bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spinal cord stimulation restores sensation, improves function, and reduces phantom pain after transtibial amputation
Authors: Nanivadekar Ameya C. , Bose Rohit , Petersen Bailey A. , Okorokova Elizaveta V. , Sarma Devapratim , Farooqui Juhi , Dalrymple Ashley N. , Levy Isaiah , Helm Eric R. , Miele Vincent J. , Boninger Michael L. , Capogrosso Marco , Bensmaia Sliman J. , Weber Douglas J. , Fisher Lee E. 
Published: September 2022

SUMMARYIn the United States, over 1.5 million people live with lower-limb amputation. Existing prosthetic limbs do not restore somatosensory feedback from the limb, resulting in functional impairments including balance deficits and an increased risk of falls. Further, these prostheses do not alleviate the severe phantom limb pain that often follows amputation. Leveraging clinically available spinal cord stimulation electrodes, we designed a system that restores somatosensation in the missing limb, thereby improving balance and gait and reducing phantom limb pain. We show that spinal cord stimulation can evoke sensations in the missing foot and that we can control the location and intensity of those sensations. Further, by modulating stimulation intensity in real time based on signals from a wireless pressure-sensitive shoe insole, subjects exhibit improvements in functional measures of balance and gait stability. Finally, over the duration of the implant period, subjects experienced a clinically meaningful decrease in phantom limb pain. These combined results demonstrate that, with an electrode technology that is currently in widespread clinical use, our approach has the potential to become an important intervention for lower-limb amputation.
Apolipoprotein E controls Dectin-1-dependent development of monocyte-derived alveolar macrophages upon pulmonary β-glucan-induced inflammatory adaptation
Authors: Theobald H. , Bejarano D.A. , Katzmarski N. , Haub J. , Schulte-Schrepping J. , Yu J. , Bassler K , Ćirović B. , Osei-Sarpong C. , Piattini F. , Vornholz L , Yu X. , Sheoran S. , Al Jawazneh A. , Chakarov S. , Haendler K , Brown G.D. , Williams D.L. , Bosurgi L. , Ginhoux F. , Ruland J. , Beyer M. , Greter M. , Kopf M. , Schultze J.L. , Schlitzer A. 
Published: September 2022

SummaryThe lung is constantly exposed to the outside world and optimal adaptation of immune responses is crucial for efficient pathogen clearance. However, mechanisms which lead to the functional and developmental adaptation of lung-associated macrophages remain elusive. To reveal such mechanisms, we developed a reductionist model of environmental intranasal β-glucan exposure, allowing for the detailed interrogation of molecular mechanisms of pulmonal macrophage adaptation. Employing single-cell transcriptomics, high dimensional imaging and flow cytometric characterization paired to in vivo and ex vivo challenge models, we reveal that pulmonary low-grade inflammation results in the development of Dectin-1 - Card9 signaling-dependent monocyte-derived macrophages (MoAM). MoAMs expressed high levels of CD11b, ApoE, Gpnmb and Ccl6, were glycolytic and produced large amounts of interleukin 6 upon restimulation. Myeloid cell specific ApoE ablation inhibited monocyte to MoAM differentiation dependent on M-CSF secretion, promoting MoAM cell death thus impeding MoAM maintenance. In vivo, β-glucan-elicited MoAMs limited the bacterial burden of Legionella pneumophilia post infection and ameliorated fibrosis severity in a murine fibrosis model. Collectively these data identify MoAMs that are generated upon environmental cues and ApoE as an important determinant for lung immune resilience.
Thalamic spindles and upstates, but not ripples, coordinate cortico-cortical and hippocampo-cortical co-ripples in humans
Authors: Dickey Charles W. , Verzhbinsky Ilya A. , Kajfez Sophie , Rosen Burke Q. , Gonzalez Christopher E. , Chauvel Patrick Y. , Cash Sydney S. , Pati Sandipan , Halgren Eric 
Published: September 2022

