bluuebunny/crossref_metadata_2025 huggingface dataset:
Dynamic Epigenetic Changes during a Relapse and Recovery Cycle in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Helliwell A.M. , Stockwell P.A. , Edgar C.D. , Chatterjee A. , Tate W.P.
Published: February 2022

Background

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease with variable severity throughout the ongoing illness. Patients experience relapses where symptoms increase in severity, leaving them with a marked reduction in quality of life. Previous work has investigated molecular differences between ME/CFS patients and healthy controls, but the dynamic changes specific to each individual patient are unknown. Precision medicine can determine how each patient responds individually during variations in their long-term illness. We apply precision medicine here to map genomic changes in two selected ME/CFS patients through a relapse recovery cycle.

Results

DNA was isolated from Peripheral Blood Mononuclear Cells (PBMCs) from two patients and a healthy age/gender matched control in a longitudinal study to capture a patient relapse. Reduced representation DNA methylation sequencing profiles were obtained from each time point spanning the relapse recovery cycle. Both patients throughout the time course showed a significantly larger methylome variability (10-20 fold) compared with the control. During the relapse changes in the methylome profiles of the two patients were detected in regulatory-active regions of the genome that were associated respectively with 157 and 127 downstream genes, indicating disturbed metabolic, immune and inflammatory functions occurring during the relapse.

Conclusions

Severe health relapses in ME/CFS patients result in functionally important changes in their DNA methylomes that, while differing among patients, lead to similar compromised physiology. DNA methylation that is a signature of disease variability in ongoing ME/CFS may have practical applications for strategies to decrease relapse frequency.
A mixture model to estimate SARS-CoV-2 seroprevalence in Chennai, India
Authors: Hitchings Matt D.T. , Patel Eshan U. , Khan Rifa , Srikrishnan Aylur K. , Anderson Mark , Kumar K.S. , Wesolowski Amy P. , Iqbal Syed H. , Rodgers Mary A. , Mehta Shruti H. , Cloherty Gavin , Cummings Derek A.T. , Solomon Sunil S.
Published: February 2022

Background

Serological assays used to estimate SARS-CoV-2 seroprevalence rely on manufacturer cut-offs established based on more severe early cases who tended to be older.

Methods

We conducted a household-based serosurvey of 4,677 individuals from 2,619 households in Chennai, India from January to May, 2021. Samples were tested for SARS-CoV-2 IgG antibodies to the spike (S) and nucelocapsid (N) proteins. We calculated seroprevalence using manufacturer cut-offs and using a mixture model in which individuals were assigned a probability of being seropositive based on their measured IgG, accounting for heterogeneous antibody response across individuals.

Results

The SARS-CoV-2 seroprevalence to anti-S and anti-N IgG was 62.0% (95% confidence interval [CI], 60.6 to 63.4) and 13.5% (95% CI, 12.6 to 14.5), respectively applying the manufacturer’s cut-offs, with low inter-assay agreement (Cohen’s kappa 0.15). With the mixture model, estimated anti-S IgG and anti-N IgG seroprevalence was 64.9% (95% Credible Interval [CrI], 63.8 to 66.0) and 51.5% (95% CrI, 50.2 to 52.9) respectively, with high inter-assay agreement (Cohen’s kappa 0.66). Age and socioeconomic factors showed inconsistent relationships with anti-S IgG and anti-N IgG seropositivity using manufacturer’s cut-offs, but the mixture model reconciled these differences. In the mixture model, age was not associated with seropositivity, and improved household ventilation was associated with lower seropositivity odds.

Conclusions

With global vaccine scale-up, the utility of the more stable anti-S IgG assay may be limited due to the inclusion of the S protein in several vaccines. SARS-CoV-2 seroprevalence estimates using alternative targets must consider heterogeneity in seroresponse to ensure seroprevalence is not underestimated and correlates not misinterpreted.
Protection of Omicron sub-lineage infection against reinfection with another Omicron sub-lineage
Authors: Chemaitelly Hiam , Ayoub Houssein H. , Coyle Peter , Tang Patrick , Yassine Hadi M. , Al-Khatib Hebah A. , Smatti Maria K. , Hasan Mohammad R. , Al-Kanaani Zaina , Al-Kuwari Einas , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Abdul-Rahim Hanan F. , Nasrallah Gheyath K. , Al-Kuwari Mohamed Ghaith , Butt Adeel A. , Al-Romaihi Hamad Eid , Al-Thani Mohamed H. , Al-Khal Abdullatif , Bertollini Roberto , Abu-Raddad Laith J.
Published: February 2022

BACKGROUND

The SARS-CoV-2 Omicron (B.1.1.529) variant has two main sub-lineages, BA.1 and BA.2 with significant genetic distance between them. This study investigated protection of infection with one sub-lineage against reinfection with the other sub-lineage in Qatar during a large BA.1 and BA.2 Omicron wave, from December 19, 2021 to February 21, 2022.

METHODS

Two national matched, retrospective cohort studies were conducted to estimate effectiveness of BA.1 infection against reinfection with BA.2 (N=20,197; BA.1-against-BA.2 study), and effectiveness of BA.2 infection against reinfection with BA.1 (N=100,925; BA.2-against-BA.1 study). Associations were estimated using Cox proportional-hazards regression models.

