bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translaminar Recurrence from Layer 5 Suppresses Superficial Cortical Layers
Authors: Onodera Koun , Kato Hiroyuki K 
Published: February 2022

SummaryInformation flow in the sensory cortex has been described as a predominantly feedforward sequence with deep layers as the output structure. Although recurrent excitatory projections from layer 5 (L5) to superficial L2/3 have been identified by anatomical and physiological studies, their functional impact on sensory processing remains unclear. Here, we use layer-selective optogenetic manipulations in the primary auditory cortex to demonstrate that feedback inputs from L5 suppress the activity of superficial layers, contrary to the prediction from their excitatory connectivity. This suppressive effect is predominantly mediated by translaminar circuitry through intratelencephalic (IT) neurons, with an additional contribution of subcortical projections by pyramidal tract (PT) neurons. Furthermore, L5 activation sharpened tone-evoked responses of superficial layers in both frequency and time domains, indicating its impact on cortical spectro-temporal integration. Together, our findings challenge the classical view of feedforward cortical circuitry and reveal a major contribution of inhibitory recurrence in shaping sensory representations.
Dexamethasone Inhibits Cytokine-Induced, DUOX2-Related VEGF-A Expression and DNA damage in Human Pancreatic Cancer Cells and Growth of Pancreatic Cancer Xenografts
Authors: Wu Yongzhong , Konaté Mariam M. , Hollingshead Melinda , Karim Baktiar , Diebold Becky , Lu Jiamo , Antony Smitha , Meitzler Jennifer L. , Juhasz Agnes , Jiang Guojian , Dahan Iris , Roy Krishnendu , Doroshow James H. 
Published: February 2022

ABSTRACTPreviously, we demonstrated that pro-inflammatory cytokines enhance dual oxidase 2 (DUOX2)-dependent production of reactive oxygen species by human pancreatic ductal carcinoma (PDAC) cells, and that DUOX2 expression is significantly increased in patients with early stages of PDAC. In genetically-engineered mouse models of PDAC, dexamethasone (Dex) decreases formation of pancreatic intraepithelial neoplasia (PanIn) foci as well as PDAC invasiveness. Herein, we report that Dex, in a concentration- and time-dependent fashion, inhibited pro-inflammatory cytokine (IFN-γ/LPS/IL-17A/IL-4)-mediated enhancement of DUOX2 expression in BxPC-3, CFPAC-1, and AsPC-1 human PDAC cell lines, as well as DUOX2–induced DNA damage. The inhibitory effects of Dex were abolished by pre-treatment with the Dex antagonist RU-486. Examination of the human DUOX2 promoter in silico revealed a putative negative glucocorticoid receptor (GR) binding element (IRnGRE). Western analysis, using nuclear extracts from Dex-treated PDAC cells, demonstrated that Dex activated the glucocorticoid receptor in PDAC cell nuclei in the presence of certain co-repressors, such as NCoR-1/2 and histone deacetylases (HDAC1, 2, and 3). Dex produced no anti-proliferative effects on PDAC cellsin vitro. However, Dex significantly decreased the growth of BxPC-3 xenografts while decreasing inflammatory and immune cell infiltration of the microenvironment, as well as the mRNA expression of DUOX2 and VEGF-A, in BxPC-3 tumors. In contrast, Dex had no effect on the growth of xenografts developed from MIA-PaCa cells that are unresponsive to pro-inflammatory cytokines in culture. In summary, these studies suggest that suppression of inflammation-related DUOX2 expression by Dex could diminish the oxidative milieu supporting PDAC growth and development.
Increased low-frequency brain responses to music after psilocybin therapy for depression
Authors: Wall Matthew B. , Lam Cynthia , Ertl Natalie , Kaelen Mendel , Roseman Leor , Nutt David J. , Carhart-Harris Robin L. 
Published: February 2022

