bluuebunny/crossref_metadata_2025 huggingface dataset:
Transfer learning of an in vivo-derived senescence signature identifies conserved and tissue-specific senescence across species and diverse pathologies
Authors: Cherry Christopher , Andorko James I , Krishnan Kavita , Mejias Joscelyn C , Nguyen Helen Hieu , Stivers Katlin B , Gray-Gaillard Elise F , Ruta Anna , Hamada Naomi , Hamada Masakazu , Sturmlechner Ines , Trewartha Shawn , Michel John H , Huyer Locke Davenport , Wolf Matthew T , Tam Ada , Peña Alexis N , Le Saux Claude Jordan , Fertig Elana J , Baker Darren J , Housseau Franck , van Deursen Jan M , Pardoll Drew M , Elisseeff Jennifer H
Published: March 2022

Senescent cells (SnCs) contribute to normal tissue development and repair but accumulate with aging where they are implicated in a number of pathologies and diseases. Despite their pathological role and therapeutic interest, SnC phenotype and function in vivo remains unclear due to the challenges in identifying and isolating these rare cells. Here, we developed an in vivo-derived senescence gene expression signature using a model of the foreign body response (FBR) fibrosis in a p16Ink4a-reporter mouse, a cell cycle inhibitor commonly used to identify SnCs. We identified stromal cells (CD45-CD31- CD29+) as the primary p16Ink4a expressing cell type in the FBR and collected the cells to produce a SnC transcriptomic signature with bulk RNA sequencing. To computationally identify SnCs in bulk and single-cell data sets across species and tissues, we used this signature with transfer learning to generate a SnC signature score (SenSig). We found senescent pericyte and cartilage-like fibroblasts in newly collected single cell RNAseq (scRNASeq) data sets of murine and human FBR suggesting populations associated with angiogenesis and secretion of fibrotic extracellular matrix, respectively. Application of the senescence signature to human scRNAseq data sets from idiopathic pulmonary fibrosis (IPF) and the basal cell carcinoma microenvironment identified both conserved and tissue-specific SnC phenotypes, including epithelial-derived basaloid and endothelial cells. In a wound healing model, ligand-receptor signaling prediction identified putative interactions between SnC SASP and myeloid cells that were validated by immunofluorescent staining and in vitro coculture of SnCs and macrophages. Collectively, we have found that our SenSig transfer learning strategy from an in vivo signature outperforms in vitro-derived signatures and identifies conserved and tissue-specific SnCs and their SASP, independent of p16Ink4a expression, and may be broadly applied to elucidate SnC identity and function in vivo.
Spatial scenario of tropical deforestation and carbon emissions for the 21stcentury
Authors: Vieilledent Ghislain , Vancutsem Christelle , Bourgoin Clément , Ploton Pierre , Verley Philippe , Achard Frédéric
Published: March 2022

Tropical forests are disappearing at an alarming rate due to human activities. Here, we provide spatial models of deforestation in 92 countries covering all the tropical moist forests in the world. Our results question the global effectiveness of protected areas in curbing deforestation and allow reinterpreting the impact of roads on deforestation in terms of both accessibility and forest fragmentation. Using our models, we derived high-resolution pantropical maps of the deforestation risk and future forest cover for the 21stcentury under a “business-as-usual” scenario based on the deforestation rates observed in the 2010s. Under this scenario, 48% (39–56%) of tropical moist forests are expected to disappear during the course of the 21stcentury, and 41 tropical countries will have lost all their forests by 2100. The remaining forests in 2100 will be highly fragmented and located in remote places, preferentially in protected areas, far from roads and villages, and at high elevations. We also show that future deforestation will likely concern forests with higher aboveground carbon stocks, and hence that carbon emissions from tropical deforestation are expected to increase (from 0.432–0.585 Pg/yr in 2020 to 0.583–0.628 Pg/yr in 2100). Considering also the decrease in carbon uptake in aboveground biomass (from 0.589 Pg/yr in 2000 to 0.312 Pg/yr in 2100) associated with the decrease in forest cover, tropical moist forests would become a major net carbon source in the 21stcentury under this scenario.
Structure-based Evolution of G protein-biased μ-opioid Receptor Agonists
Authors: Wang Haoqing , Hetzer Florian , Huang Weijiao , Qu Qianhui , Meyerowitz Justin , Kaindl Jonas , Hübner Harald , Skiniotis Georgios , Kobilka Brian K. , Gmeiner Peter
Published: March 2022

The μ-opioid receptor (μOR) is the major target for opioid analgesics. Activation of μOR initiates signaling through G protein pathways as well as through β-arrestin recruitment. μOR agonists that are biased towards G protein signaling pathways demonstrate diminished side effects. PZM21, discovered by computational docking, is a G protein biased μOR agonist. Here we report the cryoEM structure of PZM21 bound μOR in complex with Gi protein. Structure-based evolution led to multiple PZM21 analogs with more pronounced Gi protein bias and increased lipophilicity to improve CNS penetration. Among them, FH210 shows extremely low potency and efficacy for arrestin recruitment. We further determined the cryoEM structure of FH210 bound to μOR in complex with Gi protein and confirmed its expected binding pose. The structural and pharmacological studies reveal a potential mechanism to reduce β-arrestin recruitment by the μOR, and hold promise for developing next-generation analgesics with fewer adverse effects.