RESULTS

In the BA.1-against-BA.2 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.01-0.07%) for the BA.1-infected cohort and at 0.62% (95% CI: 0.51-0.75%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.1 infection against reinfection with BA.2 was estimated at 94.9% (95% CI: 88.4-97.8%). In the BA.2-against-BA.1 study, cumulative incidence of infection was estimated at 0.03% (95% CI: 0.02-0.04%) for the BA.2-infected cohort and at 0.17% (95% CI: 0.15-0.21%) for the uninfected-control cohort, 15 days after the start of follow-up. Effectiveness of BA.2 infection against reinfection with BA.1 was estimated at 85.6% (95% CI: 77.4-90.9%).

CONCLUSIONS

Infection with an Omicron sub-lineage appears to induce strong, but not full protection against reinfection with the other sub-lineage, for at least several weeks after the initial infection.
Clinical and Virologic Factors associated with Outcomes of COVID-19 before and after Vaccination among Veterans: Retrospective Analysis from Six New England States
Authors: Lee Megan , Cosentino Danielle , Kyriakides Tassos C. , Cavallaro Tricia , Stack Gary , Gupta Shaili
Published: February 2022

Background

A region-wide analysis of COVID-19 outcomes in New England has not been done. We aimed to characterize clinical, demographic, and vaccination status affecting COVID-19 clinical outcomes and describe viral epidemiology.

Methods

Clinical variables of Veterans with COVID-19 in Veterans Administration healthcare systems in six New England states from April 8, 2020, to September 2, 2021 were correlated with outcomes of 30-day mortality, non-psychiatric hospitalization, intensive care unit admission (ICU-care), and post-vaccination infection. We sequenced 754 whole viral genomes and 197 partial genomes.

Results

Of 4,170 Veterans with COVID-19, 81% were White, 8% women, mean age was 60.1 ±17.7 years, and 2,399 became fully vaccinated. Overall, 19% Veterans needed hospitalization, 2.8% required ICU-care, and 3.7% died. Veterans with post-vaccination COVID-19 were older, with higher rates of tobacco/drug use, CKD, and malignancy, and 0.38% died. Among the unvaccinated, ICU-care and mortality correlated with age, while hospitalization correlated with age, male sex, black race, drug use, chronic heart disease, COPD, CKD, and chronic liver disease. Age, CKD, and alcohol use correlated with hospitalization in vaccinated patients.

Most New England Veterans (>97%) were infected with B.1 sub-lineages with the D614G mutation in 2020 and early 2021. B.1.617.2 lineage (71%) predominated after July 2021, including the post-vaccination infections.

Conclusion

In New England Veterans with mean age of 60 years, age and CKD significantly correlated with hospitalization regardless of vaccination-status. Age correlated with mortality and ICU-care among the unvaccinated. The Delta variant of SARS-CoV-2 (B.1.617.2) dominated post-vaccination infections.
Current status and future opportunities in modeling Multiple Sclerosis clinical characteristics
Authors: Liu Joshua , Kelly Erin , Bielekova Bibiana
Published: February 2022

Development of effective treatments requires understanding of disease mechanisms. For diseases of the central nervous system (CNS), like Multiple sclerosis (MS), human pathology studies and animal models tend to identify candidate disease mechanisms. However, these studies cannot easily link identified processes to clinical outcomes, such as MS severity, required for causality assessment of candidate mechanisms. Technological advances now allow generation of thousands of biomarkers in living human subjects, derived from genes, transcripts, medical images and proteins or metabolites in biological fluids. These biomarkers can be assembled into computational models of clinical value, provided such models are generalizable. Reproducibility of models increases with technical rigor of study design, such as blinding, implementing controls, using large cohorts that encompass entire spectrum of disease phenotypes and, most importantly, validating models in independent cohort(s).

To facilitate growth of this important research area, we performed a meta-analysis of publications that model MS clinical outcomes (n=302), extracting effect sizes, while also scoring technical quality of study design using pre-defined criteria. Finally, we generated a Shiny-App-based website that allows dynamic exploration of data using selective filtering.

On average, published studies fulfilled only one out of seven criteria of study design rigor. Only 15.2% of studies used any validation strategy, and only 8% used the gold standard of independent cohort validation. Many studies also used small cohorts, e.g., for MRI and blood biomarker predictors the median sample size was below 100 subjects. We observed inverse relationships between reported effect sizes and the numbers of study design criteria fulfilled, expanding analogous reports from non-MS fields, that studies that fail to limit bias over-estimate effect sizes.

In conclusion, the presented meta-analysis represents a useful tool for researchers, reviewers, and funders to improve design of future modeling studies in MS and to easily compare new studies with published literature. We expect that this will accelerate research in this important area, leading to development of robust models with proven clinical value.
Elevated fecal mitochondrial DNA from symptomatic norovirus infections suggests potential health relevance of human mitochondrial DNA in fecal source tracking
Authors: Zhu Kevin J. , Suttner Brittany , Knee Jackie , Capone Drew , Moe Christine L. , Stauber Christine E. , Konstantinidis Kostas T. , Wallach Thomas E. , Pickering Amy J. , Brown Joe
Published: February 2022

