bluuebunny/crossref_metadata_2025 huggingface dataset:
Plcg2M28Linteracts with high fat-high sugar diet to accelerate Alzheimer’s disease-relevant phenotypes in mice
Authors: Oblak Adrian L. , Kotredes Kevin P. , Pandey Ravi , Reagan Alaina M. , Ingraham Cynthia , Perkins Bridget , Lloyd Chris , Baker Deborah , Lin Peter B. , Soni Disha M. , Tsai Andy , Persohn Scott C. , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Meyers Jill A. , Peters Johnathon , Figueiredo Lucas L. , Sasner Michael , Territo Paul R. , Rizzo Stacey J. Sukoff , Carter Gregory W. , Lamb Bruce T. , Howell Gareth R.
Published: February 2022

Obesity is recognized as a significant risk factor for Alzheimer’s disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies to date have focused on the use of early-onset AD models. Here we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed a high fat/high sugar diet. We focused on three mouse models created through the IU/JAX/Pitt MODEL-AD Center, LOAD1, LOAD1.Plcg2M28Land LOAD1.Mthfr677C>T. At 2 months of age, animals were placed on a high fat/high sugar diet (HFD) that induces obesity, or a control diet (CD) that does not, until 12 months of age. Throughout the study, blood was collected to assess cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. At the completion of the study, blood and brains were collected for analysis. As expected, animals fed the HFD, regardless of genotype or sex, showed a significant increase in body weight compared to those fed the CD. Glucose and cholesterol increased as a function of HFD as well. Interestingly, LOAD1.Plcg2M28Ldemonstrated an increase in microglia density as well as alterations in regional brain glucose and perfusion when on a HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr677C>Tanimals when fed a HFD. Furthermore, LOAD1.Plcg2M28Lbut not LOAD1.Mthfr677C>Tor LOAD1 animals showed transcriptomics correlations to human AD modules. Our results show HFD affects brain health in a genotype-specific manner. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.
Extensive in vitro and in vivo protein translation via in situ circularized RNAs
Authors: Kumar Aditya , Palmer Nathan , Miyasaki Katelyn , Finburgh Emma , Xiang Yichen , Portell Andrew , Dailamy Amir , Suhardjo Amanda , Chew Wei Leong , Kwon Ester J. , Mali Prashant
Published: February 2022

RNAs are a powerful therapeutic class. However their inherent transience impacts their activity both as an interacting moiety as well as a template. Circularization of RNA has been demonstrated as a means to improve persistence, however simple and scalable approaches to achieve this are lacking. Utilizing autocatalytic RNA circularization, here we engineer in situcircularized RNAs (icRNAs). This approach enables icRNA delivery as simple linear RNA that is circularized upon delivery into the cell, thus making them compatible with routine synthesis, purification, and delivery formulations. We confirmed extensive protein translation from icRNAs both in vitro and in vivo and explored their utility in three contexts: first, we delivered the SARS-CoV-2 Omicron spike protein in vivo as icRNAs and showed corresponding induction of humoral immune responses; second, we demonstrated robust genome targeting via zinc finger nucleases delivered as icRNAs; and third, to enable compatibility between persistence of expression and immunogenicity, we developed a novel long range multiplexed (LORAX) protein engineering methodology to screen progressively deimmunized Cas9 proteins, and demonstrated efficient genome and epigenome targeting via their delivery as icRNAs. We anticipate this highly simple and scalable icRNA methodology could have broad utility in basic science and therapeutic applications.
Mechanochemical tuning of a kinesin motor essential for malaria parasite transmission
Authors: Liu Tianyang , Shilliday Fiona , Cook Alexander D. , Tewari Rita , Sutherland Colin J. , Roberts Anthony. J. , Moores Carolyn A.
Published: February 2022

Kinesins are a superfamily of molecular motors that undertake ATP-dependent microtubule-based movement or regulate microtubule dynamics. Plasmodium species, which cause malaria and kill hundreds of thousands annually, encode 8-9 kinesins in their genomes. Of these, two – kinesin-8B and kinesin-8X -are canonically classified as kinesin-8s, which in other eukaryotes typically modulate microtubule dynamics. Unexpectedly, Plasmodium kinesin-8B is required for development of the flagellated male gamete in the mosquito host, and its absence completely blocks parasite transmission. To understand the molecular basis of kinesin-8B’s essential role, we characterised the in vitro properties of the kinesin-8B motor domains from P. berghei and P. falciparum. Both motors drive plus-end directed ATP-dependent microtubule gliding, but also catalyse ATP-dependent microtubule depolymerisation. We determined the microtubule-bound structures of these motors using cryo-electron microscopy. P. berghei and P. falciparum kinesin-8B exhibit a very similar mode of microtubule interaction, in which Plasmodium-distinct sequences at the microtubule-kinesin interface influence motor function. Intriguingly, however, P. berghei kinesin-8B exhibits a non-canonical structural response to ATP analogue binding such that neck linker docking is not induced. Nevertheless, the neck linker region is absolutely required for motility and depolymerisation activities of these motors. Taken together, these data suggest that the mechanochemistry of Plasmodium kinesin-8Bs has been functionally tuned to efficiently contribute to flagella formation.
An in vivo model of echovirus-induced meningitis in neonates
Authors: Wells Alexandra I. , Coyne Carolyn B.
Published: February 2022

