bluuebunny/crossref_metadata_2025 huggingface dataset:
Homologous and heterologous boosting with CoronaVac and BNT162b2: a randomized trial (the Cobovax study)
Authors: Leung Nancy H. L. , Cheng Samuel M. S. , Cohen Carolyn A. , Martín-Sánchez Mario , Au Niki Y. M. , Luk Leo L. H. , Tsang Leo C. H. , Kwan Kelvin K. H. , Chaothai Sara , Fung Lison W. C. , Cheung Alan W. L. , Chan Karl C. K. , Li John K. C. , Ng Yvonne Y. , Kaewpreedee Prathanporn , Jia Janice Z. , Ip Dennis K. M. , Poon Leo L. M. , Leung Gabriel M. , Peiris J. S. Malik , Valkenburg Sophie A. , Cowling Benjamin J.
Published: August 2022

Background

There are few trials comparing homologous and heterologous third doses of COVID-19 vaccination with inactivated vaccines and mRNA vaccines.

Methods

We conducted an open-label randomized trial in adults >=18 years of age who received two doses of inactivated vaccine (CoronaVac) or mRNA vaccine (BNT162b2) >=6 months earlier, randomised in 1:1 ratio to receive a third dose of either vaccine. We compared the reactogenicity, immunogenicity and cell-mediated immune responses, and assessed vaccine efficacy against infections during follow-up.

Results

We enrolled 219 adults who previously received two doses of CoronaVac and randomised to CoronaVac (“CC-C”, n=101) or BNT162b2 (“CC-B”, n=118) third dose; and 232 adults who previously received BNT162b2 and randomised to CoronaVac (“BB-C”, n=118) or BNT162b2 (“BB-B”, n=114). There were more frequent reports of mild reactions in recipients of third-dose BNT162b2, which generally subsided within 7 days. Antibody responses against the ancestral virus, Omicron BA.1 and BA.2 subvariant by surrogate neutralization and PRNT50were stronger for the recipients of a third dose of BNT162b2 over CoronaVac irrespective of prior vaccine type. CD4+T cells boost only occurred in CoronaVac-primed arms. We did not identify differences in CD4+and CD8+T cell responses between arms. When Omicron BA.2 was circulating, we identified 58 infections with cumulative incidence of 15.3% and 15.4% in the CC-C and CC-B (p=0.93), and 16.7% and 14.0% in the BB-C and BB-B arms, respectively (p=0.56).

Conclusions

Similar levels of incidence of infection in each arm suggest all third dose combinations may provide similar degrees of protection against prevalent Omicron BA.2 infection, despite very weak antibody responses to BA.2 in the recipients of a CoronaVac third dose. Further research is warranted to identify appropriate correlates of protection for inactivated COVID-19 vaccines.
Assessing glucose-6-phosphate dehydrogenase (G6PD) during COVID-19 requires caution: evidence on the impact of the infection upon enzyme activity
Authors: de Almeida Rodrigues Maria Gabriela , de Melo Gisely Cardoso , Barros Dias Ádila Liliane , Sartim Marco Aurélio , Xavier Mariana Simão , Abreu Netto Rebeca Linhares , Almeida Val Fernando Fonseca , Baía-da-Silva Djane Clarys , Brito-Sousa José Diego , Monteiro Wuelton Marcelo , de Lacerda Marcus Vinicius Guimarães , de Souza Sampaio Vanderson
Published: August 2022

Glucose-6 phosphate dehydrogenase deficiency (G6PDd) was suggested as a risk factor of severity in patients with COVID-19. In this article, we assessed the influence of G6PDd on the infection, severity, and clinical progression of patients with COVID-19. This prospective cohort study included adult participants (≥18 years old) who had clinical and/or radiological COVID-19 findings or positive RT-PCR results. Epidemiological and clinical data were extracted from electronic medical records. G6PD activity was measured in SD Biosensor STANDARD G6PD® equipment at admission and one year after discharge. Samples were genotyped for the three most common single nucleotide polymorphisms (SNPs) for G6PDd in the Brazilian Amazon s1050828, rs1050829 and rs5030868, corresponding to G6PD African A-(G202A, A376G), G6PD African A+(A376G) and G6PD Mediterranean(C563T), respectively. Seven hundred fifty-three patients were included, of which 123 (16.3%) were G6PDd. The G6PDd group had a higher mean hemoglobin, and lower values of C-reactive protein and leukocytes at admission. There was no association between G6PDd and COVID-19 severity, considering that the frequency of G6PDd who needed to be hospitalized (1.9%) or demanding invasive mechanical ventilation (16.0%) or died (21.1%) was lower than G6PD normal patients. Only 29 out of 116 (25%) participants carried the African genotype. Out of 30 participants tested as G6PDd during disease, only 11 (36.7%) results agreed one year after discharge. In conclusion, caution must be taken when G6PDd screening in patients with acute COVID-19.
Gold Nanourchins Improve Virus Targeting and Plasmonic Coupling for Virus Diagnosis on a Smartphone Platform
Authors: Liu Yaning , Ye Haihang , Bayram Abdullah , Zhang Tingting , Cai Qi , Xie Chen , Huynh HoangDinh , Peerzade Saquib Ahmed M. A. , Kahn Jeffrey S. , Qin Zhenpeng
Published: August 2022