An end goal of fecal source tracking (FST) is to provide information on risk of transmission of waterborne illnesses associated with fecal contamination. Ideally, concentrations of FST markers in ambient waters would reflect exposure risk. Human mtDNA is an FST marker that is exclusively human in origin and may be elevated in feces of individuals experiencing gastrointestinal inflammation. In this study, we examined whether human mtDNA is elevated in fecal samples from individuals with symptomatic norovirus infections using samples from the US, Mozambique, and Bangladesh. We quantified hCYTB484 (human mtDNA) and HF183/BacR287 (human-associated Bacteroides) FST markers using droplet digital PCR. We observed the greatest difference in concentrations of hCYTB484 when comparing samples from individuals with symptomatic norovirus infections versus individuals without norovirus infections or diarrhea symptoms: log10 increase of 1.42 in US samples (3,820% increase, p-value = 0.062), 0.49 in Mozambique (308% increase, p-value = 0.061), and 0.86 in Bangladesh (648% increase, p-value = 0.035). We did not observe any trends in concentrations of HF183/BacR287 in the same samples. These results suggest concentrations of fecal mtDNA increase during symptomatic norovirus infection and that mtDNA in environmental samples may represent an unambiguously human source-tracking marker that correlates with enteric pathogen exposure risk.
Why Risk Factors Minimally Change the ROC Curve AUC
Authors: Stern Ralph H.
Published: February 2022

Novel risk factors that improve statistical measures of fit on addition to established clinical prediction models often minimally change measures of discrimination (ROC curve AUC or c-index). As a result, measures of discrimination have been suggested to be insensitive in the evaluation of such models.

To understand this phenomenon, it is necessary to focus on the population risk distributions produced by models with and without the risk factor. This is because these risk distribution fully determines the risk distributions of cases/patients and controls/nonpatients, which in turn fully determine the ROC curve and its AUC. Broader population risk distributions result in larger ROC curve AUCs.

A fully independent risk factor with a relative risk of 2 added to the standard cardiovascular risk model produces risk distributions of those with or without the risk that are clearly different (which is evaluated by statistical measures of fit), while minimally broadening the population risk distributions (which is evaluated by measures of discrimination). The reason for this is that although addition of the risk factor replaces every risk stratum with higher and lower risk strata, this depopulated risk stratum is largely repopulated by similar splitting in neighboring risk strata. The interweaving of the the up and down migration paths to and from every point on the risk distribution results in a largely compensatory shuffling of risk assignments with minimal changes in the ROC curve AUC.
An open, analysis-ready, and quality controlled resource for pediatric brain white-matter research
Authors: Richie-Halford Adam , Cieslak Matthew , Ai Lei , Caffarra Sendy , Covitz Sydney , Franco Alexandre R. , Karipidis Iliana I. , Kruper John , Milham Michael , Avelar-Pereira Bárbara , Roy Ethan , Sydnor Valerie J. , Yeatman Jason ,   The Fibr Community Science Consortium, Satterthwaite Theodore D. , Rokem Ariel
Published: February 2022

We created resources to facilitate research on the role of human brain microstructure in the development of mental health disorders, based on openly-available diffusion MRI (dMRI) data from the Healthy Brain Network (HBN) study. First, we curated the HBN dMRI data (N=2747) into the Brain Imaging Data Structure and preprocessed it according to best-practices, including denoising and correcting for motion effects, susceptibility-related distortions, and eddy currents. Preprocessed, analysis-ready data was made openly available. Data quality plays a key role in the analysis of dMRI, and we provide automated quality control (QC) scores for every scan, as part of the data release. To scale QC to this large dataset, we trained a neural network through the combination of a small data subset scored by experts and a larger set scored by community scientists. The network performs QC highly concordant with that of experts on a held out set (ROC-AUC = 0.947). A further analysis of the neural network demonstrates that it relies on image features with relevance to QC. Altogether, this work both delivers a resource for transdiagnostic research in brain connectivity and pediatric mental health and serves as a novel tool for automated QC of large datasets.
A three-dimensional human adipocyte model of fatty acid-induced obesity
Authors: Pieters Vera M. , Rjaibi Saifedine T. , Singh Kanwaldeep , Li Nancy T. , Khan Safwat T. , Nunes Sara S. , Dal Cin Arianna , Gilbert Penney M. , McGuigan Alison P.
Published: February 2022

Obesity prevalence has reached pandemic proportions, leaving individuals at high risk for the development of diseases such as cancer and type 2 diabetes. In obesity, to accommodate excess lipid storage, adipocytes become hypertrophic, which is associated with an increased pro-inflammatory cytokine secretion and dysfunction of metabolic processes such as insulin signaling and lipolysis. Targeting adipocyte dysfunction is an important strategy to prevent the development of obesity-associated disease. However, it is unclear how accurately animal models reflect human biology, and the long-term culture of human hypertrophic adipocytes in an in vitro 2D monolayer is challenging due to the buoyant nature of adipocytes. Here we describe the development of a human 3D in vitro disease model that recapitulates hallmarks of obese adipocyte dysfunction. First, human primary adipose-derived stromal cells are embedded in hydrogel, and infiltrated into a thin cellulose scaffold. The thin microtissue profile allows for efficient assembly and image-based analysis. After adipocyte differentiation, the scaffold is stimulated with oleic or palmitic acid to mimic caloric overload. Using functional assays, we demonstrated that this treatment induced important obese adipocyte characteristics such as a larger lipid droplet size, increased basal lipolysis, insulin resistance and activation of macrophages through adipocyte-conditioned media. This 3D disease model mimics physiologically relevant hallmarks of obese adipocytes, to enable investigations into the mechanisms by which dysfunctional adipocytes contribute to disease.
Intentional stocking undermines ecological stability
Authors: Terui Akira , Urabe Hirokazu , Senzaki Masayuki , Nishizawa Bungo
Published: February 2022