AbstractThe co-occurrence of brief ∼90Hz oscillations (co-ripples) may be important for integrating information across the neocortex and hippocampus and, therefore, essential for sleep consolidation, and cognition in general. However, how such co-ripples are synchronized is unknown. We tested if cortico-cortical and hippocampal-cortical ripple co-occurrences are due to the simultaneous direct propagation of thalamic ripples, and/or if they are coordinated by lower frequency thalamic waves. Using human intracranial recordings, we found that ripples are generated in the anterior and posterior thalamus during local spindles on the down-to-upstate transition in non-rapid eye movement sleep, with similar characteristics as cortical and hippocampal ripples. However, thalamic ripples only infrequently co-occur or phase-lock, with cortical and hippocampal ripples. In contrast, thalamo-cortical spindles and upstates were strongly coordinated with cortico-cortical and hippocampo-cortical co-rippling. Thus, while thalamic ripples may not directly drive multiple cortical or hippocampal sites at ripple frequency, thalamo-cortical spindles and upstates may provide the input necessary for spatially distributed co-rippling to integrate information in the cortex.Significance StatementWidespread networks of ∼90 Hz oscillations, called “ripples,” have recently been identified in humans and may help to bind information in the cortex and hippocampus for memory. However, it is not known whether the thalamus generates ripples, and if so whether they, or other thalamic waves, coordinate networks of co-occurring cortical and hippocampal ripples. Here, we show that the human thalamus generates ∼90 Hz ripples during NREM sleep. While thalamic ripples do not appear to directly synchronize ripple co-occurrence in the cortex and hippocampus, our data provide evidence that propagating thalamo-cortical spindles and upstates organize these networks. Thus, the thalamus projects slower frequency waves that modulate higher frequency hippocampo-cortical oscillatory networks for memory in humans.
Major cell-types in multiomic single-nucleus datasets impact statistical modeling of links between regulatory sequences and target genes
Authors: Leblanc F. JA , Lettre G. 
Published: September 2022

AbstractMost variants identified by genome-wide association studies (GWAS) are located in non-coding regions of the genome. While largely untested functionally, it is assumed that most of these GWAS variants modulate the activity of enhancers. Epigenomic profiling, including ATACseq, is one of the main tools used to define enhancers. Because enhancers are overwhelmingly cell-type specific, inference of their activity is greatly limited in complex tissues that include multiple cell-types. Multiomic assays that probe in the same nucleus both the open chromatin landscape and gene expression levels enable the study of correlations (links) between these two modalities. Current best practices to infer the regulatory effect of candidate cis-regulatory elements (cCREs) in multiomic data involve removing biases associated with peak coverage and GC content by generating null distributions of matched ATACseq peaks drawn from different chromosomes. This is done under the assumption that the tested cis- and the matched trans-ATACseq peaks are uncorrelated. This strategy has been broadly adopted by popular single-nucleus multiomic workflows such as Signac. Here, we uncovered limitations and confounders of this approach. We found a strong loss of power to detect a regulatory effect for cCREs with high read counts in the dominant cell-type. We showed that this is largely due to cell-type-specific trans-ATACseq peak correlations creating bimodal null distributions. We tested alternative models and concluded that physical distance and/or the raw Pearson correlation coefficients are the best predictors for peak-gene links when compared to predictions from Epimap (e.g. CD14 area under the curve [AUC] = 0.51 with the method implemented in Signac vs 0.71 with the Pearson correlation coefficients) or validation by CRISPR perturbations (AUC = 0.63 vs 0.73).
Brain glucose metabolism and ageing: A 5-year longitudinal study in a large PET cohort
Authors: Pak Kyoungjune , Malén Tuulia , Santavirta Severi , Shin Seunghyeon , Nam Hyun-Yeol , De Maeyer Sven , Nummenmaa Lauri 
Published: September 2022