Table of Contents Graphical Abstract

We obtained cryoEM structures of the μ-opioid receptor (μOR) bound to the lead compound PZM21 and the newly developed agonist FH210 to understand the mechanism of their biased signaling and to guide the evolution of next-generation analgesics with fewer adverse effects.
Two mosquito odorant receptors with reciprocal specificity mediated by a single amino acid residue
Authors: Franco Flávia P. , Xu Pingxi , Harris Brandon J. , Yarov-Yarovoy Vladimir , Leal Walter S.
Published: March 2022

The southern house mosquito,Culex quinquefasciatus, utilizes two odorant receptors, CquiOR10 and CquiOR2, narrowly tuned to oviposition attractants and well conserved among mosquito species. They detect skatole and indole, respectively, with reciprocal specificity. We swapped the seven transmembrane (TM) domains of CquiOR10 and CquiOR2 and identified TM2 as a specificity determinant. With additional mutations, we showed that CquiOR10A73L behaved like CquiOR2. Conversely, CquiOR2L74A recapitulated CquiOR10 specificity. Next, we generated structural models of CquiOR10 and CquiOR10A73L using RoseTTAFold and AlphaFold and docked skatole and indole using RosettaLigand. These modeling studies suggested space-filling constraints around A73. Consistent with this hypothesis, CquiOR10 mutants with a bulkier residue (Ile, Val) were insensitive to skatole and indole, whereas CquiOR10A73G retained the specificity to skatole and showed a more robust response than the wildtype receptor CquiOR10. On the other hand, Leu to Gly mutation of the indole receptor CquiOR2 reverted the specificity to skatole. Lastly, CquiOR10A73L, CquiOR2, and CquiOR2L74I were insensitive to 3-ethylindole, whereas CquiOR2L74A and CquiOR2L74G gained activity. Additionally, CquiOR10A73G gave more robust responses to 3-ethylindole than CquiOR10. Thus, we suggest the specificity of these receptors is mediated by a single amino acid substitution, leading to finely tuned volumetric space to accommodate specific oviposition attractants.
Genetic background and mistranslation frequency determine the impact of mistranslating tRNASerUGG
Authors: Berg Matthew D. , Zhu Yanrui , Loll-Krippleber Raphaël , San Luis Bryan-Joseph , Genereaux Julie , Boone Charles , Villen Judit , Brown Grant W. , Brandl Christopher J.
Published: March 2022

Transfer RNA variants increase the frequency of mistranslation, the mis-incorporation of an amino acid not specified by the “standard” genetic code, to frequencies approaching 10% in yeast and bacteria. Cells cope with these variants by having multiple copies of each tRNA isodecoder and through pathways that deal with proteotoxic stress. In this study, we define the genetic interactions of the gene encoding tRNASerUGG,G26A, which mistranslates serine at proline codons. Using a collection of yeast temperature sensitive alleles, we identify negative synthetic genetic interactions between the mistranslating tRNA and 109 alleles representing 91 genes, with nearly half of the genes having roles in RNA processing or protein folding and turnover. By regulating tRNA expression, we then compare the strength of the negative genetic interaction for a subset of identified alleles under differing amounts of mistranslation. The frequency of mistranslation correlated with impact on cell growth for all strains analyzed; however, there were notable differences in the extent of the synthetic interaction at different frequencies of mistranslation depending on the genetic background. For many of the strains the extent of the negative interaction with tRNASerUGG,G26Awas proportional to the frequency of mistranslation or only observed at intermediate or high frequencies. For others the synthetic interaction was approximately equivalent at all frequencies of mistranslation. As humans contain similar mistranslating tRNAs these results are important when analyzing the impact of tRNA variants on disease, where both the individual’s genetic background and the expression of the mistranslating tRNA variant need to be considered.
Prenatal methadone exposure leads to long-term memory impairments and disruptions of dentate granule cell function in a sex-dependent manner
Authors: Gamble Meredith E. , Marfatia Rhea , Diaz Marvin R.
Published: March 2022

Prenatal opioid exposures lead to extensive cognitive and emotion-regulation problems in children, persisting at least through school-age. Methadone, an opioid typically used for the treatment of opioid use disorder, has been approved for use in pregnant women for several decades. Importantly, however, the impacts of prenatal methadone exposure (PME), particularly on offspring as they progress into adulthood, has not been extensively examined. In recent years, children and young animal models have shown cognitive deficits related to PME, including evidence of hippocampal dysfunction. The present work aims to examine the persistent nature of these deficits, as well as determine how they may differ by sex. Pregnant Sprague Dawley rats either received subcutaneous methadone or water injections twice daily from gestational days 3-20 or were left undisturbed. Following postnatal day 70, male and female offspring were behaviorally tested for impairments in recognition memory using the Novel Object Recognition task and working spatial memory through Spontaneous Alternation. Additionally, using whole-cell patch-clamp electrophysiology, hippocampal dentate granule cell function was examined in adult offspring. Results indicate that methadone-exposed females showed decreased excitability and increased inhibition of these dentate granule cells, while males did not. These findings were accompanied by impairments in female working spatial memory and impaired recognition memory of both sexes. Overall, this work supports the continued investigation of the long-term effects of PME on adult male and female learning and memory, as well as promotes further exploration of adult hippocampal function as a neural mechanism impacted by this exposure.
The GR2D2 Estimator for the Precision Matrices
Authors: Gan Dailin , Yin Guosheng , Zhang Yan Dora
Published: March 2022