AbstractPsychedelic-assisted psychotherapy with psilocybin is an emerging therapy with great promise for depression, and modern psychedelic therapy (PT) methods incorporate music as a key element. Music is an effective emotional/hedonic stimulus that could also be useful in assessing changes in emotional responsiveness following psychedelic therapy. Brain responses to music were assessed before and after PT using functional Magnetic Resonance Imaging (fMRI) and ALFF (Amplitude of Low Frequency Fluctuations) analysis methods. Nineteen patients with treatment-resistant depression underwent two treatment sessions involving administration of psilocybin, with MRI data acquired one week prior and the day after completion of the second of two psilocybin dosing sessions. Comparison of music-listening and resting-state scans revealed significantly greater ALFF in bilateral superior temporal cortex for the post-treatment music scan, and in the right ventral occipital lobe for the post-treatment resting-state scan. ROI analyses of these clusters revealed a significant effect of treatment in the superior temporal lobe for the music scan only. Somewhat consistently, voxelwise comparison of treatment effects showed relative increases for the music scan in the bilateral superior temporal lobes and supramarginal gyrus, and relative decreases in the medial frontal lobes for the resting-state scan. ALFF in these music-related clusters was significantly correlated with intensity of subjective effects felt during the dosing sessions. These data suggest a specific effect of PT on the brain’s response to a hedonic stimulus (music), implying an elevated responsiveness to music after psilocybin therapy that was related to subjective drug effects felt during dosing.
Quantitative, multiplexed, targeted proteomics for ascertaining variant specific SARS-CoV-2 antibody response
Authors: Doykov Ivan , Spiewak Justyna , Gilmour Kimberly C. , Gibbons Joseph M , Pade Corinna , McKnight Áine , Noursadeghi Mahdad , Maini Mala K , Manisty Charlotte , Treibel Thomas , Captur Gabriella , Fontana Marianna , Boyton Rosemary J , Altmann Daniel M , Brooks Tim , Semper Amanda , Moon James C , Mills Kevin , Heywood Wendy 
Published: February 2022

AbstractDetermining the protection an individual has to SARS-CoV-2 variants of concern (VoC) will be crucial for future immune surveillance and understanding the changing immune response. As further variants emerge, current serology tests are becoming less effective in reflecting neutralising capability of the immune system. A better measure of an evolving antigen-antibody immune response is needed. We describe a multiplexed, baited, targeted-proteomic assay for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. This enables a more sophisticated and informative characterisation of the antibody response to vaccination and infection against VoC. Using this assay, we detail different and specific responses to each variant by measuring several antibody classes, isotypes and associated complement binding. Furthermore, we describe how these proteins change using serum from individuals collected after infection, first and second dose vaccination. We show complete IgG1 test concordance with gold standard ELISA (r>0.8) and live virus neutralisation against Wuhan Hu-1, Alpha B.1.1.7, Beta B.1.351, and Delta B.1.617.1 variants (r>0.79). We also describe a wide degree of heterogeneity in the immunocomplex of individuals and a greater IgA response in those patients who had a previous infection. Significantly, our test points to an important role the complement system may play particularly against VoC. Where we observe altered Complement C1q association to the Delta VoC response and a stronger overall association with neutralising antibodies than IgG1. A detailed understanding of an individual’s antibody response could benefit public health immunosurveillance, vaccine design and inform vaccination dosing using a personalised medicine approach.
SARS-CoV-2 infection in Africa: A systematic review and meta-analysis of standardised seroprevalence studies, from January 2020 to December 2021
Authors: Lewis HC , Ware H , Whelan M , Subissi L , Li Z , Ma X , Nardone A , Valenciano M , Cheng B , Noel K , Cao C , Yanes-Lane M , Herring B , Talisuna A , Nsenga N , Balde T , Clifton DA , Van Kerkhove M , Buckeridge DL , Bobrovitz N , Okeibunor J , Arora RK , Bergeri I ,   the UNITY Studies Collaborator Group
Published: February 2022