The past decades have witnessed efforts to unveil ecological risks associated with massive releases of captive-bred individuals (stock enhancement). Still, we may underestimate the negative impact because current schemes rarely consider the consequences of stock enhancement for the whole ecological community. Here, we use theory and long-term data of Japanese stream fish communities to show that stock enhancement undermines community stability. Our theory predicted that stock enhancement destabilizes community dynamics by facilitating competitive exclusion. Consistent with this prediction, fish communities showed greater temporal fluctuations and fewer species richness in rivers with the intensive stocking of hatchery masu salmon - a major freshwater resource in the region. Our findings paint a bleak picture for stock enhancement, reinforcing the recurrent calls for alternative management strategies.
Variation in supplemental carbon dioxide requirements defines lineage-specific antibiotic resistance acquisition in Neisseria gonorrhoeae
Authors: Rubin Daniel H.F. , Ma Kevin C. , Westervelt Kathleen A. , Hullahalli Karthik , Waldor Matthew K. , Grad Yonatan H.
Published: February 2022

The evolution of the obligate human pathogen Neisseria gonorrhoeae has been shaped by selective pressures from diverse host niche environments1,2 as well as antibiotics3,4. The varying prevalence of antibiotic resistance across N. gonorrhoeae lineages5 suggests that underlying metabolic differences may influence the likelihood of acquisition of specific resistance mutations6,7. We hypothesized that the requirement for supplemental CO2, present in approximately half of isolates8, reflects one such example of metabolic variation. Here, using a genome-wide association study and experimental investigations, we show that CO2-dependence is attributable to a single substitution in a β-carbonic anhydrase, canB. CanB19E is necessary and sufficient for growth in the absence of CO2, and the hypomorphic CanB19G variant confers CO2-dependence. Furthermore, ciprofloxacin resistance is correlated with CanB19G in clinical isolates, and the presence of CanB19G increases the likelihood of acquisition of ciprofloxacin resistance. Together, our results suggest that metabolic variation has impacted the acquisition of fluoroquinolone resistance.
A nucleation-and-growth model for the packaging of genome in linear virus-like particles: impact of multiple packaging signals
Authors: de Bruijn René , Wielstra P.C.M. , Calcines-Cruz Carlos , van Waveren Tom , Hernandez-Garcia Armando , van der Schoot Paul
Published: February 2022

Inspired by recent experiments on the spontaneous assembly of virus-like particles from a solution containing a synthetic coat protein and double-stranded DNA, (1) we put forward a kinetic model that has as main ingredients a stochastic nucleation and a deterministic growth process. The efficiency and rate of the packaging of the DNA turn out to strongly increase by introducing proteins onto the DNA template that are modified using CRISPR-Cas techniques to bind specifically at predesignated locations, mimicking assembly signals in viruses. Our model shows that treating these proteins as nucleation-inducing diffusion barriers is sufficient to explain experimentally observed increase in encapsulation efficiency, but only if the nucleation rate is sufficiently high. We find an optimum in the encapsulation kinetics for conditions where the number of packaging signals is equal to the number of nucleation events that can occur during time required to fully encapsulate the DNA template, presuming that the nucleation events can only take place adjacent to a packaging signal. Our theory is in satisfactory agreement with the available experimental data.

SIGNIFICANCE

The rate and efficiency of the encapsulation of double-stranded DNA by synthetic coat proteins was recently found to be strongly enhanced by the presence of specifically positioned protein molecules on the DNA that mimic so-called packaging signals. We present a kinetic theory based on the initial stochastic nucleation and subsequent deterministic elongation of the protein coat with the aim to explain these findings. We find that equidistantly placed nucleation sites that also act as diffusion barriers on the DNA have profound and non-trivial effects, and they can either slow down or speed up encapsulation, depending on how fast nucleation is on the time scale of the elongation process. Our findings may contribute to the rational design of linear virus-like particles.
A key role of orientation in the coding of visual motion direction
Authors: Moon Jongmin , Tadin Duje , Kwon Oh-Sang
Published: February 2022

Despite the fundamental importance of visual motion processing, our understanding of how the brain represents basic aspects of motion is incomplete. While it is generally believed that direction is the main representational feature of motion, motion processing is also influenced by non-directional orientation signals that are present in most motion stimuli. Here, we aimed to test whether this non-directional motion axis determines motion perception even when orientation is completely absent from the stimulus. Using stimuli with and without orientation signals, we found that serial dependence in a simple motion direction estimation task was predominantly determined by the orientation of the previous motion stimulus. Moreover, the observed attraction profiles closely matched the characteristic pattern of serial attraction found in orientation perception. Evidently, the sequential integration of motion signals depends solely on the orientation of motion, indicating a fundamental role of non-directional orientation in the coding of visual motion direction.
Dissecting the effects of adaptive encoding and predictive inference on a single perceptual estimation
Authors: Moon Jongmin , Kwon Oh-Sang
Published: February 2022