Point-of-care detection of pathogens is critical to monitor and combat viral infections. Here, we demonstrate a plasmonic coupling assay (PCA) using gold nanourchins (AuNUs) as labels for the colorimetric quantification of viruses. The antibody functionalized AuNUs allow for rapid and highly specific identification of viruses and provide strong color change for sensitive detection. Using respiratory syncytial virus (RSV) as a target, we demonstrate that the AuNU-based PCA achieves a detection limit of 1,402 PFU/mL (equivalent to 17 copies/μL) that is 3.1- and 5.7-times lower than the rod- and sphere-based counterparts, respectively. The improved detection sensitivity arises from the higher virus binding capability and stronger plasmonic coupling at long distances (∼10 nm) by AuNU probes. The detection can be performed with a portable smartphone-based spectrometer and is validated by testing RSV-spiked nasal swab clinical samples. Our study reports a rapid and sensitive approach for intact virus detection and provides a potential toolkit at the point of care.

Graphical abstract
Predicting the efficacy of variant-modified COVID-19 vaccine boosters
Authors: Khoury David S. , Docken Steffen S. , Subbarao Kanta , Kent Stephen J. , Davenport Miles P. , Cromer Deborah
Published: August 2022

As a result of the emergence and circulation of antigenically distinct SARS-CoV-2 variants, a number of variant-modified COVID-19 vaccines have been developed. Here we perform a meta-analysis of the available data on neutralisation titres from clinical studies comparing booster vaccination with either the current ancestral-based vaccines or variant-modified vaccines. We then use this to predict the relative efficacies of these booster vaccines under different scenarios.
Progression and trajectory network of age-related functional impairments and their associations with mortality: a two-decade prospective study
Authors: Chen Hui , Wang Binghan , Lv Rongxia , Zhou Tianjing , Shen Jie , Song Huan , Xu Xiaolin , Ma Yuan , Yuan Changzheng
Published: August 2022

Objective

To characterize the progression and trajectory network of age-related functional impairments and assess their associations with mortality.

Design

Prospective cohort study.

Setting

The Health and Retirement Study (HRS, 2000-2020).

Participants

A total of 17 914 HRS participants aged from 51 to 90 years in 2000.

Main outcome measure

Age-related functional impairments including visual impairment, hearing impairment, cognitive impairment, physical frailty, restless sleep, and depression, all measured using structural questionnaires biennially or quadrennially. All-cause mortality was ascertained from multiple sources.

Results

During follow-up (median=12 years), the incidence rates of visual impairment (59.3 cases/1000 person years), hearing impairment (52.1 cases/1000 person years), physical frailty (31.7 cases/1000 person years), and cognitive impairment (42.5 cases/1000 person years) increased exponentially with age (P-trend <0.001), while those of restless sleep (75.6 cases/1000 person years) and depression (35.6 cases/1000 person years) increased relatively slowly. We detected bidirectional associations among all ARFIs (P <0.001). Overall, each additional ARFI was associated with 13% (11%-15%) higher risk of mortality, with independent associations observed for physical frailty (hazard ratio: 1.59, 95% confidence interval: 1.49-1.69), depression (1.38, 1.30-1.46), visual impairment (1.19, 1.13-1.26), and cognitive impairment (1.13, 1.06-1.21).

Conclusions

ARFIs were highly interconnected as a network and were associated with mortality, which highlighted the importance of integrated strategies to monitor and manage the ARFIs to achieve healthy longevity.

SUMMARY BOXES

WHAT IS ALREADY KNOWN ON THIS TOPIC

Aging is characterized by changes in multiple functions, such as visual, hearing, and cognitive impairments.

Specific age-related functional impairments are associated bidirectionally.

WHAT THIS STUDY ADDS

In a prospective study, the incidence rates of visual impairment, hearing impairment, physical frailty, and cognitive impairment increased exponentially as age increased, while incidence rates of restless sleep and depression increased relatively slowly with age.

The six ARFIs are bidirectionally related to each other and predicted higher risk of mortality in a dose-response manner, with independent associations observed for visual impairment, cognitive impairment, physical frailty, and depression.
Molecular mechanisms of tubulogenesis revealed in the sea star hydro-vascular organ
Authors: Perillo Margherita , Swartz S. Zachary , Pieplow Cosmo , Wessel Gary M.
Published: August 2022

A fundamental goal in the organogenesis field is to understand how cells organize into tubular shapes. Toward this aim, we have established the hydro-vascular organ in the sea star Patiria miniata as a model for tubulogenesis. In this animal, bilateral tubes grow out from the tip of the developing gut, and precisely extend to specific sites in the larva. This growth requires cell migration coupled with mitosis in distinct zones. Cell proliferation requires FGF signaling, whereas the three-dimensional orientation of the organ depends on Wnt signaling. Specification and maintenance of tube cell fate requires Delta/Notch signaling. Moreover, we identify target genes of the FGF pathway that contribute to tube morphology, revealing molecular mechanisms for tube outgrowth. Finally, we report that FGF activates the Six1/2 transcription factor, which serves as an evolutionarily ancient regulator of branching morphogenesis. This study uncovers novel mechanisms of tubulogenesis in vivo and we propose that cellular dynamics in the sea star hydro-vascular organ represents a key comparison for understanding the evolution of vertebrate organs.