Echoviruses are amongst the most common causes of aseptic meningitis worldwide, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation is poorly understood, owing at least in part to the lack of in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an in vivo neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We found that expression of the human homologue of the neonatal Fc receptor (FcRn), the primary echovirus receptor, in neonatal mice was not sufficient for infection of the brain. However, ablation of type I, but not III, IFN signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms including delayed motor skills and hind limb weakness. We also defined the immunological response of the brain to echovirus infections and identified key cytokines induced by this infection. Lastly, we found that echoviruses robustly replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an in vivo model of aseptic meningitis associated with echovirus infections and defines the specificity of echoviral infections within the meninges.

Significance Statement

Echoviruses are amongst the most common causes of aseptic meningitis worldwide, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust in vivo models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the neonatal Fc receptor (FcRn), the primary receptor for echoviruses, and ablation of type I interferon (IFN) signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.
Ancestral reconstruction of duplicated signaling proteins reveals the evolution of signaling specificity
Authors: Nocedal Isabel , Laub Michael T.
Published: February 2022

Gene duplication is crucial to generating novel signaling pathways during evolution. However, it remains unclear how the redundant proteins produced by gene duplication ultimately acquire new interaction specificities to establish insulated paralogous signaling pathways. Here, we used ancestral sequence reconstruction to resurrect and characterize a bacterial two-component signaling system that duplicated in α-proteobacteria. We determined the interaction specificities of the signaling proteins that existed before and immediately after this duplication event and then identified key mutations responsible for establishing specificity in the two systems. Just three mutations, in only two of the four interacting proteins, were sufficient to establish specificity of the extant systems. Some of these mutations weakened interactions between paralogous systems to limit crosstalk. However, others strengthened interactions within a system, indicating that the ancestral interaction, although functional, had the potential to be strengthened. Our work suggests that protein-protein interactions with such latent potential may be highly amenable to duplication and divergence.
Brain cortical changes are related to inflammatory biomarkers in hospitalized SARS-CoV-2 patients with neurological symptoms
Authors: Sanabria-Diaz Gretel , Etter Manina Maja , Melie-Garcia Lester , Lieb Johanna , Psychogios Marios-Nikos , Hutter Gregor , Granziera Cristina
Published: February 2022

Increasing evidence shows that the brain is a target of SARS-CoV-2. However, the consequences of the virus on the cortical regions of hospitalized patients are currently unknown. The purpose of this study was to assess brain cortical gray matter volume (GMV), thickness (Th), and surface area (SA) characteristics in SARS-CoV-2 hospitalized patients with a wide range of neurological symptoms and their association with clinical indicators of inflammatory processes. A total of 33 patients were selected from a prospective, multicenter, cross-sectional study during the ongoing pandemic (August 2020-April 2021) at Basel University Hospital. Retrospectively biobank healthy controls with the same image protocol served as controls group. For each anatomical T1w MPRAGE image, the Th and GMV segmentation were performed with the FreeSurfer-5.0. Cortical measures were compared between groups using a linear regression model. The covariates were age, gender, age*gender, MRI magnetic field strength, and total intracranial volume/mean Th/Total SA. The association between cortical features and laboratory variables was assessed using partial correlation adjusting for the same covariates. P-values were adjusted using false discovery rate (FDR). Our findings revealed a lower cortical gray matter volume in orbitofrontal and cingulate regions in patients compared to controls. The orbitofrontal grey matter volume was negatively associated with protein levels, CSF-blood/albumin ratio and CSF EN-RAGE level. CSF EN-RAGE and CSF/Blood-albumin ratio, which are neuroinflammatory biomarkers, were associated with cortical alterations in gray matter volume and thickness in frontal, orbitofrontal, and temporal regions. Our data suggest that viral-triggered inflammation leads to increased neurotoxic damage in some cortical areas.
Cytoplasmic Expression of LMP1 and its Nuclear Translocation in Nasopharyngeal Carcinoma Correlates with Epithelial-mesenchymal Transition
Authors: Luo Weiren
Published: February 2022

