate that the high capital intensity nature of farming is an effective barrier to entry. BFRs are more likely to do better in counties where agriculture is more important to the economy and with more off-farm work opportunities. The net entry is positively associated with higher input/output price index and the use of insurance but is unaffected by government payments and farm and off-farm income. The authors observe substitutability between farming and alternative self-employment for more entrepreneurial young people. Net entry increases with availability of non-real-estate loans but decreases with real estate credit. Thus, for BFRs to acquire the assets needed to reach optimal scale, access to credit remains essential.

Originality/value

The authors are not aware of other work that estimates how barriers to entry and other economic factors including access to credit affect entry and exit of BFRs of various ages and young and women farmers using the Census of Agriculture data up to 2017.
The relationship between needs, motivations and information sharing behaviors on social media: focus on the self-connection and social connection
Authors: Kim Miyea , Jun Mina , Han Jeongsoo
Published: January 2022

Purpose

The purpose of this study is to investigate the factors that influence the information sharing behavior of individuals on social media. Furthermore, the study analyzes the effect that individuals’ self-connection to social media has on information sharing through self-efficacy and the effect of social-connection on information sharing through empathy.

Design/methodology/approach

A survey questionnaire was developed and distributed to social media users from general participants in the Republic of Korea. A total of 824 valid responses were obtained. Hypotheses were tested using structural equation modeling and applying SmartPLS 3.0.

Findings

The result indicated that individuals are motivated to share information through self-connection and social connection. Furthermore, the mediation analysis revealed that the effect of self-connection on information sharing in social media is mediated by self-efficacy. Also, social connection will increase information sharing not only directly but also indirectly through its positive effect on empathy.

Originality/value

The authors focused on the basic needs of humans and tried to reveal the relationship between human needs and motivational beliefs, which are self-efficacy and empathy, and information sharing behavior on social media. Through the individual's fundamental needs that social media can satisfy, individuals will gain positive psychological benefits through using social media. This study considered what psychological benefits social media can provide.
The role of expert judgments in wine quality assessment: the mismatch between chemical, sensorial and extrinsic cues
Authors: Parga-Dans Eva , Alonso González Pablo , Otero-Enríquez Raimundo
Published: January 2022

Purpose

The complexity in determining the quality of a credence good like wine increases due to the lack of mandatory ingredient labeling. This has generated a significant information asymmetry in the wine market, leading consumers to delegate their purchase decisions to expert rankings and wine guides. This paper explores whether expert assessments reduce the information asymmetry caused by the absence of ingredient labeling in the wine market.

Design/methodology/approach

By employing analysis of variance (ANOVA) in a sample of 304 wines included in the Wine Guide of the Spanish Consumers Organization (OCU), this paper assesses the extent to which expert assessments based on sensory evaluations converge with the objective cues provided by laboratory analysis in wine quality evaluations.

Findings

Results reveal a mismatch between expert assessments and laboratory analyses. Chemical aspects such as SO2 levels or volatile acidity, sensorial factors such as intensity and persistence, and extrinsic variables such as the region of origin or wine type play an important role in the quality ranking of wines.

Originality/value

These findings call for the inclusion of objective intrinsic cues in expert sensory assessments to provide consumers reliable information about wines and to resolve the apparent dissonances in wine quality assessments.