Highlights

❖ The hydro-vascular organ of the sea star presents a valuable model of tubulogenesis

❖ In this organ tube extension is driven by cell migration coupled with cell proliferation at specific growth zones

❖ The Wnt pathway controls directional outgrowth

❖ The FGF pathway promotes regionalized cell proliferation

❖ The Notch/Delta pathway is essential in cell fate repression in tubulogenesis

❖ A screen of FGF function revealed essential target gene expression, including the transcription factor Six1/2

❖ Within a sister group to chordates, the sea star will reveal ancient mechanisms of tubulogenesis
Modulation of motor vigour by expectation of reward probability trial-by-trial is preserved in healthy ageing and Parkinson’s disease patients
Authors: Tecilla Margherita , Grossbach Michael , Gentile Giovanni , Holland Peter , Antonini Angelo , Ruiz Maria Herrojo
Published: August 2022

Motor improvements, such as faster movement times or increased velocity, have been consistently associated with reward magnitude in deterministic contexts. Yet whether individual inferences on reward probability influence motor vigour dynamically remains undetermined. Here we investigated how dynamically inferring volatile action-reward contingencies modulated motor performance trial-by-trial in healthy younger (HYA, 37) and older adults (HOA, 37), and in medicated Parkinson’s Disease patients (PD, 20). We conducted an online study that coupled a standard one-armed bandit decision-making paradigm with a motor sequence task and used a validated hierarchical Bayesian model to fit trial-by-trial data. Our results showed that stronger predictions about the tendency of the action-reward contingency led to faster performance tempo on a trial-by-trial basis without modulating reaction times (RT). Using Bayesian linear mixed models, we demonstrated in HYA, HOA and PD a similar sensitivity (slope) of execution tempo to inferences about the reward probabilities, despite HOA and PD being generally slower than HYA (intercept). In a second experiment in HYA (39), we additionally showed that subjective inferences about credit assignment – whether lack of reward is associated with an incorrect decision or execution error – led to a similar modulation of motor vigour by reward expectation. Our study is the first to reveal that the dynamic updating of beliefs about volatile action-reward contingencies positively biases motor performance through faster execution tempo, without affecting RT. We also provide novel evidence for a preserved sensitivity of motor vigour to inferences about the action-reward mapping in ageing and medicated PD.

SIGNIFICANCE STATEMENT

Navigating a world rich in uncertainty relies on updating beliefs about the probability that our actions lead to reward. Here we investigated how inferring the action-reward contingencies in a volatile environment modulated motor vigour trial-by-trial in healthy younger and older adults, and in Parkinson’s Disease patients on medication. We found an association between trial- by-trial predictions about the tendency of the action-reward contingency and performance tempo, with stronger expectations speeding performance. We additionally provided evidence for a similar sensitivity of performance tempo to the strength of these predictions in all groups. Thus, dynamic beliefs about the changing relationship between actions and their outcome invigorated motor performance. This positive bias was not compromised by age or Parkinson’s disease.
Inaccurate fossil placement does not compromise tip-dated divergence times
Authors: Koch Nicolas Mongiardino , Garwood Russell J , Parry Luke A
Published: August 2022

Time-scaled phylogenies underpin the interrogation of evolutionary processes across deep timescales, as well as attempts to link these to Earth’s history. By inferring the placement of fossils and using their ages as temporal constraints, tip dating under the fossilised-birth death (FBD) process provides a coherent prior on divergence times. At the same time, it also links topological and temporal accuracy, as incorrectly placed fossil terminals should misinform divergence times. This could pose serious issues for obtaining accurate node ages, yet the interaction between topological and temporal error has not been thoroughly explored. We simulate phylogenies and associated morphological datasets using methodologies that incorporate evolution under selection, and are benchmarked against empirical datasets. We find that datasets of moderate sizes (300 characters) and realistic levels of missing data generally succeed in inferring the correct placement of fossils on a constrained extant backbone topology, and that true node ages are usually contained within Bayesian posterior distributions. While increased fossil sampling improves the accuracy of inferred ages, topological and temporal errors do not seem to be linked: analyses in which fossils resolve less accurately do not exhibit elevated errors in node age estimates. At the same time, divergence times are systematically biased, a pattern that stems from a mismatch between the FBD prior and the shape of our simulated trees. While these results are encouraging, suggesting even fossils with uncertain affinities can provide useful temporal information, they also emphasise that paleontological information cannot overturn discrepancies between model priors and the true diversification history.
Beet curly top Iran virus Rep and V2 gene work as suppressors of post-transcriptional gene silencing through separate mechanisms
Authors: Ebrahimi Saeideh , Eini Omid , Baßler Alexandra , Yildirim Zeynep , Wassenegger Michael , Krczal Gabi , Uslu Veli Vural
Published: August 2022