The human visual system exploits continuity in the visual environment, which induces two contrasting perceptual phenomena: repulsive aftereffects and attractive serial dependences. Recent studies have theorized that these two effects concurrently arise in perceptual processing, but empirical evidence that directly supports this hypothesis lacks. Here we show that the two effects concurrently modulate estimation behavior in a typical sequence of perceptual tasks. We first demonstrate that observers’ estimation error as a function of both the previous stimulus and response cannot be fully described by either attractive or repulsive bias but is instead well captured by a summation of repulsion from the previous stimulus and attraction toward the previous response. We then reveal that the repulsive bias is centered on the observer’s sensory encoding of the previous stimulus, which is again repelled away from the preceding trials, whereas the attractive bias is centered precisely on the previous response, which is the observer’s best prediction about the incoming stimuli. Our findings provide strong evidence that sensory coding is shaped by dynamic tuning of the system to the past stimuli, inducing repulsive aftereffects, and followed by inference incorporating the prediction from the past estimation, leading to attractive serial dependence.
A role for thalamic projection GABAergic neurons in circadian responses to light
Authors: Brock O. , Gelegen C.E. , Salgarella I. , Sully P. , Jager P. , Menage L. , Mehta I. , Jęczmień-Łazur J. , Djama D. , Strother L. , Coculla A. , Vernon A. , Brickley S. , Holland P. , Cooke S. , Delogu A.
Published: February 2022

The thalamus is an important hub for sensory information and participates in sensory perception, regulation of attention, arousal and sleep. These functions are executed primarily by glutamatergic thalamocortical neurons that extend axons to the cortex and initiate cortico-thalamocortical connectional loops. However, the thalamus also contains projection GABAergic neurons that do not engage in direct communication with the cortex. Here, we have harnessed recent insight into the development of the intergeniculate (IGL), the ventrolateral geniculate (LGv) and the perihabenula (pHB) to specifically target and manipulate thalamic projection GABAergic neurons in female and male mice. Our results show that thalamic GABAergic neurons of the IGL and LGv receive retinal input from diverse classes of ipRGCs, but not from the M1 ipRGC type, while those in the pHB lack direct retinal input. We describe the synergistic role of the photoreceptor melanopsin and the thalamic neurons of the IGL/LGv in circadian entrainment to dim light. We identify a requirement for the thalamic IGL/LGv in the rapid changes in vigilance states associated with circadian light transitions. Furthermore, we map a previously undescribed thalamic network of developmentally related GABAergic neurons in the IGL/LGv complex and the pHB potentially involved in light-dependent mood regulation.

Significance statement

The intergeniculate leaflet and ventral geniculate nucleus are part of the extended circadian system and mediate some non-image-forming visual functions. Here we show that each of these structures has a thalamic (dorsal) as well as prethalamic (ventral) developmental origin. We map the retinal input to thalamus-derived cells in the IGL/LGv complex and discover that while ipRGC input is dominant, this is not likely to originate from M1-ipRGCs. We describe the extent of similarity in synaptic input to developmentally related cells in the IGL/LGv and in the perihabenula nucleus (pHB). We implicate thalamic cells in the IGL/LGv in vigilance state transitions at circadian light changes and in overt behavioural entrainment to dim light, the latter exacerbated by concomitant loss of melanopsin expression.
Thymidine rescues ATR kinase inhibition induced deoxyuridine contamination in genomic DNA, cell death, and Type 1 interferon expression
Authors: Sugitani Norie , Vendetti Frank P. , Cipriano Andrew J. , Pandya Pinakin , Deppas Joshua J. , Moiseeva Tatiana N. , Schamus-Haynes Sandra , Wang Yiyang , Palmer Drake , Osmanbeyoglu Hatice U. , Bostwick Anna , Snyder Nathaniel W. , Gong Yi-Nan , Aird Katherine M. , Delgoffe Greg M. , Beumer Jan H. , Bakkenist Christopher J.
Published: February 2022

ATR kinase is a central regulator of the DNA damage response (DDR) and cell cycle checkpoints. ATR kinase inhibitors (ATRi’s) combine with radiation to generate CD8+ T cell-dependent responses in mouse models of cancer. We show that ATRi’s induce CDK1-dependent origin firing across active replicons in CD8+ T cells activated ex vivo while simultaneously decreasing the activity of rate-limiting enzymes for nucleotide biosynthesis. These pleiotropic effects of ATRi induce deoxyuridine (dU) contamination in genomic DNA, R loops, RNA-DNA polymerase collisions, and type-1 interferons (IFN-1). Remarkably, thymidine rescues ATRi-induced dU contamination, cell death, and IFN-1 expression in proliferating CD8+ T cells. Thymidine also rescues ATRi-induced cancer cell death. We propose that ATRi-induced dU contamination contributes to dose-limiting leukocytopenia and inflammation in the clinic and CD8+ T cell dependent anti-tumor responses in mouse models. We conclude that ATR is essential to limit dU contamination in genomic DNA and IFN-1 expression.
Model-free analysis in the spectral domain of postmortem mouse brain EPSI reveals inconsistencies with model-based analyses of the free induction decay
Authors: Trinkle Scott , Wildenberg Gregg , Kasthuri Narayanan , Rivière Patrick La , Foxley Sean
Published: February 2022

Purpose

Dysmyelinating disorders lead to abnormalities in myelin structure that produce detectable effects in an echo-planar spectroscopic imaging (EPSI) signal. To estimate the voxel-wise proportion of myelin, data are typically fit to compartmental models in the time domain. This work characterizes limitations in these models by comparing high-resolution water spectra measured in postmortem fixed mouse brains to spectra predicted from time-domain models fit to the same data, specifically by comparing spectra from control and shiverer mice, a model for dysmyelination.