ABSTRACTBackgroundAgeing and clinical factors impact brain glucose metabolism. However, there is a substantial variation of the reported effects on brain glucose metabolism across studies due to the limited statistical power and cross-sectional study designs.MethodsWe retrospectively analyzed data from 441 healthy males (mean 42.8, range 38-50 years) who underwent health check-up program twice at baseline and 5-year follow-up. Health check-up program included 1) brain 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET), 2) anthropometric and body composition measurements, 3) blood samples, and 4) questionnaires for stress and depression. After spatial normalization of brain FDG PET scans, standardized uptake value ratio (SUVR) was measured from 12 region-of-interests. We used hierarchical clustering analysis to reduce their dimensionality before the Bayesian hierarchical modelling. Five clusters were established for predicting regional SUVR; 1) metabolic cluster (body mass index, waist-to-hip ratio, fat percentage, muscle percentage, homeostatic model assessment index-insulin resistance), 2) blood pressure (systolic, diastolic), 3) glucose (fasting plasma glucose level, HbA1c), 4): psychological cluster (stress, depression), and 5) heart rate. The effects of clinical variable clusters on regional SUVR were investigated using Bayesian hierarchical modelling with brms that applies the Markov-Chain Monte Carlo sampling tools.ResultsAll the clinical variables except depression changed during the 5-year follow-up. SUVR decreased in caudate, cingulate, frontal lobe and parietal lobe and increased in cerebellum, hippocampus, occipital lobe, pallidum, putamen, temporal lobe and thalamus. SUVRs of thalamus, pallidum, hippocampus, putamen and parietal lobe were negatively associated with metabolic cluster and the effects of glucose on SUVRs varied across regions. SUVRs of thalamus, hippocampus, cingulate, cerebellum increased and those with occipital lobe decreased with heart rate. The effects of blood pressure and psychological cluster markedly overlapped with zero across regions.ConclusionRegionally selective decline in brain glucose utilization begins already in the middle age, while individual differences in brain glucose metabolism remain stable. In addition to ageing, brain glucose utilization is also associated with metabolic cluster, blood glucose levels and heart rate. These effects are also consistent over the studied period of 5 years in the middle adulthood.
A Scalable 3D High-Content Imaging Protocol for Measuring a Drug Induced DNA Damage Response Using Immunofluorescent Sub-nuclear γH2AX Spots in Patient Derived Ovarian Cancer Organoids
Authors: Keles Hakan , Schofield Christopher A. , Rannikmae Helena , Edwards Erin Elizabeth , Mohamet Lisa 
Published: September 2022

ABSTRACTThe high morbidity rate of ovarian cancer has remained unchanged during the past four decades, partly due to lack of understanding of disease mechanisms and difficulties in developing new targeted therapies. Defective DNA damage detection and repair is one of the hallmarks of cancer cells and is a defining characteristic of ovarian cancer. Most in vitro studies to date, involve viability measurements at scale using relevant cancer cell lines, however, the translation to clinic is often lacking. The use of patient derived organoids is closing that translational gap yet the 3D nature of organoid cultures present challenges for assay measurements beyond viability measurements. In particular, high-content imaging has the potential for screening at scale providing a better understanding of mechanism of action of drugs or genetic perturbagens. In this study we report a semi-automated and scalable immunofluorescence imaging assay utilising the development of a 384-well plate based subnuclear staining and clearing protocol and optimisation of 3D confocal image analysis for studying DNA damage dose response in human ovarian cancer organoids. The assay was validated in four organoid models and demonstrated a predictable response to Etoposide drug treatment with lowest efficacy observed in the clinically most resistant model. This imaging and analysis method can be applied to other 3D organoid and spheroid models for use in high content screening.
A dialysis medium refreshment cell culture set-up for an osteoblast-osteoclast coculture
Authors: Vis M.A.M. , de Wildt B.W.M. , Ito K. , Hofmann S. 
Published: September 2022

AbstractCulture medium exchange leads to loss of valuable auto- and paracrine factors produced by the cells. However, frequent renewal of culture medium is necessary for nutrient supply and to prevent waste product accumulation. Thus it remains the gold standard in cell culture applications. The use of dialysis as a medium refreshment method could provide a solution as low molecular weight molecules such as nutrients and waste products could easily be exchanged, while high molecular weight components such as growth factors, used in cell interactions, could be maintained in the cell culture compartment. This study investigates a dialysis culture approach for an in vitro bone remodeling model. In this model, both the differentiation of human mesenchymal stromal cells (MSCs) into osteoblasts and monocytes (MCs) into osteoclasts is studied. A custom-made simple dialysis culture system with a commercially available cellulose dialysis insert was developed. The data reported here revealed increased osteoblastic and osteoclastic activity in the dialysis groups compared to the standard non-dialysis groups, mainly shown by significantly higher alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) activity, respectively. This simple culture system has the potential to create a more efficient microenvironment allowing for cell interactions via secreted factors in mono- and cocultures and could be applied for many other tissues.
The local tumor microbiome is associated with survival in late-stage colorectal cancer patients
Authors: Debelius Justine W. , Engstrand Lars , Matussek Andreas , Brusselaers Nele , Morton James T. , Stenmarker Margaretha , Olsen Renate S. 
Published: September 2022