Up to now, the prognostic significance of latent membrane protein 1 (LMP1) in nasopharyngeal carcinoma (NPC) tissues still remains controversial. This study aims to investigate aberrant localization of LMP1 and its relationship with epithelial-mesenchymal transition (EMT) in NPC samples by immunohistochemistry and immunofluorescence. Both cytoplasmic and nuclear LMP1 expressions were observed in NPC tissues. In some tissues, nuclear LMP1 was frequently observed at tumor invasive front and tumor buddings. Nuclear LMP1 expression was significantly associated with lymph node metastasis (P=0.031), local recurrence (P=0.002), lymphatic invasion (P= 0.004) and tumor budding (P=0.001). Furthermore, nuclear LMP1 showed significant correlations with EMT markers including E-cadherin (P=0.037), Vimentin (P < 0.001), N-cadherin (P=0.003), Snail (P=0.003) and Twist (P=0.002), but not significantly linked with Fibronectin (P=0.103) and Slug (P=0.503). According to cytoplasmic LMP1, it correlated strongly with lymphatic invasion (P=0.044), vascular invasion (P=0.003) and EMT proteins including E-cadherin (P=0.014), Vimentin (P=0.006), N-cadherin (P=0.003), Snail (P=0.008) and Slug (P=0.007), whereas not significantly associated with Fibronectin (P=0.221) and Twist (P=0.106). However, multivariate analysis showed that nuclear LMP1 (P=0.844) and cytoplasmic LMP1 (P=0.291) were not independent predictors for NPC. In conclusion, we demonstrate firstly that abnormal localization of LMP1 correlates with EMT properties and aggressiveness in NPC, respectively.
AugmentA: Patient-specific Augmented Atrial model Generation Tool
Authors: Azzolin Luca , Eichenlaub Martin , Nagel Claudia , Nairn Deborah , Sánchez Jorge , Unger Laura , Dössel Olaf , Jadidi Amir , Loewe Axel
Published: February 2022

Digital twins of patients’ hearts are a promising tool to assess arrhythmia vulnerability and to personalize therapy. However, the process of building personalized computational models can be challenging and requires a high level of human interaction. A pipeline to standardize the generation of a patient’s atrial digital twin from clinical data is therefore desirable. We propose a patient-specific Augmented Atria generation pipeline (AugmentA) as a highly automated framework which, starting from clinical geometrical data, provides ready-to-use atrial personalized computational models. AugmentA consists firstly of a preprocessing step applied to the input geometry. Secondly, the atrial orifices are identified and labelled using only one reference point per atrium. If the user chooses to fit a statistical shape model (SSM) to the input geometry, it is first rigidly aligned with the given mean shape before a nonrigid fitting procedure is applied. AugmentA automatically generates the fiber orientation and finds local conduction velocities by minimizing the error between the simulated and clinical local activation time (LAT) map. The pipeline was tested on a cohort of 29 patients on both segmented magnetic resonance images (MRI) and electroanatomical maps of the left atrium. Moreover, the pipeline was applied to a bi-atrial volumetric mesh derived from MRI. The pipeline robustly integrated fiber orientation and anatomical region annotations in 38.4±5.7 s. The error between insilico and clinical LAT maps was on average 12.7 ms. In conclusion, AugmentA offers an automated and comprehensive pipeline delivering atrial digital twins from clinical data in procedural time.
A novel molecular subtype of hepatocellular carcinoma based on the tumor purity and tumor microenvironment-related polygenic risk scores
Authors: Lin Yan , Liang Rong , Gao Xing , He Ziqin , Lu Lu , Luo Min , Li Qian , Wang Xiaobo , Li Yongqiang , Wu Guobin , Luo Xiaoling , Ye Jiazhou
Published: February 2022

Purpose

The purpose of the present study was to use malignant cell-related and tumor microenvironment (TME)-related molecules to develop a novel molecular subtype of hepatocellular carcinoma (HCC).

Methods

The tumor purity (TP)-related and TME-related genes were identified and separately used to construct the TP-related and TME-related polygenic risk score (PRS). According to the two PRSs, we developed the TP-TME risk classification which was validated in two external data sets from The Cancer Genome Atlas Program and International Cancer Genome Consortium database. We also performed functional enrichment and drug repositioning analysis to reveal the potential biological heterogeneity among different subtypes.