Methods

Perfusion-fixed, resected control (n = 5) and shiverer (n = 4) mouse brains were imaged using 3D EPSI with 100 µm isotropic resolution. The free induction decay (FID) was sampled every 2.74 ms over 192 echoes and Fourier transformed to produce water spectra with 1.9 Hz resolution. FIDs were also fit to two biophysical models and the resulting fits were converted to spectra with a Fourier transform. Spectral asymmetry was computed and compared before and after fitting the data to models.

Results

Spectra derived from both models did not show the magnitude of asymmetric broadening observed in the raw data. Correlations between data- and model-derived asymmetries and estimated frequency shifts are weak, leading to a reduction in spectral sensitivity to changes in white-matter structure after fitting the data to models.

Conclusion

The results demonstrate spectral inconsistencies between biophysical model predictions and measured data, promoting the further incorporation of spectral analysis methods to develop and benchmark new model-based approaches.
The impacts of fine-tuning, phylogenetic distance, and sample size on big-data bioacoustics
Authors: Provost Kaiya L. , Yang Jiaying , Carstens Bryan C.
Published: February 2022

Vocalizations in animals, particularly birds, are critically important behaviors that influence their reproductive fitness. While recordings of bioacoustic data have been captured and stored in collections for decades, the automated extraction of data from these recordings has only recently been facilitated by artificial intelligence methods. These have yet to be evaluated with respect to accuracy of different automation strategies and features. Here, we use a recently published machine learning framework to extract syllables from ten bird species ranging in their phylogenetic relatedness from 1 to 85 million years, to compare how phylogenetic relatedness influences accuracy. We also evaluate the utility of applying trained models to novel species. Our results indicate that model performance is best on conspecifics, with accuracy progressively decreasing as phylogenetic distance increases between taxa. However, we also find that the application of models trained on multiple distantly related species can improve the overall accuracy to levels near that of training and analyzing a model on the same species. When planning big-data bioacoustics studies, care must be taken in sample design to maximize sample size and minimize human labor without sacrificing accuracy.
NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization
Authors: Narang Sonali , Evensen Nikki A. , Saliba Jason , Pierro Joanna , Loh Mignon L. , Brown Patrick A. , Mulder Heather , Shao Ying , Easton John , Ma Xiaotu , Tsirigos Aristotelis , Carroll William L.
Published: February 2022

The NSD2 p.E1099K (EK) mutation has been shown to be enriched in patients with relapsed ALL and found to play a role in clonal fitness dependent on the underlying genetic/epigenetic landscape of the cells. To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we systematically integrated Hi-C, ATAC-seq, RNA-seq and ChIP-seq data from three B-ALL cell lines heterozygous for NSD2 EK (RS4;11, RCH-ACV, SEM) and assessed changes upon knockdown. NSD2 knockdown revealed widespread remodeling of the 3D genome, specifically in terms of compartmentalization. Systematic integration of these datasets revealed significant switches in A/B compartments with a strong bias towards B compartments upon knockdown, suggesting that NSD2 EK plays a prominent role in maintaining A compartments through enrichment of H3K36me2 epigenetic marks. In contrast, we identified few changes in intra-TAD activity suggesting that the NSD2 EK impacts transcriptional changes through a remarkable dependence on compartmentalization. Furthermore, EK-mediated reorganization of compartments highlights the existence of a common core of compacting loci shared across the three cell lines that explain previously described phenotypes as well as serve as targets for therapeutic intervention. This study offers a novel mechanism by which NSD2 EK drives clonal evolution and drug resistance.
Monkeys exhibit human-like gaze biases in economic decisions
Authors: Lupkin Shira M. , McGinty Vincent B.
Published: February 2022

In economic decision-making individuals choose between items based on their perceived value. For both humans and nonhuman primates, these decisions are often carried out while shifting gaze between the available options. Recent studies in humans suggest that these shifts in gaze actively influence choice, manifesting as a bias in favor of the items that are viewed first, viewed last, or viewed for the overall longest duration in a given trial. This suggests a mechanism that links gaze behavior to the neural computations underlying value-based choices. In order to identify this mechanism, it is first necessary to develop and validate a suitable animal model of this behavior. To this end, we have created a novel value-based choice task for macaque monkeys that captures the essential features of the human paradigms in which gaze biases have been observed. Using this task, we identified gaze biases in the monkeys that were both qualitatively and quantitatively similar to those in humans. In addition, the monkeys’ gaze biases were well-explained using a sequential sampling model framework previously used to describe gaze biases in humans—the first time this framework has been used to assess value-based decision mechanisms in nonhuman primates. Together, these findings suggest a common mechanism that can explain gaze-related choice biases across species, and open the way for mechanistic studies to identify the neural origins of this behavior.
Meiotic DNA breaks activate a streamlined phospho-signaling response that largely avoids protein level changes
Authors: Kar Funda M. , Vogel Christine , Hochwagen Andreas
Published: February 2022