ABSTRACTObjectiveColorectal cancer survival has been linked to the microbiome. Single organism analyses suggest Fusobacterium nucleatum as a marker of poor prognosis. However, in situ imaging of tumors demonstrate a polymicrobial tumor-associated community. To understand the role of these polymicrobial communities in survival, we performed an untargeted study of the microbiome in late-stage colorectal cancer patients.DesignWe conducted a nested case-control study in late-stage cancer patients undergoing resection for primary adenocarcinoma. The microbiome of paired colorectal tumor and adjacent tissue samples was profiled using 16S rRNA sequencing; we used compositionally aware ordination and differential ranking to profile the microbial community.ResultsWe found a consistent difference in the microbiome between paired tumor and adjacent tissue, despite strong individual microbial identities. Tumors had higher relative abundance of genus Fusobacteria and Campylobacter at the expense of members of families Lachnospriaceae and Rumminococeae. Furthermore, a larger difference between normal and tumor tissue was associated with prognosis: patients with shorter survival had a larger difference between normal and tumor tissue. We found the difference was specifically related to taxa previously associated with cancer. Within the tumor tissue, we identified a 39 member community statistic associated with survival; for every log2 fold increase in this value, an individual’s odds of survival increased by 20% (OR survival 1.20; 95% CI 1.04, 1.33).ConclusionOur results suggest that a polymicrobial tumor-specific microbiome is associated with survival in late-stage colorectal cancer patients.
Post-vaccination neutralization responses to Omicron sub-variants
Authors: Jacobsen Henning , Katzmarzyk Maeva , Higdon Melissa M , Jiménez Viviana Cobos , Sitaras Ioannis , Bar-Zeev Naor , Knoll Maria Deloria 
Published: September 2022

AbstractBackgroundThe emergence of the Omicron variant (B.1.1.529) which correlated with dramatic losses in cross-neutralization capacity of post-vaccination sera raised concerns about the effectiveness of COVID-19 vaccines against infection and disease. Clinically relevant sub-variants (BA.1, BA.1.1, BA.2, BA.2.12.1, BA.3, and BA.4/5) subsequently emerged rapidly.MethodsWe evaluated published and pre-print studies reporting sub-variant specific reductions in cross-neutralization compared to the prototype strain of SARS-CoV-2 and between sub-variants. Median fold-reduction across studies was calculated by sub-variant and vaccine platform.ResultsAmong 153 studies with post-vaccination data, after primary vaccination the sub-variant specific fold-reduction in neutralization capacity compared to the prototype antigen varied widely, from median 4.2-fold for BA.3 to 21.9-fold for BA.4/5; in boosted participants fold-reduction was similar for all sub-variants (5.9-fold to 7.1-fold) except for BA.4/5 which was 12.7-fold. Relative to BA.1, the other Omicron sub-variants had similar neutralization capacity post-primary vaccination (range median 0.8-fold to 1.1-fold) and post-booster (0.9-fold to 1.2-fold) except for BA.4/5 which was higher (2.0-fold). Omicron sub-variant specific responder rates were low post-primary vaccination (range median 33.5% to 56.7%) compared to the prototype (median 96.0%), but improved post-booster (range median 85.4% to 92.6%).ConclusionFold-reductions in neutralization titers among Omicron sub-variants compared to the prototype strain varied widely post-primary vaccination but were comparable post-booster, except for BA.4/5 which had higher fold-reduction (2-fold relative to BA.1). Considering large fold-decreases in neutralization titers to the parental strain for all Omicron sub-variants, vaccine effectiveness is very likely to be reduced against all Omicron sub-variants, and probably more so against Omicron BA.4/5.
The impact of income-support interventions on life course risk factors and health outcomes during childhood: a systematic review in high income countries
Authors: Boccia Delia , Maritano Silvia , Pizzi Costanza , Richiardi Matteo G , Lioret Sandrine , Richiardi Lorenzo 
Published: September 2022