Beet curly top Iran Virus (BCTIV) is a yield-limiting geminivirus belonging to the becurtovirus genus. The genome organization of BCTIV is unique such that the complementary strand of BCTIV resembles mastreviruses, whereas the virion strand organization is close to curtoviruses. Geminiviruses are known to avoid the plant defense system by suppressing the RNA interference mechanisms both at the transcriptional gene silencing (TGS) and post-transcriptional gene silencing (PTGS) level. Multiple geminivirus genes have been identified as viral suppressors of RNA silencing (VSR) but VSR activity remains elusive in becurtoviruses. By screening all verified open reading frames in the BCTIV genome, we found that only V2 and Rep were able to suppress specific PTGS mechanisms, triggered by the expression of a partial or full-length sense-strand transcript of the target gene (S-PTGS). BCTIV-V2 could suppress S-PTGS more efficiently than BCTIV-Rep when then the target GFP gene is transiently expressed. On the other hand, S-PTGS is suppressed by Rep but not V2 when target GFP is only stably expressed. Deletional mutagenesis of BCTIV-Rep implicated that multiple domains are required for its VSR activity. Furthermore, neither V2 nor Rep could fully suppress local PTGS induced by inverted repeat targeting GFP (GFP-IR). Also, in a closer look at the spread of local silencing by GFP-IR, we observed that V2 or Rep are not able to suppress the movement of sRNAs. Nevertheless, Rep suppressed the systemic silencing induced by GFP-IR in 16C plants. Northern blot analyses showed that BCTIV-Rep inhibits silencing by mitigating sRNA production, whereas BCTIV-V2 does not alter sRNA levels. In summary, both the silencing phenotype and the molecular signatures of silencing implicate distinct modes of VSR activity of BCTIV-Rep and -V2.
Stimulation of the catalytic activity of the tyrosine kinase Btk by the adaptor protein Grb2
Authors: Nocka Laura M. , Groves Jay T. , Kuriyan John
Published: August 2022

The Tec-family kinase Btk contains a lipid-binding Pleckstrin homology and Tec homology (PH-TH) module connected by a proline-rich linker to a “Src module”, an SH2-SH3-kinase unit also found in Src-family kinases and Abl. We showed previously that Btk is activated by PH-TH dimerization, which is triggered on membranes by the phosphatidyl inositol phosphate PIP3, or in solution by hexakisinositol phosphate (IP6) (Wang et al. 2015, https://doi.org/10.7554/eLife.06074). We now report that the ubiquitous adaptor protein growth-factor-receptor-bound protein 2 (Grb2) binds to and substantially increases the activity of PIP3-bound Btk on membranes. Using reconstitution on supported-lipid bilayers, we find that Grb2 can be recruited to membrane-bound Btk through interaction with the proline-rich linker in Btk. This interaction requires intact Grb2, containing both SH3 domains and the SH2 domain, but does not require that the SH2 domain be able to bind phosphorylated tyrosine residues – thus Grb2 bound to Btk is free to interact with scaffold proteins via the SH2 domain. We show that the Grb2-Btk interaction recruits Btk to scaffold-mediated signaling clusters in reconstituted membranes. Our findings indicate that PIP3-mediated dimerization of Btk does not fully activate Btk, and that Btk adopts an autoinhibited state at the membrane that is released by Grb2.
The Behaviour of F-statistics over Time
Authors: Li Song , Wiuf Carsten
Published: August 2022

We study the behaviour of the F2-statistic and Fst-statistic, respectively, over time in a Wright-Fisher model with mutation and migration. We give precise conditions for when the F2-statistic is non-monotonic, that is, increases over time until a certain point and then starts decreasing. We show that even for small population sizes, the two statistics are well approximated by population size scaled expressions.
Understanding the effects of mesenchymal stromal cell therapy for treating osteoarthritis using an in vitro co-culture model
Authors: Shang Vivian , Li Jiarong , Little Christopher B. , Li Jiao Jiao
Published: August 2022

Osteoarthritis (OA) is a leading cause of chronic pain and disability, for which there is no cure. Mesenchymal stromal cells (MSCs) have been used in clinical trials for treating OA due to their unique functions to send paracrine anti-inflammatory and trophic signals. Interestingly, these studies have shown mainly short-term effects of MSCs in improving pain and joint function, rather than sustained and consistent benefits. This may reflect a change or loss in the therapeutic effects of MSCs after intra-articular injection. This study aimed to unravel the reasons behind the variable efficacy of MSC injections for OA using an in vitro co-culture model. Osteoarthritic human synovial fibroblasts (OA-HSFs) exposed to MSCs showed short-term downregulation of pro-inflammatory and pro-catabolic genes, but the MSCs showed upregulation of pro-inflammatory genes and impaired ability to undergo osteogenesis and chondrogenesis in the presence of OA-HSFs. Moreover, short-term exposure of OA-HSFs to MSCs was insufficient for inducing sustained changes to their diseased behaviour. These findings suggest MSCs may not provide long-term effects in correcting the OA joint environment due to adopting the diseased phenotype of the surrounding tissues, which have important implications in the future development of effective stem cell-based OA treatments with long-term therapeutic efficacy.
CXCL12 in late-stage osteoblasts and osteocytes is required for load-induced bone formation in mice
Authors: Cabahug-Zuckerman Pamela , Liu Chao , Atria Pablo , Cai Cinyee , Fang Emily , Qureshi Shahar , Rooklin Rikki , Ponce Cesar , Morocho Camila , Castillo Alesha B.
Published: August 2022