Meiotic cells introduce a large number of programmed DNA breaks into their genome to stimulate meiotic recombination and ensure controlled chromosome inheritance and fertility. An intricate checkpoint network involving key kinases and phosphatases coordinates the repair of these DNA breaks during meiosis, but the precise DNA break-dependent phosphorylation targets remain poorly understood. It is also unknown whether meiotic DNA breaks change gene expression akin to the canonical DNA-damage response. To address these questions, we analyzed the meiotic DNA break response in Saccharomyces cerevisiae using multiple systems-level approaches. We identified 332 DNA break-dependent phosphorylation sites, vastly expanding the number of known DNA break-dependent phosphorylation events during meiotic prophase. Only about half of these events occurred in recognition motifs for the known meiotic checkpoint kinases Mec1 (ATR), Tel1 (ATM) and Mek1 (CHK2), suggesting that additional kinases contribute to the meiotic DNA break response. Surprisingly, the numerous changes in phosphorylation were accompanied by very few changes in protein levels despite a clearly detectable transcriptional response. To explain this dichotomy, we show that meiotic entry lowers the expression baseline of many mRNAs enough so that subsequent break-dependent mRNA production has no measurable effects on the largely stable proteome.
DLGAP1-AS2-Mediated Phosphatidic Acid Synthesis Confers Chemoresistance via Activation of YAP Signaling
Authors: Nan Yabing , Luo Qingyu , Wu Xiaowei , Liu Shi , Zhao Pengfei , Chang Wan , Zhou Aiping , Liu Zhihua
Published: February 2022

Squamous cell carcinomas (SCCs) constitute a group of human malignancies that originate from the squamous epithelium. Most SCC patients experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and explore novel chemosensitizer targets, we performed whole-transcriptome sequencing of paired resistant/parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 associates with histones to regulate the distal elements of FAM3 metabolism regulating signaling molecule D (FAM3D) and reduces extracellular FAM3D protein secretion. FAM3D interacts with Gαi-coupled G protein-coupled receptor (GPCR) formyl peptide receptor (FPR) 1 and FPR2 to suppress phospholipase D (PLD) activity; thus, reduced FAM3D activates PLD signaling. Moreover, activated PLD promotes phosphatidic acid (PA) production and subsequent yes-associated protein (YAP) nuclear translocation. Accordingly, in vivo administration of a D-AS2-targeting antisense oligonucleotide sensitizes SCC to cisplatin treatment. In summary, our study reveals that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential in SCC chemoresistance and that D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents.

Significance

This study identifies D-AS2 as a targetable lipid-related lncRNA that activates YAP signaling via PLD/PA axis to trigger chemoresistance in SCC.
A three gene signature predicts response to selinexor in multiple myeloma
Authors: Restrepo Paula , Bhalla Sherry , Aleman Adolfo , Leshchenko Violetta , Melnekoff David T , Agte Sarita , Jiang Joy , Madduri Deepu , Richter Joshua , Richard Shambavi , Chari Ajai , Cho Hearn Jay , Jagannath Sundar , Walker Christopher J , Landesman Yosef , Laganà Alessandro , Parekh Samir
Published: February 2022

Selinexor is the first selective inhibitor of nuclear export (SINE) to be approved for treatment of relapsed or refractory multiple myeloma (MM). There are currently no known genomic biomarkers or assays to help select MM patients at higher likelihood of response to selinexor. Here, we aim to characterize transcriptomic correlates of response to selinexor-based therapy, and present a novel, three-gene expression signature that predicts selinexor response in MM. We analyzed RNA sequencing of CD138+ tumor cells from bone marrow of 100 MM patients who participated in the BOSTON study and identified three genes upregulated in responders. Then, we validated this gene signature in 64 patients from the STORM cohort of triple-class refractory MM, and additionally in an external cohort of 35 patients treated in a real world setting outside of clinical trials. We also found that the signature tracked with response in a cohort of 57 patients with recurrent glioblastoma treated with selinexor. Furthermore, the genes involved in the signature, WNT10A, DUSP1, and ETV7, reveal a potential mechanism through upregulated interferon-mediated apoptotic signaling that may prime tumors to respond to selinexor-based therapy. This signature has important clinical relevance as it could identify cancer patients that are most likely to benefit from treatment with selinexor-based therapy.
Loneliness and diurnal cortisol levels during COVID-19 lockdown: the roles of living situation, relationship status and relationship quality
Authors: Hopf Dora , Schneider Ekaterina , Aguilar-Raab Corina , Scheele Dirk , Ditzen Beate , Eckstein Monika
Published: February 2022

Loneliness and social isolation have become increasing concerns during COVID-19 lockdown through neuroendocrine stress-reactions, physical and mental health problems. We investigated living situation, relationship status and quality as potential moderators for trait and state loneliness and salivary cortisol levels (hormonal stress-responses) in healthy adults during the first lockdown in Germany.N=1242 participants (mean age = 36.32, 78% female) filled out an online questionnaire on demographics, trait loneliness and relationship quality. Next,N=247 (mean age = 32.6, 70% female) completed ecological momentary assessment (EMA), collecting twelve saliva samples on two days and simultaneously reporting their momentary loneliness levels. Divorced/widowed showed highest trait loneliness, followed by singles and partnerships. The latter displayed lower momentary loneliness and cortisol levels compared to singles. Relationship satisfaction significantly reduced loneliness levels in participants with a partner and those who were living apart from their partner reported loneliness levels similar to singles living alone. Living alone was associated with lower loneliness levels. Hierarchical linear models revealed a significant cross-level interaction between relationship status and momentary loneliness in predicting cortisol. The results imply that widowhood, being single, living alone and low relationship quality represent risk factors for loneliness and having a partner buffers neuroendocrine stress responses during lockdown.
Waning Effectiveness of the Third Dose of the BNT162b2 mRNA COVID-19 Vaccine
Authors: Patalon Tal , Saciuk Yaki , Peretz Asaf , Perez Galit , Lurie Yoav , Maor Yasmin , Gazit Sivan
Published: February 2022