AbstractIn high income countries one in five children still lives in poverty. This is known to adversely shape the life course health trajectory of these children; however, much less is understood on whether social and fiscal policies have the capacity to reverse this damage, which intervention is likely to be most effective and when these interventions should be delivered to maximise their impact. This systematic review attempts to address these questions by looking at the impact of income-support interventions delivered during the first 1,000 days of life on cardiovascular, metabolic, respiratory and mental health outcomes. The review was restricted to experimental or quasi experimental studies conducted in high income countries. Studies of interest were retrieved from multidisciplinary database as well as health, economic, social sciences-specific literature browsers. Evidence of interest were summarised via narrative synthesis approach. Robustness of findings was assessed by tabulating impact by health outcome, type of intervention and study design. Overall, 18 relevant papers were identified, including 16 independent studies, one meta-analysis of randomized control trials (RCTs) and one pooled analysis of RCTs. Income-support interventions included: unconditional/conditional cash transfers, income tax credit, welfare to work, and minimum wage salary policies. Most studies were conducted in North America. Overall, the evidence suggested a positive, albeit small, effect of most policies on birth weight outcomes, but limited effect on mental health indicators. Results seemed to be robust to the type of intervention, but not to the study design, with RCTs consistently less likely to detect an impact. Given the large number of people targeted by these programs, one could infer that – despite small – the observed effect may be still relevant at population level. Nonetheless, the limited generalisability of the evidence gathered hampers firm conclusions. For the future, the breath and scope of this literature need to be broadened to fully exploit the potential of these interventions and understand how their public health impact can be maximised.
Associations between trajectories of obesity prevalence in English primary school children and the UK soft drink industry levy: an interrupted time series analysis of surveillance data
Authors: Rogers Nina T. , Cummins Steven , Forde Hannah , Jones Catrin P. , Mytton Oliver , Rutter Harry , Sharp Stephen J. , Theis Dolly , White Martin , Adams Jean 
Published: September 2022

AbstractBackgroundSugar sweetened beverages (SSBs) are the primary source of dietary added sugars in children, with high consumption commonly observed in more deprived areas where obesity prevalence is also highest. Associations between SSB consumption and obesity in children have been widely reported. In March 2016, a two-tier soft drinks industry levy (SDIL) on drinks manufacturers to encourage reformulation of SSBs in the UK was announced, and then implemented in April 2018. We examined trajectories in the prevalence of obesity at ages 4-5 years and 10-11 years, 19 months after the implementation of SDIL, overall and by sex and deprivation.Methods and FindingsData were from the National Child Measurement Programme and included annual repeat cross-sectional measurement of over one million children aged 4-5 and 10-11 years in state-maintained primary schools. Interrupted time series analysis of monthly obesity prevalence data from September 2013 to November 2019 was used to estimate absolute and relative changes in obesity prevalence compared to a counterfactual (adjusted for temporal variations in obesity prevalence) estimated from the trend prior to SDIL announcement. Differences between observed and counterfactual estimates were examined in November 2019 by age (4-5 or 10-11 years) and additionally by sex and deprivation quintile. In 10-11 year old children there was an overall absolute reduction in obesity prevalence (defined as >95thcentile on the UK90 growth charts) of 0.8% (95%CI: 0.3, 1.3). In 10-11 year old girls the reduction was 1.6% (95%CI: 1.1, 2.1), with greatest reductions in the two most deprived quintiles (e.g. there was an absolute reduction of 2.4% (95%CI: 1.6, 3.2) in prevalence of obesity in the most deprived quintile). In 10-11 year old boys, there was no change in obesity prevalence, except in the least deprived quintile where there was a 1.6% (95%CI: 0.7,2.5) absolute increase. In 4-5 year old children, relative to the counterfactual, there were overall increases in obesity prevalence in both genders (combined) and all deprivation quintiles except the most deprived where there was no change.ConclusionsOur results suggest the SDIL was associated with decreased prevalence of obesity in 10-11 year old girls, with the greatest effects in those living in the most deprived areas. Additional strategies beyond SSB taxation will be needed to reduce obesity prevalence overall, and particularly in older boys and younger children.Trial registrationISRCTN18042742