Increased physical loading of the skeleton activates new bone formation ensuring its ability to meet mechanical demands over time; however, the capacity of bone to respond to mechanical stimulation diminishes with age. Osteocytes, the cells embedded and dispersed throughout mineralized bone matrix, are master regulators of mechanoadaptation through recruitment of new bone-forming cells, the osteoblasts, via signaling to osteoprogenitors located on bone surfaces. We previously demonstrated that in vivo and in vitro mechanical stimulation significantly upregulated the chemokine C-X-C Motif Chemokine Ligand 12 (CXCL12) and its receptor, CXCR4, in osteocytes and bone lining cells, and that CXCR4 antagonism with AMD3100 attenuated in vivo load-induced bone formation. Here, we extended this work by showing that ablation of CXCL12+ cells and deletion of cxcl12 in late-stage osteoblasts and osteocytes significantly attenuated in vivo load-induced bone formation in the mouse tibia. This bone loading phenotype was rescued by treatment with recombinant CXCL12. To address mechanism, we showed that in vitro deletion of cxcl12 and cxcr4, separately, in bone marrow stromal cells resulted in significantly reduced osteogenic differentiation. Furthermore, CXCL12 treatment enhanced GSK-3b phosphorylation and β-catenin translocation to the nucleus, the former of which was partially blocked by AMD3100. Finally, CXCL12 synergized Wnt signaling leading to significantly increased total β-catenin protein and Axin2 expression, a Wnt signaling target gene. These findings together demonstrate that CXCL12 expression in late-stage osteoblasts and osteocytes is essential for load-induced bone formation, in part, by regulating osteogenic differentiation through activation of the Wnt signaling pathway.

Significance

Skeletal adaptation to mechanical loading is contingent on the recruitment of new osteoblasts to bone surfaces. CXCL12, a chemokine expressed by osteolineage cells, targets effector cells expressing its receptor CXCR4, including osteoprogenitors. Exogenous mechanical loading of mouse hind limbs upregulates CXCL12 in osteocytes, bone lining cells and marrow cells, while antagonizing CXCR4 led to significantly attenuated load-induced bone formation. Here, we show that CXCL12 expression in late-stage osteoblasts and osteocytes is required for load-induced bone formation. Treatment with recombinant CXCL12 rescued the bone loading phenotype suggesting that the CXCL12/CXCR4 signaling pathway may be a feasible drug target for promoting load-induced bone formation when exercise alone is insufficient to counteract low bone mass and osteoporosis.
Myxococcus xanthus, a nonpathogenic bacterium, eliminates Cryptococcus neoformans, a fungal pathogen of human, independent of cell-cell contact
Authors: Zhang Huan , Pettibon Joshua D. , Patel Raj , Nan Beiyan
Published: August 2022

Each year an estimated 1.2 billion people suffer from fungal diseases and 1.5 - 2 million die from fungal infections - surpassing the loss from malaria and tuberculosis1-3. Due to the similarities between fungal and human cells, the lack of fungal-specific targets has become the major hurdle for antifungal discovery. Many fungi, including the deadly human pathogen Cryptococcus neoformans, are found in soil, where they compete with other microorganisms, including bacteria. However, most bacteria that inhibit fungal growth are pathogens and their antifungal effects strictly rely on cell-cell contact. Here we show that Myxococcus xanthus, a nonpathogenic, soil-dwelling bacterium, efficiently eliminates C. neoformans and strongly inhibits the production of fungal virulence factors. Remarkably, these antifungal activities do not require cell-cell contact. Using fluorescence microscopy, we found that M. xanthus increases the permeability of C. neoformans cells. Our results on the cross-kingdom interaction between M. xanthus and C. neoformans will reveal fundamental mechanisms for bacterial-fungal interactions and suggest novel strategies for antifungal therapies.
Using deep learning predictions of inter-residue distances for model validation
Authors: Rodríguez Filomeno Sánchez , Chojnowski Grzegorz , Keegan Ronan M. , Rigden Daniel J.
Published: August 2022

Determination of protein structures typically entails building a model that satisfies the collected experimental observations and its deposition in the Protein Data Bank (PDB). Experimental limitations can lead to unavoidable uncertainties during the process of model building, which result in the introduction of errors into the deposited model. Many metrics are available for model validation, but most are limited to the consideration of the physico-chemical aspects of the model or its match to the map. The latest advances in the field of deep learning have enabled the increasingly accurate prediction of inter-residue distances, an advance which has played a pivotal role in the recent improvements observed in the field of protein ab initio modelling. Here we present new validation methods based on the use of these precise inter-residue distance predictions, which are compared with the distances observed in the protein model. Sequence register errors are particularly clearly detected, and the register shifts required for their correction can be reliably determined. The method is available in the package ConKit (www.conkit.org).
A search for “perio-probiotics” by longitudinal dissection of oral bacterial community shifts during the onset and resolution of gingivitis
Authors: Hall Michael W , Wellappuli Nimali C , Huang Ruo Chen , Wu Kay , Lam David K , Glogauer Michael , Beiko Robert G , Senadheera Dilani B
Published: August 2022

Aim

To understand the spatiotemporal dynamics of bacterial succession during gingivitis, and to identify taxa with a critical role in gum health with prognostic value.

Materials and methods

Longitudinal microbiome data were collected from 15 individuals after completely discontinuing all forms of oral hygiene, and subsequently reintroducing it for three and two weeks, respectively. Sequences from the 16S rRNA V4-V5 gene region from sub- and supra-gingival plaque, saliva, and tongue sites were annotated and mapped to a reference tree of Human Oral Microbiome Database sequences.