Results

The three TP-TME risk subtypes of HCC had significantly different prognosis and biological characteristics. The TP-TME low risk subtype had the best prognosis and was characterized by well-differentiated, the TP-TME high risk subtype had the worst prognosis and was characterized by aberrant activation of TGFβ and WNT pathways, and the TP-TME high risk subtype had the moderate prognosis and was characterized by exhibited activated MYC targets and proliferation-related gene sets. These three TP-TME risk subtypes may respond differently to immunotherapy (e.g., immune checkpoint inhibitors and chimeric antigen receptor-modified T cells) or other drug therapies.

Conclusion

By combining the TP-related PRS and TME-related PRS, we proposed and validated the TP-TME risk subtyping system to divide patients with HCC into three subtypes with distinct biological characteristics and prognoses. These findings highlight the significant clinical implications of the TP-TME risk subtyping system and provide potential personalized immunotherapy strategies for HCC.
Modeling Covid-19 incidence by the renewal equation after removal of administrative bias and noise
Authors: Alvarez Luis , Morel Jean-David , Morel Jean-Michel
Published: February 2022

The sanitary crisis of the past two years has focused the public’s attention on quantitative indicators of the spread of the COVID-19 pandemic. The daily reproduction number Rt, defined by the average number of new infections caused by a single infected individual at time t, is one of the best metrics for estimating the epidemic trend. In this paper, we give a complete observation model for sampled epidemiological incidence signals obtained through periodic administrative measurements. The model is governed by the classic renewal equation using an empirical reproduction kernel, and subject to two perturbations: a time-varying gain with a weekly period and a white observation noise. We estimate this noise model and its parameters by extending a variational inversion of the model recovering its main driving variable Rt. Using Rt, a restored incidence curve, corrected of the weekly and festive day bias, can be deduced through the renewal equation. We verify experimentally on many countries that, once the weekly and festive days bias have been corrected, the difference between the incidence curve and its expected value is well approximated by an exponential distributed white noise multiplied by a power of the magnitude of the restored incidence curve.

Simple Summary

In the past two years, the COVID-19 incidence curves and reproduction number Rt have been the main metrics used by policy makers and journalists to monitor the spread of this global pandemic. However, these metrics are not always reliable in the short term, because of a combination of delay in detection, administrative delays and random noise. In this article, we present a complete model of COVID-19 incidence, faithfully reconstructing the incidence curve and reproduction number from the renewal equation of the disease and precisely estimating the biases associated with periodic weekly bias, festive day bias and residual noise.
Reliable estimation of SARS-CoV-2 anti-spike protein IgG titers from single dilution optical density values in serologic surveys
Authors: Andrade Belitardo Emilia M. M. , Nery Nivison , Aguilar Ticona Juan P. , Portilho Moyra Machado , Ribeiro Guilherme S. , Reis Mitermayer G. , Costa Federico , Cummings Derek A. T. , Ko Albert I. , Fofana Mariam O.
Published: February 2022

Background

As the COVID-19 pandemic evolves, there is a need for reliable and scalable seroepidemiology methods to estimate incidence, monitor the dynamics of population-level immunity, and guide mitigation and immunization policies. Our aim was to evaluate the reliability of normalized ELISA optical density (nOD) at a single dilution as a predictor of SARS-CoV-2 immunoglobulin titers derived from serial dilutions.

Methods

We conducted serial serological surveys of a community-based cohort from the city of Salvador, Brazil after two sequential COVID-19 epidemic waves. Anti-SARS-CoV-2 spike protein immunoglobulin G (anti-S IgG) ELISA (Euroimmun AG) was performed with serial 3-fold dilutions of sera from 54 of the 1101 cohort participants. We estimated interpolated ELISA titers, used parametric models to fit the relationship between nOD at a single 1:100 dilution and interpolated titers, and assessed the correlation between changes in nOD and changes in titers.

Results

The relationship between nOD at a single 1:100 dilution and interpolated titers fit a log-log curve, with a residual standard error of 0.304. We derived a conversion table of nOD to interpolated titer values. Additionally, there was a high correlation between changes in nOD and changes in interpolated titers between paired serial samples (r = 0.836, ρ = 0.873). Changes in nOD reliably predicted increases and decreases in titers, with 98.1% agreement (κ = 95.9%).

Conclusion

Single nOD measurements can reliably estimate SARS-CoV-2 antibody titers, significantly reducing time, labor, and resource needs when conducting large-scale serological surveys to ascertain population-level changes in exposure and immunity.