AbstractIntroductionEstimating COVID-19 cumulative incidence in Africa remains problematic due to challenges in contact tracing, routine surveillance systems and laboratory testing capacities and strategies. We undertook a meta-analysis of population-based seroprevalence studies to estimate SARS-CoV-2 seroprevalence in Africa to inform evidence-based decision making on Public Health and Social Measures (PHSM) and vaccine strategy.MethodsWe searched for seroprevalence studies conducted in Africa published 01-01-2020 to 30-12-2021 in Medline, Embase, Web of Science, and Europe PMC (preprints), grey literature, media releases and early results from WHO Unity studies. All studies were screened, extracted, assessed for risk of bias and evaluated for alignment with the WHO Unity protocol for seroepidemiological investigations. We conducted descriptive analyses of seroprevalence and meta-analysed seroprevalence differences by demographic groups, place and time. We estimated the extent of undetected infections by comparing seroprevalence and cumulative incidence of confirmed cases reported to WHO. PROSPERO: CRD42020183634.ResultsWe identified 54 full texts or early results, reporting 151 distinct seroprevalence studies in Africa Of these, 95 (63%) were low/moderate risk of bias studies. SARS-CoV-2 seroprevalence rose from 3.0% [95% CI: 1.0-9.2%] in Q2 2020 to 65.1% [95% CI: 56.3-73.0%] in Q3 2021. The ratios of seroprevalence from infection to cumulative incidence of confirmed cases was large (overall: 97:1, ranging from 10:1 to 958:1) and steady over time. Seroprevalence was highly heterogeneous both within countries - urban vs. rural (lower seroprevalence for rural geographic areas), children vs. adults (children aged 0-9 years had the lowest seroprevalence) - and between countries and African sub-regions (Middle, Western and Eastern Africa associated with higher seroprevalence).ConclusionWe report high seroprevalence in Africa suggesting greater population exposure to SARS-CoV-2 and protection against COVID-19 disease than indicated by surveillance data. As seroprevalence was heterogeneous, targeted PHSM and vaccination strategies need to be tailored to local epidemiological situations.
Transitions between metabolically unhealthy and healthy obesity over 27 years from midlife to late-life
Authors: Ler Peggy , Zhan Yiqiang , Finkel Deborah , Dahl Aslan Anna K , Karlsson Ida K 
Published: February 2022

AbstractBackgroundMetabolically healthy obesity may be a transient phenotype, but studies with long follow-up, especially covering late-life, are lacking. We therefore describe transitions between body mass index and metabolic health (BMIxMH) categories in a sample with up to 27 years of follow-up, from midlife to late-life.MethodsWe used cohort data from 786 Swedish twins with objective measures of BMIxMH. Metabolic health was defined as absence of metabolic syndrome (MetS). Measurements were categorized into age 50-64, 65-79, or ≥80. Frequencies of transitions between 50-64 and 65-79, and between 65-79 and ≥80 were calculated. One-hundred individuals had measurements in all three age categories, and their dynamic transitions across time were visualized. We also examined frequencies of attrition due to drop-out or death.ResultsThe proportion of individuals with MetS and with overweight or obesity increased over time. However, 28% of individuals with metabolically healthy normal weight and around one fifth of those with metabolically healthy overweight or obesity remained stable across all three age categories. Transitions from MetS to metabolic health were also common, occurring in 7-49% of individuals with metabolically unhealthy normal weight, overweight, and obesity. Drop-out and death during follow-up was comparable across BMIxMH categories.ConclusionsTransitions between metabolically healthy and unhealthy categories were relatively common in both directions across all BMI categories. The similar frequencies of drop-outs and deaths indicate that bias due to differences in attrition between BMIxMH categories is not a major issue in this sample.
A Framework for Assessing the Impact of Accelerated Approval
Authors: Gould A. Lawrence , Campbell Robert K. , Loewy John W. , Beckman Robert A. , Dey Jyotirmoy , Schiel Anja , Burman Carl-Fredrik , Zhou Joey , Antonijevic Zoran , Miller Eva R. , Tang Rui 
Published: February 2022