Results

Suspending oral hygiene induced gingivitis, which was resolved after its resumption to baseline. Most significant shifts in bacterial abundance were observed in dental plaque, but not in saliva and tongue sites. During gingivitis-induction, baseline microbiota dominated by Streptococcus, was superseded by increased Prevotella, Fusobacterium, Leptotrichia, and Porphyromonas genera. Converse to its decline during disease-induction, gum health restoration was accompanied by a significant increase in streptococci.

Conclusion

We present the most comprehensive, spatiotemporal map of bacterial succession during gingivitis onset and resolution. We have identified taxa with potential as probiotic candidates for gum disease (i.e., perio-probiotics), and suggest tooth-associated plaque and not saliva or tongue plaque should be used in future prognostic tests.
Plasma Proteome Perturbation for CMV DNAemia in Kidney Transplantation
Authors: Sigdel Tara K. , Boada Patrick , Kerwin Maggie , Rashmi Priyanka , Gjertson David , Rossetti Maura , Sur Swastika , Munar Dane , Cimino James , Ahn Richard , Pickering Harry , Sen Subha , Parmar Rajesh , Fatou Benoit , Steen Hanno , Schaenman Joanna , Bunnapradist Suphamai , Reed Elaine F. , Sarwal Minnie M. ,   CMV Systems Immunobiology Group
Published: August 2022

Background

Cytomegalovirus (CMV) infection, either de novo or as reactivation after allotransplantation and chronic immunosuppression, is recognized to cause detrimental alloimmune effects, inclusive of higher susceptibility to graft rejection and substantive impact on chronic graft injury and reduced transplant survival. To obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host we evaluated changes in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR).

Methods

LC-MS-based proteomics was conducted on 168 serially banked plasma samples, from 62 propensity score-matched kidney transplant recipients. Patients were stratified by CMV replication status into 31 with CMV DNAemia and 31 without CMV DNAemia. Patients had blood samples drawn at protocol times of 3- and 12-months post-transplant. Additionally, blood samples were also drawn before and 1 week and 1 month after detection of CMV DNAemia. Plasma proteins were analyzed using an LCMS 8060 triple quadrupole mass spectrometer. Further, public transcriptomic data on time matched PBMCs samples from the same patients was utilized to evaluate integrative pathways. Data analysis was conducted using R and Limma.

Results

Samples were segregated based on their proteomic profiles with respect to their CMV Dnaemia status. A subset of 17 plasma proteins was observed to predict the onset of CMV at 3 months post-transplant enriching platelet degranulation (FDR, 4.83E-06), acute inflammatory response (FDR, 0.0018), blood coagulation (FDR, 0.0018) pathways. An increase in many immune complex proteins were observed at CMV infection. Prior to DNAemia the plasma proteome showed changes in the anti-inflammatory adipokine vaspin (SERPINA12), copper binding protein ceruloplasmin (CP), complement activation (FDR=0.03), and proteins enriched in the humoral (FDR=0.01) and innate immune responses (FDR=0.01).

Conclusion

Plasma proteomic and transcriptional perturbations impacting humoral and innate immune pathways are observed during CMV infection and provide biomarkers for CMV disease prediction and resolution. Further studies to understand the clinical impact of these pathways can help in the formulation of different types and duration of anti-viral therapies for management of CMV infection in the immunocompromised host.
Cell type-specific role of CBX2-cPRC1 at the onset of spermatogonial differentiation
Authors: Kim Jongmin J. , Steinson Emma R. , Lau Mei Sheng , Page David C. , Kingston Robert E.
Published: August 2022

Polycomb group (PcG) proteins maintain the repressed state of lineage-inappropriate genes and are therefore essential for embryonic development and adult tissue homeostasis. One critical function of PcG complexes is modulating chromatin structure. Canonical Polycomb repressive complex 1 (cPRC1), particularly its component CBX2, can compact chromatin and phase separate in vitro. These activities are hypothesized to be critical for forming a repressed physical environment in cells. While much has been learned by studying these PcG activities in cell culture models, it is largely unexplored how cPRC1 regulates adult stem cells and their subsequent differentiation during tissue homeostasis in living animals. Here, we show that CBX2 is upregulated as spermatogonial stem cells differentiate and is required in the differentiating spermatogonia of the male germ line. CBX2 forms condensates, similar to previously described Polycomb bodies, that co-localize with repressed target genes in differentiating spermatogonia. Single cell analyses of mosaic Cbx2 mutant testes show CBX2 is specifically required to produce differentiating, A1 spermatogonia. Furthermore, the domain of CBX2 responsible for compaction and phase separation is needed for the long-term maintenance of male germ cells in the animal. These results emphasize that the regulation of chromatin structure by CBX2 at a specific stage of spermatogenesis is critical for the continued production of sperm and, ultimately, the transmission of genetic material to the next generation.
Neither sharpened nor lost: the unique role of attention in children’s neural representations
Authors: Jung Yaelan , Forest Tess Allegra , Bernhardt-Walther Dirk , Finn Amy S.
Published: August 2022