Biological networks are important for the analysis of human diseases, which summarize the regulatory interactions and other relationships between different molecules. Understanding and constructing networks for molecules, such as DNA, RNA and proteins, can help elucidate the mechanisms of complex biological systems. The Gaussian Graphical Models (GGMs) are popular tools for the estimation of biological networks. Nonetheless, reconstructing GGMs from high-dimensional datasets is still challenging. Current methods cannot handle the sparsity and high-dimensionality issues arising from datasets very well. Here we developed a new GGM, called the GR2D2 (Graphical R2-induced Dirichlet Decomposition) model, based on the R2D2 priors for linear models. Besides, we provided a data-augmented block Gibbs sampler algorithm. The R code is available at https://github.com/RavenGan/GR2D2. The GR2D2 estimator shows superior performance in estimating the precision matrices compared to existing techniques in various simulation settings. When the true precision matrix is sparse and of high dimension, the GR2D2 provides the estimates with smallest information divergence from the underlying truth. We also compare the GR2D2 estimator to the graphical horseshoe estimator in five cancer RNA-seq gene expression datasets grouped by three cancer types. Our results show that GR2D2 successfully identifies common cancer pathways and cancer-specific pathways for each dataset.
Multiple-timescale dynamics, mixed mode oscillations and mixed affective states in a model of Bipolar Disorder
Authors: Pavlidis Efstathios , Campillo Fabien , Goldbeter Albert , Desroches Mathieu
Published: March 2022

Mixed affective states in bipolar disorder (BD) is a common psychiatric condition that occurs when symptoms of the two opposite poles coexist during an episode of mania or depression. A four-dimensional model by A. Goldbeter [27, 28] rests upon the notion that manic and depressive symptoms are produced by two competing and auto-inhibited neural networks. Some of the rich dynamics that this model can produce, include complex rhythms formed by both small-amplitude (subthreshold) and large-amplitude (suprathreshold) oscillations and could correspond to mixed bipolar states. These rhythms are commonly referred to asmixed mode oscillations (MMOs)and they have already been studied in many different contexts [7, 50]. In order to accurately explain these dynamics one has to apply a mathematical apparatus that makes full use of the timescale separation between variables. Here we apply the framework of multiple-timescale dynamics to the model of BD in order to understand the mathematical mechanisms underpinning the observed dynamics of changing mood. We show that the observed complex oscillations can be understood as MMOs due to a so-calledfolded-node singularity. Moreover, we explore the bifurcation structure of the system and we provide possible biological interpretations of our findings. Finally, we show the robustness of the MMOs regime to stochastic noise and we propose a minimal three-dimensional model which, with the addition of noise, exhibits similar yet purely noise-driven dynamics. The broader significance of this work is to introduce mathematical tools that could be used to analyse and potentially control future, more biologically grounded models of BD.
A model for quorum-sensing mediated stochastic biofilm nucleation
Authors: Sinclair Patrick , Brackley Chris A. , Carballo-Pacheco Martín , Allen Rosalind J.
Published: March 2022

Surface-attached bacterial biofilms cause disease and industrial biofouling, as well as being widespread in the natural environment. Density-dependent quorum sensing is one of the mechanisms implicated in biofilm initiation. Here we present and analyse a model for quorum-sensing triggered biofilm initiation. In our model, individual, planktonic bacteria adhere to a surface, pro-liferate and undergo a collective transition to a biofilm phenotype. This model predicts a stochastic transition between a loosely attached, finite, layer of bacteria near the surface, and a growing biofilm. The transition is governed by two key parameters: the collective transition density relative to the carrying capacity, and the immigration rate relative to the detachment rate. Biofilm initiation is complex, but our model suggests that stochastic nucleation phenomena may be relevant.
Association of genetically-predicted lipid traits and lipid-modifying targets with the risk of heart failure
Authors: Xiao Jun , Ji Jianguang , Yang Xi , Chen Keyuan , Chen Liangwan , Huang Wuqing
Published: March 2022

Aims

To assess the association of lipid traits and lipid-modification via licensed or investigational targets with heart failure (HF) risk using 2-sample Mendelian randomization (MR) study.

Methods and results

Genetic variants obtained from genome-wide association studies (GWASs) in UK Biobank as instrumental variables to investigate the association of lipid traits (low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), apolipoprotein B (ApoB) and apolipoprotein AI (ApoAI)) and lipid-modifying effect of eight licensed or investigational drug targets with HF risk by using the inverse-variance weighted method. In this study, we observed that genetically-predicted levels of LDL-C, TG, LDL-C and ApoB were significantly related to HF risk, which were mainly mediated by CHD. Further MR analyses identified PCSK9, CETP and LPL, but not HMGCR, as potential targets to prevent HF. The genetic proxy of LDL-C and ApoB increase modified by PCSK9 showed similar evidence in increasing risk of HF (PLDL-C=1.27*10−4; PApoB=1.94*10−4); CETP played a role in HF risk via modifying all investigational lipid traits with the strongest evidence though ApoB (P=5.87*10−6); LPL exerted effects on HF via modifying most lipid traits with the strongest evidence observed via modifying TG (P=3.73*10−12).