AbstractThe FDA’s Accelerated Approval program (AA) is a regulatory program to expedite availability of products to treat serious or life-threatening illnesses that lack effective treatment alternatives. Ideally, all of the many stakeholders such as patients, physicians, regulators, and health technology assessment [HTA] agencies that are affected by AA should benefit from it. In practice, however, there is intense debate over whether evidence supporting AA is sufficient to meet the needs of the stakeholders who collectively bring an approved product into routine clinical care. As AAs have become more common, it becomes essential to be able to determine their impact objectively and reproducibly in a way that provides for consistent evaluation of therapeutic decision alternatives. We describe the basic features of an approach for evaluating AA impact that accommodates stakeholder-specific views about potential benefits, risks, and costs. The approach is based on a formal decision-analytic framework combining predictive distributions for therapeutic outcomes (efficacy and safety) based on statistical models that incorporate findings from AA trials with stakeholder assessments of various actions that might be taken. The framework described here provides a starting point for communicating the value of a treatment granted AA in the context of what is important to various stakeholders.
Adherence to prophylaxis and bleeding outcome: a multicenter Nigerian study
Authors: Nwagha Theresa U. , Okoye Helen C. , Yuguda Saleh , Udo Christiana E. , Ogunfemi Mutiat K , Gwarzo Dalhat H. , Osuji Joel N. 
Published: February 2022

ABSTRACTBackgroundIn Nigeria, low-dose prophylaxis is the standard of care as it reduces bleeding, development of target joints, arthropathy, and improvement of quality of life. Non-adherence or poor adherence can prevent the achievement of these outcomes. The levels and determinants of (non-)adherence among persons with haaemophilia (PWH) in Sub-Saharan Africa have not been evidenced.ObjectiveTo evaluate self-reported adherence among PWH, provide evidence of determinants/predictors of adherence and establish the associations between nonadherence and presence of target joints and annualized bleed rate.MethodologyA cross-sectional survey of 42 participants on low-dose prophylaxis recruited during outpatient appointments in 5 haemophilia treatment centers in Nigeria. We used the validated Haemophilia Regimen Treatment Adherence Scale-Prophylaxis (VERITAS -Pro), 24 questions on six subscales (time, dose, plan, remember, skip, and communicate) questionnaire. The options of VERITAS -Pro were represented in a 5 Likert scale and the possible subscale ranged from 4 points (most adherent) to 20 points (least adherent) and the possible total score ranged from 24 (most adherent) to 120 (least adherent) the cutoff for overall adherence put at > 61 to indicate nonadherence. Information on the presence of target joints, the number of target joints, and annualized bleeding rates were collected from medical files.ResultsThe mean age of the participants was 9.79 (6.29) years, with 96.6% having hemophilia A and 79.3% having target joints. Overall adherence to the prophylaxis regimen was 81.0%. The mean total VERITAS-Pro for the adherent group and the non-adherent group was 37.35 ±9.08 and 63.0± 6.37, respectively. The mean subscale scores for the adherent group ranged from 0.67 (communication) to 8.68 (planning), while the mean subscale scores range from 1.0 communication to 13.88 (planning) for the nonadherent group. The mean difference of all except the dosing subscale was statistically significant with p<0.05. Only the skipping subscale showed a statistically significant positive correlation with ABR in the non-adherent group p=0.02.ConclusionsThe findings indicate that adherence was very good, and most were in communication with their treatment centers. The skipping subscale was significantly associated with ABR for the nonadherent group. Interventions aimed at improving adherence are the key to better treatment outcomes. A multicenter study was needed to assess the reason for poor adherence.
Flower visitation of alien plants is non-linearly related to phylogenetic and floral similarity to native plants
Authors: Razanajatovo Mialy , Joseph Felana Rakoto , Andrianina Princy Rajaonarivelo , van Kleunen Mark 
Published: February 2022