One critical feature of children’s cognition is their relatively immature attention. Decades of research have shown that children’s attentional abilities mature slowly over the course of development, including the ability to filter out distracting information. Despite such rich behavioral literature, little is known about how developing attentional abilities modulate neural representations in children. This information is critical to understanding exactly how attentional development shapes the way children process information. One intriguing possibility is that attention might be less likely to impact neural representations in children as compared with adults. In particular, representations of attended items may be less likely to be sharpened relative to unattended items in children as compared to adults. To investigate this possibility, we measured brain activity using fMRI while adults (21-31 years) and children (7-9 years) performed a one-back working memory task in which they were directed to attend to either motion direction or an object in a complex display where both were present. We used multivoxel pattern analysis and compared decoding accuracy of attended and unattended information. Consistent with attentional sharpening, we found higher decoding accuracy for task-relevant information (i.e., objects in the object-attended condition) than for task-irrelevant information (i.e., motion in the object-attended condition) in adults’ visual cortices. However, in children’s visual cortices, both task-relevant and task-irrelevant information were decoded equally well. What’s more, exploratory whole-brain analysis showed that the children represent task-irrelevant information more than adults in multiple regions across the brain, including the prefrontal cortex. These findings show that 1) attention does not sharpen neural representations in the child visual cortex, and further 2) that the developing brain can represent more information than the adult brain.
Serinc5 restricts HIV membrane fusion by altering lipid order and heterogeneity in the viral membrane
Authors: Ward Amanda E. , Sokovikova Daria , Waxham M. Neal , Heberle Frederick A. , Levental Ilya , Levental Kandice R. , Kiessling Volker , White Judith M. , Tamm Lukas K.
Published: August 2022

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A compelling body of work also suggests Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5’s effects on HIV pseudoviral membranes. Using fluorescence lifetime imaging with an order sensitive dye, FLIPPER-TR, and by measuring pseudoviral membrane thickness via cryo electron microscopy (cryoEM), Serinc5 was found to increase membrane heterogeneity, skewing the distribution towards a larger fraction of the viral membrane in an ordered phase. We also directly observed for the first time the coexistence of membrane domains within individual viral membrane envelopes. Using a TIRF-based single particle fusion assay, we found that incorporation of exogenous phosphatidylethanolamine (PE) into the viral membrane rescued HIV pseudovirus fusion from restriction by Serinc5, which was accompanied by decreased membrane heterogeneity and order. This effect was specific for PE and did not depend on acyl chain length or saturation. Together, these data suggest that Serinc5 alters multiple interrelated properties of the viral membrane—lipid chain order, rigidity, line tension, and lateral pressure—which decrease accessibility of fusion intermediates and disfavor completion of fusion. These biophysical insights into Serinc5 restriction of HIV infectivity could contribute to the development of novel antivirals that exploit the same weaknesses of HIV and potentially other enveloped viruses.
Structural insights into viral genome replication by the severe fever with thrombocytopenia syndrome virus L protein
Authors: Williams Harry M. , Thorkelsson Sigurdur R. , Vogel Dominik , Milewski Morlin , Busch Carola , Cusack Stephen , Grünewald Kay , Quemin Emmanuelle R.J. , Rosenthal Maria
Published: August 2022

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a phenuivirus that has rapidly become endemic in several East Asian countries. The large (L) protein of SFTSV, which includes the RNA-dependent RNA polymerase (RdRp), is responsible for catalysing viral genome replication and transcription. Here, we present 5 cryo-electron microscopy (cryo-EM) structures of the L protein in several states of the genome replication process, from pre-initiation to late-stage elongation, at a resolution of up to 2.6 Å. We identify how the L protein binds the 5′ viral RNA in a hook-like conformation and show how the distal 5′ and 3′ RNA ends form a duplex positioning the 3′ RNA terminus in the RdRp active site ready for initiation. We also observe the L protein stalled in the early- and late-stages of elongation with the RdRp core accommodating a 9-bp product-template duplex. This duplex ultimately splits with the template binding to a designated 3′ secondary binding site. The structural data and observations are complemented byin vitrobiochemical and cell-based mini-replicon assays. Altogether, our data provide novel key insights into the mechanism of viral genome replication by the SFTSV L protein and will aid drug development against segmented negative-strand RNA viruses.
Dosage differences in12-OXOPHYTODIENOATE REDUCTASEgenes modulate wheat primary root growth
Authors: Gabay G. , Wang H. , Zhang J. , Moriconi J. I. , Burguener G. F. , Howell T. , Lukaszewski A. , Staskawicz B. , Cho M.-J. , Tanaka J. , Fahima T. , Ke H. , Dehesh K. , Zhang G.-L. , Gou J.-Y. , Hamberg M. , Maria G. Santa , Dubcovsky J.
Published: August 2022

Wheat is an essential crop for global food security and is well adapted to a wide variety of soils1. However, the gene networks regulating different root architectures remain poorly understood. We report here the identification of a cluster of a monocot-specific12-OXOPHYTODIENOATE REDUCTASEgenes from subfamily III (OPRIII) that modulate key differences in wheat root architecture associated with grain yield under water-limited conditions. Wheat plants with a loss-of-function mutation inOPRIIIshowed longer seminal roots, whereas plants with increasedOPRIIIdosage or transgenic over-expression showed reduced seminal root growth, precocious development of lateral roots and increased jasmonic acid (JA). A JA-biosynthesis inhibitor eliminated the root differences, confirming a JA-mediated mechanism. Multiple transcriptome analysis of transgenic and wild-type lines revealed significant enriched JA-biosynthetic and reactive oxygen species (ROS) pathways that paralleled changes in ROS distribution. TheOPRIIIgenes provide a useful entry point to engineer root architecture in wheat and other cereals.
Extracellular heparan 6-O-endosulfatases SULF1 and SULF2 in HNSC and other malignancies
Authors: Yang Yang , Ahn Jaeil , Edwards Nathan , Benicky Julius , Rozeboom Aaron M. , Davidson Bruce , Karamboulas Christina , Nixon Kevin C.J. , Ailles Laurie , Goldman Radoslav
Published: August 2022