Conclusions

This 2-sample MR study provided genetic evidence of the associations between lipid traits and HF risk, which were mostly mediated by CHD. Besides, drug target MR studies indicated that PCSK9 inhibition, CETP inhibition and LPL activation, but not statins, were effective in reducing HF risk.
Intubation and Inhospital mortality in trauma patients with Glasgow Coma Scale Score eight or less. A multicenter cohort study
Authors: Soni Kapil Dev , Bansal Varun , Khajanchi Monty , Veetil Deepa Kizhakke , Geoffrey Anderson , Rayker Nakul , Sarang Bhakti , David Siddharth , Wärnberg Martin Gerdin , Roy Nobhojit
Published: March 2022

Background

Most trauma societies recommend intubation of trauma patients with Glasgow coma scale (GCS) ≤ 8, without robust evidence supporting it.

Methods

We examined the association between intubation and inhopital 30 day mortality in trauma patients arriving with GCS ≤ 8. The data were obtained using the Towards Improved Trauma Care Outcomes (TITCO) registry in India cohort. We compared the outcomes of patients with GCS ≤ 8 who were intubated within one hour after arrival with those who were intubated later or not at all, using multiple analytical approaches to evaluate the consistency of the findings. We also examined the association in multiple subgroups to identify any variability of the effect.

Results

Of 3476 patients who arrived with a GCS ≤ 8, 1671 (48.1%) were intubated within an hour and 1805 (51.9%) were intubated later or not intubated at all. Overall, 1957 (56.3%) patients died in whole cohort. A total of 947 (56.7%) patients died in intubation group and 1010 (56%) died in non intubation group. In the main analysis, there was no significant association between intubation within an hour and mortality(OR=1.18,[CI,0.76-1.84], p value = 0.467). This result was consistent across multiple sensitivity analysis.

Conclusion

In this observational study of trauma patients with GCS ≤ 8, who present to tertiary care hospitals, intubation within one hour after arrival was not associated with increased or decreased risk of inhospital mortality compared to intubation after one hour or no intubation. Further studies are needed to precisely evaluate the benefit of intubation and thus supporting the recommendations.
Effects of genetic liability to Alzheimer’s disease on circulating metabolites across the life course
Authors: Compton Hannah , Smith Madeleine L , Bull Caroline , Korologou-Linden Roxanna , Ben-Shlomo Yoav , Bell Joshua A. , Anderson Emma L
Published: March 2022

Objective

Alzheimer’s disease (AD) has several known genetic determinants, yet the mechanisms through which they lead to disease onset remain poorly understood. This study aims to estimate the effects of genetic liability to AD on plasma metabolites measured at seven different stages across the life course.

Methods

Genetic and metabolomic data from 5,648 offspring from the Avon Longitudinal Study of Parents and Children birth cohort were used. Linear regression models examined the association between higher AD liability, as measured by a genetic risk score (GRS), and plasma metabolites measured at 8, 16, 18 and 25 years of age. Two hundred twenty-nine metabolites were studied, most relating to lipid/lipoprotein traits. Two-sample Mendelian randomization was performed using summary statistics from age-stratified genome-wide association studies (GWAS) of the same metabolites for 118,466 participants from the UK Biobank, to examine the persistence of any AD liability effects into late adulthood.

Results

The GRS including theAPOE4isoform demonstrated the strongest positive associations for cholesterol-related traits per doubling of genetic liability to AD, e.g., for low-density lipoprotein cholesterol (LDL-C) at age 25yrs (0.12 SD; 95% CI 0.09, 0.14), with similar magnitudes of association across age groups in ALSPAC. In the UK Biobank, the effect of AD liability decreased with age tertile for several lipid traits (e.g., LDL-C, youngest: 0.15 SD; 95% CI 0.07, 0.23, intermediate: 0.13 SD; 95% CI 0.07, 0.20, oldest: 0.10 SD; 95% CI 0.05, 0.16). Across both cohorts, the effect of AD liability on high-density lipoprotein cholesterol (HDL-C) attenuated as age increased. Fatty acid metabolites also demonstrated positive associations in both cohorts, though smaller in magnitude compared with lipid traits. Sensitivity analyses indicated that these effects were driven by theAPOE4isoform.

Conclusions

These results support a profound influence of theAPOE4isoform on circulating lipids and fatty acids from early life to later adulthood. Such lipid and fatty acid traits may be implicated in early AD pathogenesis and warrant further investigation as potential targets for preventing the onset of AD.
Informal Sector Employment and the Health Outcomes of Older Workers in India
Authors: Chowdhury Poulomi , Mohanty Itismita , Singh Akansha , Niyonsenga Theo
Published: March 2022

A large proportion of the older population in India constitutes an undeniable share of workforce after the retirement age. This stresses the need to understand the implications of working at older ages on health outcomes. The main objective of this study is to examine the variations in health outcomes by formal/informal sector of employment of older workers using the Longitudinal Ageing Study in India. Using binary logistic regression models with interaction terms, the results of this study affirm that type of work does play a significant role in determining health outcomes even after controlling socio-economic, demographic, life-style behaviour, and work characteristics. The risk of Poor Cognitive Functioning (PCF) is high among informal workers, while formal workers suffer greatly from Chronic Health Conditions (CHC) and Functional Limitations (FL). The presence of CHC among informal workers is more damaging because it elevates their FL, whereas for formal workers presence of FL is unfavourable because it deteriorates their cognitive functioning. Therefore, present study underscores the relevance of policies focusing on providing health and healthcare benefits by respective economic activity and socio-economic position of older workers.
Incidence and Predictors of Antiretroviral Treatment Failure among Children in Public Health Facilities of Kolfe Keranyo Sub-City, Addis Ababa, Ethiopia: Institution-based retrospective cohort study
Authors: Misasew Meseret , Angassa Daniel
Published: March 2022

Background

Human immunodeficiency virus (HIV) infection is a public health concern globally. The numbers of people living with HIV worldwide in 2018 was estimated at 37.9 million; from those, 1.7 million are children. Globally, 62% of the 37.9 million people were receiving Antiretroviral treatment (ART); 53% had achieved viral suppression. This study aimed to assess the incidence and predictors of Antiretroviral treatment failure among children in Kolfe Keranyo sub-city, Addis Ababa, Ethiopia.