AbstractBiological invasions are key to understanding major ecological processes that determine the formation of novel interactions. Flower visitation to alien species may be facilitated by co-flowering natives if they share similar floral traits with the latter. However, if competition for pollinators is important, flower visitation to alien species may be higher if they have traits different from those of native species. We tested whether flower visitation to alien plants depended on phylogenetic relatedness and floral similarity to native plants.In a field experiment, we simulated invaded communities by adding potted alien plants into co-flowering native communities. We recorded flower visitation to pairs of 34 alien and 20 native species totalling 151 species combinations for 3,068 hours.Flower visitation to alien species was highest when they had intermediate floral trait distances to native species, and either low or high phylogenetic distances. The alien plants received more similar flower-visitor groups to natives when they had low phylogenetic and either low or high floral trait distances to native plants.The non-linear patterns between flower visitation and similarity of the alien and native species suggest that an interplay of facilitation and competition simultaneously drives the formation of novel plant-pollinator interactions. The shapes of the relationships of phylogenetic and floral trait distances with flower visitation to alien plants were contrasting, possibly due to different strengths of phylogenetic signal among traits.We provide experimental evidence for the effects of relatedness and functional similarity to native plants on flower visitation of alien plants. We show that such effects might be non-linear, and that effects of trait dissimilarity and phylogenetic distance on pollinator-mediated interactions can reflect different mechanisms.
Designing human Sphingosine-1-phosphate lyases using a temporal Dirichlet variational autoencoder
Authors: Lobzaev Evgenii , Herrera Michael A. , Campopiano Dominic J. , Stracquadanio Giovanni 
Published: February 2022

AbstractEnzymatic deficiencies cause the accumulation of toxic levels of substrates in a cell and are associated with life-threatening pathologies. Restoring physiological enzymes levels by injecting a recombinant version of the defective enzyme could provide a viable therapeutic option. However, these enzyme replacement therapies have had limited success, as the recombinant enzymes are less catalytically active, cause immune response and are difficult to manufacture. Moreover, the vast sequence design space makes finding enzymes with desired therapeutic properties extremely challenging.Here, we present a new enzyme engineering framework, which builds on recent advances in deep learning, variational calculus and natural language processing, to design variants of human enzymes with biochemical features comparable to the wild type protein as a way to rapidly build targeted libraries for downstream screening. We applied our method to design variants of human Sphyngosine-1-phosphate lyase (HsS1PL) as potential therapeutic treatments for nephrotic syndrome type 14 (NPHS14), and characterized their biochemical properties through extensive sequence and molecular dynamics analyses.
Efficient Bayesian inference for mechanistic modelling with high-throughput data
Authors: Martina-Perez Simon , Sailem Heba , Baker Ruth E. 
Published: February 2022

AbstractBayesian methods are routinely used to combine experimental data with detailed mathematical models to obtain insights into physical phenomena. However, the computational cost of Bayesian computation with detailed models has been a notorious problem. Moreover, while high-throughput data presents opportunities to calibrate sophisticated models, comparing large amounts of data with model simulations quickly becomes computationally prohibitive. Inspired by the method of Stochastic Gradient Descent, we propose a minibatch approach to approximate Bayesian computation. Through a case study of a high-throughput imaging scratch assay experiment, we show that reliable inference can be performed at a fraction of the computational cost of a traditional Bayesian inference scheme. By applying a detailed mathematical model of single cell motility, proliferation and death to a data set of 118 gene knockdowns, we characterise functional subgroups of gene knockdowns, each displaying its own typical combination of local cell density-dependent and -independent motility and proliferation patterns. By comparing these patterns to experimental measurements of cell counts and wound closure, we find that density-dependent interactions play a crucial role in the process of wound healing.