The duration of protection of the third (booster) dose of the BioNTech/Pfizer BNT162b2 mRNA Coronavirus Disease 2019 vaccine has yet to be sufficiently researched, while global discussions around the necessity and effectiveness of a fourth dose are already underway. By conducting a retrospective study implementing a test-negative case-control design, analyzing 546,924 PCR tests performed throughout January 2022 by 389,265 persons who received three doses of the vaccine, we found that the effectiveness in each month since vaccination decreased significantly. Compared to those vaccinated early, on August 2021, relative protection against infection waned from 53.4% a month after vaccination to 16.5% three months after vaccination. These results suggest that there is a significant waning of vaccine effectiveness against the Omicron variant of the third dose of the BNT162b2 vaccine within a few months after administration and should prompt policy discussion as to additional booster doses and vaccine development.
Post-malnutrition growth and its associations with child survival and non-communicable disease risk: A secondary analysis of the Malawi ‘ChroSAM’ cohort
Authors: Lelijveld Natasha , Cox Sioned , Anujuo Kenneth , Amoah Abena S , Opondo Charles , Cole Tim J. , Wells Jonathan C. , Thompson Debbie , McKenzie Kimberley , Abera Mubarek , Berhane Melkamu , Kerac Marko ,   CHANGE study collaborators group
Published: February 2022

Background

Rapid catch-up growth after prenatal undernutrition is associated with increased risk of non-communicable diseases (NCDs) in high-income countries. Severe malnutrition treatment programmes in low- and middle-income countries promote rapid post-malnutrition growth (PMGr) as desirable. Our aim was to explore patterns of PMGr during and in the year following treatment, and describe associations with survival and NCD risk seven years post-treatment.

Methods

Secondary data analysis from a cohort of children treated for severe malnutrition in Malawi in 2006/7. Six definitions of PMGr were derived based on a variety of timepoints, weight, weight-for-age z-score (WAZ) and height-for-age z-score (HAZ). Three categorisation methods included: no categorisation, quintiles, and latent class analysis (LCA). Associations with mortality risk, and with eight NCD indicators were analysed visually using scatter plots and boxplots, and statistically using simple and multivariable linear regression.

Findings

Faster weight gain was associated with lower risk of death (g/day during treatment aOR 0.99, 95%CI 0.99 to 1.00, p=0.04; after treatment g/kg/month aOR 0.91, 95% CI 0.87 to 0.94, p<0.001). In survivors, it was associated with greater hand grip strength in some instances (g/day during treatment 0.02, 95%CI 0.00 to 0.03, p=0.007) and larger HAZ 7-years post-discharge (adjusted Δ WAZ per day during treatment 6.62, 95%CI 1.31 to 11.9, p=0.02), both indicators of better health. However, faster weight gain in treatment was also associated with increased waist:hip ratio (adjusted g/day during treatment 0.02, 95%CI 0.01 to 0.03, p=0.003), a key indicator of later life NCD risk. The clearest patterns of association were seen when defining PMGr based on weight gain in g/day during treatment, and using the LCA method to describe growth patterns. Weight deficit at admission was a major confounder.

Conclusion

We found a complex pattern of benefits and risks associated with faster PMGr with a possible trade-off between short- and long-term benefits/risks. Peripheral versus visceral weight distribution in particular requires further exploration. Both initial weight deficit and rate of weight gain have important implications for future health. Because conclusions from observational studies can go only so far, future randomised intervention trials are needed.
Human neutrophil development and functionality are enabled in a humanized mouse model
Authors: Zheng Yunjiang , Sefik Esen , Astle John , Solis Angel G. , Öz Hasan H. , Jackson Ruaidhrí , Bruscia Emanuela M. , Halene Stephanie , Shan Liang , Flavell Richard A
Published: February 2022

Mice with a functional human immune system serve as an invaluable tool to study the development and function of human immune system in vivo. A major technological limitation of all current humanized mouse models is the lack of mature and functional human neutrophils in circulation and tissues. To overcome this, we generated a humanized mouse model named MISTRGGR, in which the mouse granulocyte colony stimulating factor (G-CSF) was replaced with human G-CSF and the mouse G-CSF receptor gene was deleted (G-CSFR) in existing MISTRG mice. By targeting the GCSF cytokine-receptor axis, we dramatically improved the reconstitution of mature circulating and tissue-infiltrating human neutrophils in MISTRGGR mice. Moreover, these functional human neutrophils in MISTRGGR are recruited upon inflammatory and infectious challenges and help reduce bacterial burden. MISTRGGR mice represent a unique mouse model that finally permits the study of human neutrophils in health and disease.

Key Points

Targeting the GCSF cytokine-receptor axis dramatically improves circulating and tissue-infiltrating human neutrophils in MISTRGGR mice.

Human neutrophils generated in MISTRGGR mice are functional and are able to respond robustly to inflammatory and infectious stimuli.