Methods

An institution-based retrospective cohort study was conducted among 250 children who were enrolled to first-line Antiretroviral treatment from January 2013 to May 2020 in Kolfe Keranyo sub-city. Data was collected by using data extraction checklist and data were extracted by reviewing children’s medical chart and electronic database. Kaplan–Meier method was used to estimate the probability of treatment failure. During bivariable analysis variables with p-value < 0.25 were taken for multivariable Cox regression analysis to assess predictors of treatment failure. Statistically significant association was declared at p-value < 0.05 with 95% confidence interval.

Result

The overall treatment failure rate within the follow-up period was 17.2%. This study also found that the overall incidence density rate was 3.45% (95% CI: 2.57-4.67) per 1000 person-month observation. Infant prophylaxis for PMTCT (AHR: 3.59, 95% CI: 1.65-7,82), drug substitution (AHR: 0.18, 95% CI: 0.09-0.37), AZT/3TC/NVP based regimen (AHR: 2.27, 95% CI: 1.14-4.25), and more than 3 episodes of poor ART adherence (AHR: 2.27, 95% CI: 1.17-4.38) were found to be predictors of treatment failure among children.

Conclusion

High proportion of treatment failure was found among children on first-line ART in Kolfe Keranyo sub-city, Addis Ababa. Infant prophylaxis for PMTCT, drug substitution, initial regimen, and poor ART adherence were found to be predictors of first-line ART treatment failure. Close follow-up of children on medication adherence and effective trainings to health care professionals need to be considered.
Modestly protective cytomegalovirus vaccination of young children effectively prevents congenital infection at the population level
Authors: Byrne Catherine , Coombs Daniel , Gantt Soren
Published: March 2022

A vaccine to prevent congenital cytomegalovirus infection (cCMV) is a public health priority. cCMV results from maternal primary or non-primary CMV infection (reinfection or reactivation of chronic infection) during pregnancy. Young children are a major source of transmission to pregnant women because they shed CMV at high viral loads for prolonged periods. CMV vaccines evaluated in clinical trials so far have demonstrated only approximately 50% efficacy against maternal primary infection. None of these have been approved, as higher levels of vaccine-induced immunity are assumed to be required to substantially reduce cCMV prevalence. Here, we designed a mathematical model to capture the relationship between viral shedding by young children and maternal CMV infections during pregnancy. Using this model, we were able to quantify the efficacy of CMV immunity following infection to protect against reinfection and viral shedding. There was a 35% reduction in the risk of infection to a seropositive person (reinfection) versus a seronegative person (primary infection), given the same exposure. Viral shedding following reinfection was only 25% the quantity of that following primary infection. We also found that a vaccine that confers the equivalent of infection-induced immunity, when given to young children, markedly reduces both CMV transmission to pregnant women and rates of cCMV. Thus, we predict that vaccine candidates that have already been shown to be only modestly protective may in fact be highly effective at preventing cCMV by interrupting child-to-mother transmission.
T1/T2 Ratio Imaging Improves Cortical Lesion Contrast in Multiple Sclerosis on 3T MRI
Authors: Manning Abigail R , Beck Erin S. , Schindler Matthew K. , Nair Govind , Parvathaneni Prasanna , Reich Daniel S. , Shinohara Russell T. , Solomon Andrew J.
Published: March 2022

Background

Cortical demyelinated lesions are prevalent in multiple sclerosis (MS) and associated with disability; their presence on MRI has recently been incorporated into MS diagnostic criteria. Presently, advanced and ultra-high-field MRI — not routinely available in clinical practice — are the most sensitive methods for detection of cortical lesions, and approaches utilizing MRI sequences obtainable in routine clinical practice remain an unmet need.

Objective

To assess the sensitivity of the ratio of T1-weighted and T2-weighted (T1/T2) signal intensity for focal cortical lesions in comparison to other established, sensitive, advanced and high-field imaging methods.

Methods

3-tesla (3T) and 7-tesla (7T) MRI collected from 10 adults with MS participating in a natural history study at the National Institutes of Health were included in the study. T1/T2 images were calculated by dividing 3T T1w images by 3T T2w fluid-attenuated inversion recovery (FLAIR) images for each participant. Cortical lesions were identified using 7T T2*w and T1w images and corresponding voxels were assessed on registered 3T images. For each participant, ratios derived from the median signal intensity of nonlesional tissue in the cortical region of the lesion and the median lesional voxel intensity were computed. These values were compared across 3T imaging sequences, including the calculated T1/T2 image, as well as T1w, T2w, and Inversion Recovery Susceptibility Weighted Imaging with Enhanced T2 weighting (IR-SWIET) images.