Highlights

Optical density at a single dilution reliably estimates SARS-CoV-2 antibody titers

Serial optical density measurements accurately identify changes in serostatus

Using single optical density values can significantly reduce resource use in serosurveys
Salinity induces discontinuous protoxylem by a DELLA-dependent mechanism promoting salt tolerance in Arabidopsis seedlings
Authors: Augstein Frauke , Carlsbecker Annelie
Published: February 2022

Salinity is detrimental to plants and developmental adjustments limiting salt uptake and transport is therefore important for acclimation to high salt. These parameters may be influenced by xylem morphology, however, how plant root xylem development is affected by salt stress remains unclear.

Through detailed phenotypic analyses, molecular and genetic techniques, we demonstrate that salt causes distinct effects on Arabidopsis seedling root xylem, and reveal underlying molecular mechanisms.

Salinity causes intermittent inhibition of protoxylem cell differentiation, generating protoxylem gaps, in Arabidopsis and other eudicot seedlings. The extent of protoxylem gaps positively correlates with salt tolerance. Reduced gibberellin signaling is required for protoxylem gap formation. Mutant analyses reveal that the xylem differentiation regulator VASCULAR RELATED NAC DOMAIN 6 (VND6), along with secondary cell wall-producing and cell wall modifying enzymes, including EXPANSIN A1 (EXP1), are involved in protoxylem gap formation, in a DELLA-dependent manner.

Salt stress impacts seedling survival and formation of protoxylem gaps is a means of enhancing salt tolerance. Salt stress likely reduces levels of bioactive gibberellins, stabilizing DELLAs, which in turn activate multiple factors modifying protoxylem differentiation. Formation of protoxylem gaps is induced in diverse eudicot species suggesting that this is an evolutionary conserved response for salt acclimation in seedlings.
Translaminar Recurrence from Layer 5 Suppresses Superficial Cortical Layers
Authors: Onodera Koun , Kato Hiroyuki K
Published: February 2022

Information 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

Previously, 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

Psychedelic-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

Determining 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

Introduction

Estimating 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.

Methods

We 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.

Results

We 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).

Conclusion

We 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

Background

Metabolically 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.

Methods

We 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.

Results

The 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.

Conclusions

Transitions 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

The 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

Background

In 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.

Objective

To 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.

Methodology

A 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.

Results

The 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.

Conclusions

The 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

Biological 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

Enzymatic 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

Bayesian 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.
Monoacylglycerol O-acyltransferase 1 is required for adipocyte differentiation in vitro but does not affect adiposity in mice
Authors: Singer Jason M. , Shew Trevor M. , Ferguson Daniel , Renkemeyer M. Katie , Pietka Terri A. , Hall Angela M. , Finck Brian N. , Lutkewitte Andrew J.
Published: February 2022

Objective

Monoacylglycerol O-acyltransferase 1 (Mogat1), a lipogenic enzyme that converts monoacylglycerol to diacylglycerol, is highly expressed in adipocytes and may regulate lipolysis by re-esterifying fatty acids released during times when lipolytic rates are low. However, the role of Mogat1 in regulating adipocyte fat storage during differentiation and diet-induced obesity is relatively understudied.

Methods

Here we generated adipocyte-specific Mogat1 knockout mice and subjected them to a high-fat diet to determine the effects of Mogat1 deficiency on diet-induced obesity. We also used Mogat1 floxed mice to develop preadipocyte cell lines wherein Mogat1 could be conditionally knocked out to study adipocyte differentiation in vitro.

Results

In preadipocytes, we found that Mogat1 knockout at the onset of preadipocyte differentiation prevented the accumulation of glycerolipids and reduced the differentiation capacity of preadipocytes. However, the loss of adipocyte Mogat1 did not affect weight gain or fat mass induced by high-fat diet in mice. Furthermore, loss of Mogat1 in adipocytes did not affect plasma lipid or glucose concentrations or insulin tolerance.

Conclusions

These data suggest Mogat1 may play a role in adipocyte differentiation in vitro but not adipose tissue expansion in response to nutrient overload in mice.

STUDY IMPORTANCE

What is already known?

Adipose tissue expansion through adipocyte precursor cell differentiation is critical for proper lipid storage during nutrient overload.

Monoacylglycerol O-acyltransferase 1 (Mogat1), a lipogenic enzyme, is highly induced during adipocyte differentiation of human and mouse precursor cells and is reduced in patients with obesity and metabolic dysfunction.

What does this study add?

Mogat1 deletion during early adipocyte differentiation reduces differentiation capacity, adipogenic gene expression and lowers glycerolipid content of differentiated adipocytes.

Adipocyte Mogat1 expression is dispensable for adiposity and metabolic outcomes high-fat fed mice and suggests compensation from other glycerolipid synthesis enzymes.

How might these results change the direction of research?

Understanding the molecular mechanisms of glycerolipid metabolism healthy adipose tissue expansion.