bluuebunny/crossref_metadata_2025_split 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

AbstractObesity 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

ABSTRACTRNAs 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

ABSTRACTKinesins 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

AbstractEchoviruses 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 StatementEchoviruses 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

AbstractGene 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

AbstractIncreasing 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

AbstractUp 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

AbstractDigital 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

AbstractPurposeThe 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).MethodsThe 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.ResultsThe 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.ConclusionBy 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

AbstractThe 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 SummaryIn 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

AbstractBackgroundAs 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.MethodsWe 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.ResultsThe 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%).ConclusionSingle 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.HighlightsOptical density at a single dilution reliably estimates SARS-CoV-2 antibody titersSerial optical density measurements accurately identify changes in serostatusUsing 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

SummarySalinity 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.