Results

614 cortical lesions were identified on 7T images. 3T T1/T2 images demonstrated a larger contrast between median nonlesional cortical signal intensity and median cortical lesion signal intensity (median ratio = 1.29, range 1.19 – 1.38) when compared to T1w (1.01, 0.97 – 1.10, p<0.002), T2w (1.17, 1.07 – 1.26, p<0.002), and IR-SWIET (1.21, 1.01 – 1.29, p<0.03).

Conclusion

T1/T2 images are sensitive to cortical lesions. Approaches incorporating T1/T2 could improve the accessibility of cortical lesion detection in research settings and clinical practice.
Altered Cerebral Blood Flow in Older Adults with Alzheimer’s Disease: A Systematic Review
Authors: Swinford Cecily G. , Risacher Shannon L. , Wu Yu-Chien , Apostolova Liana G. , Gao Sujuan , Saykin Andrew J.
Published: March 2022

The prevalence of Alzheimer’s disease is projected to reach 13 million in the U.S. by 2050. Although major efforts have been made to avoid this outcome, so far there are no treatments that can stop or reverse the progressive cognitive decline that defines Alzheimer’s disease. The utilization of preventative treatment before significant cognitive decline has occurred may ultimately be the solution, necessitating a reliable biomarker of preclinical/prodromal disease stages to determine which older adults are most at risk. Quantitative cerebral blood flow is a promising potential early biomarker for Alzheimer’s disease, but the spatiotemporal patterns of altered cerebral blood flow in Alzheimer’s disease are not fully understood. The current systematic review compiles the findings of 29 original studies that compared quantitative cerebral blood flow in older adults with mild cognitive impairment or Alzheimer’s disease to that of cognitively normal older adults and/or assessed the relationship between cerebral blood flow and objective cognitive function. Individuals with Alzheimer’s disease had relatively decreased cerebral blood flow in all brain regions investigated, especially the temporoparietal and posterior cingulate, while individuals with mild cognitive impairment had less consistent results, with relatively increased cerebral blood flow reported in the temporal lobe and thalamus. Most papers reported a positive correlation between cerebral blood flow and cognitive function. This review highlights the need for more studies comparing cerebral blood flow between cognitively normal individuals and those with mild cognitive impairment, as well as the importance of including potential confounding factors in these analyses.
SPAG6 promotes cell migration and induces epithelial-to-mesenchymal transition in luminal breast cancer cells
Authors: Mijnes Jolein , Bringezu Sarah , Berger Jonas , Schalla Carmen , Rose Michael , von Serenyi Sonja , Knüchel-Clarke Ruth , Sechi Antonio , Dahl Edgar
Published: March 2022

Understanding the involvement of promoter DNA methylation changes in the development of breast cancer may be highly informative for designing more effective therapeutic treatments. We recently characterized the Sperm Associated Antigen 6 (SPAG6) gene, encoding a flagellar motility protein, as a potential DNA methylation biomarker for blood-based early breast cancer detection. Here we present the first study to evaluate the functional role of SPAG6 in human breast cancer. In silico analysis of the HumanMethylation450 BeadChip and Illumina HiSeq data of The Cancer Genome Atlas (TCGA) was performed in both normal (n=114) and breast cancer patient tissues (n=1104) to determine SPAG6 DNA methylation and expression. Stable SPAG6 overexpressing cancer models for in vitro analysis were obtained by lentivirus-mediated gene delivery in T-47D, MCF-7, MDA-MB-231 and BT-549 breast cancer cells. Subsequently stable mock and SPAG6 cell lines were compared in cellular assays. In addition, involvement of SPAG6 in EMT was analysed by qPCR and immunolabeling experiments. All major molecular subtypes of breast cancer (luminal A, luminal B, basal-type, HER2-enriched) revealed a tumor-specific increased SPAG6 promoter hypermethylation that correlated with strong reduction in SPAG6 mRNA expression. Interestingly, a small group of luminal breast tumors exhibited SPAG6 mRNA overexpression compared to normal breast tissue. SPAG6 overexpression caused a significant reduction (p<0.05) in colony formation in basal MDA-MB-231 and BT-549 cells. In turn, luminal T-47D cells overexpressing SPAG6 showed a significant increase in colony formation (p=0.0004) and both T-47D-and MCF-7 cells overexpressing SPAG6 exhibited a robust increase in migration speed (p<0.0001). In SPAG6-positive T-47D cells SNAIL, TWIST1 and Vimentin expression was found to be significantly upregulated, while E-Cadherin expression was supressed. SPAG6 overexpressing T47D cells showed a typical epithelial-mesenchymal transition (EMT). This was accompanied by a nearly complete displacement of both actin and E-cadherin from cell-cell junctions. Our in vitro analyses give functional evidence that SPAG6 has a profound effect on colony formation, migration and intercellular junction composition in breast cancer cells. Our study is the first to show opposing SPAG6 effects in a single tumour entity depending on the molecular subtype. We propose that SPAG6 might be a key player for inducing the EMT program in luminal-type breast cancers, driving tumour progression and metastasis.
Species-specific bacterial detector for fast pathogen diagnosis of severe pneumonia patients in the intensive care unit
Authors: Wang Yan , Liang Xiaohui , Jiang Yuqian , Dong Danjiang , Zhang Cong , Song Tianqiang , Chen Ming , You Yong , Liu Han , Ge Min , Dai Haibin , Xi Fengchan , Zhou Wanqing , Chen Jian-Qun , Wang Qiang , Chen Qihan , Yu Wenkui
Published: March 2022