SULF1 and SULF2 are oncogenic in a number of human malignancies, including head and neck squamous cell carcinoma (HNSC). The function of these two heparan sulfate editing enzymes was previously considered largely redundant but the biology of cancer suggests differences that we explore in our RNAseq and RNAScope studies of HNSC and in a pan cancer analysis using the TCGA and CPTAC (proteomics) data. Our studies document a consistent upregulation of SULF1 and SULF2 in HNSC which is associated with poor survival outcomes. SULF2 expression increases in multiple malignancies but less consistently than SULF1, which uniformly increases in the tumor tissues and negatively impacts survival in several types of cancer. Meanwhile, SULF1 showed low expression in cancer cell lines and a scRNAseq study of HNSC shows that SULF1 is not supplied by epithelial tumor cells, like SULF2, but is secreted by cancer associated fibroblasts. Our RNAScope and PDX analysis of the HNSC tissues fully confirm the stromal source of SULF1 and explain the uniform impact of this enzyme on the biology of multiple malignancies. In summary, the SULF1 enzyme, supplied by a subset of cancer associated fibroblasts, is upregulated and negatively impacts HNSC survival at an early stage of the disease progression while the SULF2 enzyme, supplied by tumor cells, impacts survival at later stages of HNSC. This paradigm is common to multiple malignancies and suggests a potential for diagnostic and therapeutic targeting of the heparan sulfatases in cancer diseases.
Stimulation of the muscarinic receptor M4 activates quiescent neural precursor cells and ameliorates medial septum cholinergic lesion-induced impairments in adult hippocampal neurogenesis
Authors: Madrid Lidia I. , Bandhavkar Saurabh , Hafey Katelyn , Jimenez-Martin Javier , Milne Michael , Coulson Elizabeth J. , Jhaveri Dhanisha J.
Published: August 2022

Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis and hippocampus-dependent cognitive and mood-related functions. However, the contribution of basal forebrain medial septum (MS) and diagonal band of Broca (DBB) cholinergic neurons that innervate the hippocampus and the identity of the cholinergic receptor(s) that regulate the production and maturation of new neurons are not completely understood. Using a targeted, selective ablation approach, we show that MS/DBB cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. We demonstrate that the muscarinic acetycholine receptor subtype M4 (M4 mAChR) is expressed on a population of quiescent neural precursor cells (NPCs) and that its pharmacological stimulation via intra-hippocampal or systemic administration of M4-selective modulators leads to their activation, thereby enhancing neurogenesis in vivo. Furthermore, we show that the activation of M4 mAChR-expressing quiescent NPCs ameliorates the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis. In contrast, the impairment in the morphological maturation of adult-born neurons due to MS/DBB cholinergic neuron loss is further exacerbated by the systemic administration of an M4-selective allosteric potentiator. These findings reveal novel and stage-specific roles of cholinergic signaling in regulating adult hippocampal neurogenesis. They also uncouple the positive role of selective M4 potentiators in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic dysfunction.

Significance statement

Cholinergic signaling plays an important role in the regulation of adult hippocampal neurogenesis and cognitive function, with impairments in these processes reported as early pathogenic events in age-related dementia. Here, we uncover the presence of cholinergic-responsive hippocampal precursor cells that are are directly activated by selective stimulation of the muscarinic receptor subtype M4. Furthermore, M4-mediated stimulation rescues the decrease in the level of hippocampal neurogenesis following the sepal-hippocampal cholinergic neuron loss. We also reveal that septal-hippocampal cholinergic dysfunction impairs the structural maturation of hippocampal adult-born neurons, an effect which is further exacerbated by M4 receptor modulators. These findings reveal stage-specific roles of cholinergic signaling in regulating functionally relevant adult hippocampal neurogenesis.
Cognitive effects of thalamostriatal degeneration are ameliorated by normalizing striatal cholinergic activity
Authors: Becchi Serena , Chieng Billy , Bradfield Laura A. , Capellán Roberto , Leung Beatrice K. , Balleine Bernard W.
Published: August 2022

The loss of neurons in parafascicular thalamus (Pf) and of their inputs to dorsomedial striatum (DMS) are associated with Lewy body disease (LBD) and Parkinson’s disease dementia (PDD) and have been linked to the effects of neuroinflammation. In rats, these inputs regulate the function of striatal cholinergic interneurons (CINs) that are necessary for the flexible encoding of the action-outcome (AO) associations for goal-directed action. We found that these inputs modify the encoding, not retrieval, of new AO associations and cause burst-pause firing of CINs in the DMS during AO remapping. These adaptive effects were abolished by neuroinflammation in the Pf, resulting in the loss of goal-directed control when the rats were required to update AO associations after a change in contingency. We found that the neuronal and behavioral deficits induced by inflammation in the Pf were rescued by administration of selegiline, a MAO-B inhibitor that we found also enhances ATPase activity in CINs, suggesting a potential treatment for cognitive deficits associated with inflammation affecting the function of midline thalamic nuclei and related structures.