Rapid diagnosis of pathogens is the cornerstone of appropriate therapy and is also a great challenge to be overcome. Although NGS and some other PCR-based pathogen detection methods were applied to improve the speed and accuracy of clinical diagnosis, it was still a long way from the clinical needs of rapid and accurate diagnostic therapy in the intensive care unit (ICU). In this study, we aimed at developing a new rapid diagnostic tool, Species-Specific Bacterial Detector (SSBD), to evaluate the existence and quantification of 10 most usual pathogenic bacteria in ICU in 4 hours. Briefly, the species-specific genome fragments of each bacterium were identified by our algorithm using 1791 microbe genomes from 232 species and then used to combine with CRISPR/Cas12 to establish diagnosis tools. Based on the tests of 77 samples, SSBD demonstrated 100% sensitivity and 87% specificity compared with conventional culture test (CCT). Later on, an interventional random-grouped study was applied to evaluate the clinical benefits of SSBD. Briefly, SSBD demonstrated more accurate and faster diagnosis results and led to earlier antibiotics adjustment than CCT. Based on the results acquired by SSBD, cultivation results could deviate from the real pathogenic situation with polymicrobial infections. In addition, nosocomial infections were found widely in ICU, which should deserve more attention.
Impact of supplementary air filtration on airborne particulate matter in a UK hospital ward
Authors: Sloof D , Butler MB , Peters C , Conway Morris A , Gouliouris T , Thaxter R , Keevil VL , Beggs CB
Published: March 2022

Background

During the COVID-19 pandemic, aerosol spread of SARS-CoV-2 has been a major problem in healthcare facilities, resulting in increased use of supplementary HEPA filtration to mitigate transmission. We report here a natural experiment that occurred when an air filtration unit (AFU) on an inpatient ward for older people was accidentally switched off.

Aim

To assess aerosol transport within the ward and determine whether the AFU reduced particulate matter (PM) levels in the air.

Methods

Time-series PM, CO2, temperature and humidity data (at 1 minute intervals) was collected from multiple sensors around the ward over two days in August 2021. During this period, the AFU was accidentally switched off for approximately 7 hours, allowing the impact of the intervention on particulates (PM1-PM10) to be assessed using a Mann-Whitney test. Pearson correlation analysis of the PM and CO2 signals was also undertaken to evaluate the movement of airborne particulates around the ward.

Findings

The AFU greatly reduced PM counts of all sizes throughout the ward space (p<0.001 for all sensors), with PM signals positively correlated with indoor CO2 levels (r = 0.343 – 0.817; all p<0.001). Aerosol particle counts tended to rise and fall simultaneously throughout the ward space when the AFU was off, with PM signals from multiple locations highly correlated (e.g. r = 0.343 – 0.868 (all p<0.001) for PM1).

Conclusion

Aerosols freely migrated between the various sub-compartments of the ward, suggesting that social distancing measures alone cannot prevent nosocomial transmission of SARS-CoV-2. The AFU greatly reduced PM levels throughout the ward space.

Practical implications

Aerosols can freely migrate throughout whole wards, suggesting that social distancing measures alone are not enough to prevent SARS-CoV-2 transmission.

Appropriately sized supplementary room air filtration, if utilised correctly, can greatly reduce aerosol levels throughout ward spaces.

Air filtration devices are often placed in rooms without any consideration given to their performance. It is therefore important to commission air filtration devices using PM and CO2 sensors before they are utilised in order to demonstrate that they are effective throughout entire ward spaces.
Sex and genetic specific effects on behavioral, but not metabolic, responses to a high fat diet in heterogeneous stock rats
Authors: Deal Aaron W , Thurman Andrew , Seshie Osborne , Szalanczy Alexandria , Beeson Angela , Cockerham Mackenzie , Risemberg Ellen L , Lenzo Anne , Ozimek Noelle , Langefeld Carl , Valdar William , Solberg Woods Leah C
Published: March 2022

Obesity is a growing epidemic associated with a range of comorbidities, including anxiety and depression. Genetics and environmental factors such as diet contribute to both adiposity and anxiety/depression. Heterogeneous stock (HS) rats are an outbred colony and useful for genetic mapping of complex traits. We have previously shown that HS male rats exhibit worsened metabolic and behavioral health in response to high fat diet (HFD). This study aims to determine if females have similar response to diet and if response to diet interacts with genetic background. We measured multiple metabolic (body weight, fat pad weight, glucose tolerance, fasting glucose and insulin) and behavioral (elevated plus maze, open field test, and forced swim test) outcomes in a large cohort of male and female rats on either HFD or low fat diet (LFD). We estimated overall heritability as well as heritability of response to diet for each outcome. Both sexes showed worsened metabolic measures when fed HFD compared to LFD. In contrast, only males exhibited altered behavioral responses to HFD relative to LFD, with no effect in females. Most metabolic and behavioral measures showed overall heritability in both sexes. In contrast, although there was some evidence for gene by diet (GxD) interactions for behavioral measures in males, GxD interactions were generally not found for the metabolic measures. These data demonstrate an important role of diet, sex and genetics in metabolic and behavioral phenotypes in HS rats, with a potential role of gene by diet interactions for behavioral outcomes only in males.
Population dynamics of free-roaming dogs in Europe and implications for population control
Authors: Smith L. M. , Goold C. , Quinnell R. J. , Munteanu A.M. , Hartmann S. , Villa P. Dalla , Collins L.M.
Published: March 2022

Changes in free-roaming dog population size are important indicators of the effectiveness of dog population management. Assessing the effectiveness of different management methods also requires estimating the processes that change population size, such as the rates of recruitment into and removal from a population. This is one of the first studies to quantify the size, rates of recruitment and removal, and health and welfare status of free-roaming dog populations in Europe. We determined the size, dynamics, and health status of free-roaming dog populations in Pescara, Italy, and Lviv, Ukraine, over a 15-month study period. Both study populations had ongoing dog population management through catch-neuter-release and sheltering programmes. Average monthly apparent survival probability was 0.93 (95% CI 0.81-1.00) in Pescara and 0.93 (95% CI 0.84-0.99) in Lviv. An average of 7 dogs km-2 were observed in Pescara and 40 dogs km-2 in Lviv. Per capita entry probabilities varied between 0.09 and 0.20 in Pescara, and 0.12 and 0.42 in Lviv. In Lviv, detection probability was lower on weekdays (odds ratio: 0.74, 95% CI 0.53-0.96) and higher on market days (odds ratio: 2.58, 95% CI 1.28-4.14), and apparent survival probability was lower in males (odds ratio: 0.25, 95% CI 0.03-0.59). Few juveniles were observed in the study populations, indicating that recruitment may be occurring by movement between dog subpopulations (e.g. from local owned or neighbouring free-roaming dog populations), with important consequences for population control. This study provides important data for planning effective dog population management and for informing population and infectious disease modelling. The results emphasise the importance of dog population management efforts that encourage responsible ownership through reduced abandonment and cover the entire city to reduce the risk of dog movement between sections of the city hindering management efforts.
Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database
Authors: Rajcsanyi Luisa Sophie , Zheng Yiran , Fischer-Posovszky Pamela , Wabitsch Martin , Hebebrand Johannes , Hinney Anke
Published: March 2022

Homozygosity for pathogenic variants in the leptin gene leads to congenital leptin deficiency causing early-onset extreme obesity. This monogenic form of obesity has mainly been detected in patients from consanguineous families. Prevalence estimates for the general population using the Exome Aggregation Consortium (ExAC) database reported a low frequency of leptin mutations. One in approximately 15 million individuals will be homozygous for a deleterious leptin variant. With the present study, we aimed to extend these findings utilizing the augmented Genome Aggregation Database (gnomAD) v2.1.1 including more than 140,000 samples. In total, 68 non-synonymous and 7 loss-of-function (LoF) leptin variants were deposited in gnomAD. By predicting functional implications with the help of in silico tools, like SIFT, PolyPhen2 and MutationTaster2021, the prevalence of hetero- and homozygosity for putatively pathological variants (n = 32; pathogenic prediction by at least two tools) in the leptin gene were calculated. Across all populations, the estimated prevalence for heterozygosity for functionally relevant variants was approximately 1:2,100 and 1:17,860,000 for homozygosity. This prevalence deviated between the individual populations. Accordingly, people from South Asia were at greater risk to carry a possibly damaging leptin variant than individuals of other ancestries. Generally, this study emphasises the scarcity of deleterious leptin variants in the general population with varying prevalence for distinct study groups.
Rad51 is a druggable target that sustains replication fork progression upon DNA replication stress
Authors: Feu Sònia , Unzueta Fernando , Ercilla Amaia , Jaumot Montserrat , Agell Neus
Published: March 2022

Solving the problems that replication forks encounter when synthesizing DNA is essential to prevent genomic instability. Besides their role in DNA repair in the G2 phase, several homologous recombination proteins, specifically Rad51, have prominent roles in the S phase. Using different cellular models, Rad51 has been shown not only to be present at ongoing and arrested replication forks but also to be involved in nascent DNA protection and replication fork restart. Through pharmacological inhibition, here we study the specific role of Rad51 in the S phase. Rad51 inhibition in non-transformed cell lines did not have a major effect on replication fork progression under non-perturbed conditions, but when the same cells were subjected to replication stress, Rad51 became necessary to maintain replication fork progression. Notably, the inhibition or depletion of Rad51 did not compromise fork integrity when subjected to hydroxyurea treatment. Rad51 inhibition also did not decrease the ability to restart, but rather compromised, fork progression during reinitiation. In agreement with the presence of basal replication stress in human colorectal cancer cells, Rad51 inhibition reduced replication fork speed in these cells and increased γH2Ax foci under control conditions. These alterations could have resulted from the reduced association of DNA polymerase α to chromatin, as observed when inhibiting Rad51. It may be possible to exploit the differential dependence of non-transformed cells versus colorectal cancer cells on Rad51 activity under basal conditions to design new therapies that specifically target cancer cells.
Identification of consensus hairpin loop structure among the negative sense sub-genomic RNAs of SARS-CoV-2
Authors: Bokolia Naveen Prakash , Gadepalli Ravisekhar
Published: March 2022

SARS-CoV-2 is the causative agent of worldwide pandemic disease COVID-19. SARS-CoV-2 bears positive sense RNA genome, that have organized and complex pattern of replication/transcription process including the generation of subgenomic RNAs. Transcription regulatory sequences (TRS) have important role in the pausing of replication/transcription and generation of subgenomic RNAs. In the present bioinformatics analysis a consensus secondary structure was identified among negative sense subgenomic RNAs at the adjacent of initiation codon. This study proposed that consensus structured domain could involve in mediating the long pausing of replication/transcription complex and responsible for subgenomic RNA production.