bluuebunny/crossref_metadata_2025 huggingface dataset:
Anterior Cruciate Ligament Injury and Knee Osteoarthritis: An Umbrella Systematic Review and Meta-analysis
Authors: Webster Kate E. , Hewett Timothy E.
Published: April 2021

Objective:

To conduct a systematic review of reviews to summarize the (1) risk for development and (2) prevalence of knee osteoarthritis (OA) after anterior cruciate ligament (ACL) injury and surgical treatment and (3) compare prevalence rates between surgical and nonsurgical treatment of ACL injury.

Date sources:

Five electronic databases were searched using medical subject heading and text words up to February 2020 to identify English language reviews.

Study selection:

Studies were included if they were a systematic review or meta-analysis.

Data extraction:

Thirteen eligible reviews were included, and the main outcome extracted was knee OA prevalence or risk data and any meta-analysis results.

Data synthesis:

Results from reviews were combined with a summary meta-analysis based on odds ratios (ORs) or proportions. There was a near 7-fold and 8-fold increase in the odds for the development of knee OA post ACL injury [OR = 6.81 (5.70-8.13)] and ACL reconstruction [OR = 7.7, (6.05-9.79)]. Data were too heterogenous to specify a point estimate prevalence for OA after ACL injury, but OA prevalence was estimated at 36% (19.70-53.01) at near 10 years after reconstruction surgery. A significantly higher prevalence of OA was found for those who received surgical treatment at a minimum 10-year follow-up [OR = 1.40 (1.17-1.68)].

Conclusions:

This study combines all data from previous systematic reviews into a single source to show that ACL injury markedly increases the risk for development of knee OA, which is likely to be present in the long term in approximately a third of patients who have reconstruction surgery. Surgical treatment does not reduce OA prevalence in the longer term compared with nonsurgical treatment.
High-School Football and Midlife Brain Health Problems
Authors: Iverson Grant L. , Merz Zachary C. , Terry Douglas P.
Published: April 2021

Objective:

To examine whether middle-aged men who played high-school football experience worse mental health or cognitive functioning than men who did not play high-school football.

Design:

Cross-sectional cohort study.

Setting:

Online survey completed remotely.

Participants:

A total of 435 men between the ages of 35 and 55 completed the study, of whom 407 were included in the analyses after excluding participants who answered embedded validity items incorrectly (n = 16), played semiprofessional football (n = 2), or experienced a recent concussion (n = 10).

Assessment of Risk Factors:

Self-reported high school football participation, compared with those who played contact sports, noncontact sports, and no sports.

Main Outcome Measures:

A lifetime history of depression or anxiety; mental health or cognitive problems in the past year; current depression symptoms, and post–concussion-like symptoms.

Results:

Middle-aged men who played high-school football did not have a higher prevalence of being prescribed medication for anxiety or depression or receiving treatment from a mental health professional. Similarly, there were no significant differences between groups on the rates in which they endorsed depression, anxiety, anger, concentration problems, memory problems, headaches, migraines, neck or back pain, or chronic pain over the past year. A greater proportion of those who played football reported sleep problems over the past year and reported being prescribed medication for chronic pain and for headaches.

Conclusions:

Men who played high-school football did not report worse brain health compared with those who played other contact sports, noncontact sports, or did not participate in sports during high school.
Usefulness of serial FIB-4 score measurement for predicting the risk of hepatocarcinogenesis after hepatitis C virus eradication
Authors: Kumada Takashi , Toyoda Hidenori , Yasuda Satoshi , Tada Toshifumi , Tanaka Junko
Published: April 2021

Objectives

There is insufficient information to evaluate the correlation between fibrosis regression and hepatocellular carcinoma (HCC) risk after hepatitis C virus eradication. We analyzed serial changes in fibrosis (FIB)-4 scores after sustained virological response (SVR).

Methods

The subjects were 717 patients who achieved SVR by interferon (IFN)-based therapy (IFN Group) and 635 patients who achieved SVR by direct-acting antiviral (DAA) therapy (DAA Group). We performed propensity score matching because the baseline characteristics differed between the IFN and DAA groups, and then applied inverse probability weighting (IPW). We compared the changes in FIB-4 scores between the IFN and DAA groups. We also investigated the dynamics of FIB-4 scores, which are useful for predicting hepatocarcinogenesis.

Results

Using time-dependent receiver operating characteristic curve analysis and an IPW-adjusted Cox proportional hazards model, we identified an FIB-4 cutoff of 1.50 for predicting hepatocarcinogenesis. The percentages of patients in the IFN and DAA groups who demonstrated IPW-adjusted cumulative reduction and increase in FIB-4 scores indicated no significant differences. No HCC developed during the 5-year follow-up period in 547 of the 1352 patients whose FIB-4 score was <1.50 at SVR or improved from ≥1.50 to <1.50 during follow-up. Only one patient developed HCC, at 7.3 years; this individual had diabetes mellitus and excessive alcohol intake.

Conclusion

There was no difference in FIB-4 score reduction between the IFN and DAA groups. Patients whose FIB-4 scores improved to <1.50 or remained at <1.50 during follow-up after SVR had extremely low hepatocarcinogenesis rates.
Impact of pain on mental effort assessed as cardiovascular reactivity
Authors: Cancela Tamara , Silvestrini Nicolas
Published: April 2021

Introduction:

Pain typically impairs task performance, increases fatigue, and is associated with behavioral disengagement. Together, this suggests that pain impacts effort, defined as the mobilization of resources to carry out behavior. However, empirical evidence on this issue is lacking.

Objectives:

Drawing on motivational intensity theory, this study investigated the impact of pain on effort mobilization during cognitive task performance.

Methods:

We administered individually adjusted painful thermal stimulations during an easy memory task during which we measured effort as cardiovascular reactivity—a valid and objective measure. Control conditions included painful stimulations alone, the memory task alone, and the memory task with nonpainful heat stimulations. We expected pain to increase subjective difficulty due to additional demand on cognitive functioning, and in turn effort according to motivational intensity theory. Effort-related cardiovascular reactivity was predicted to increase along these conditions: pain-alone, task-alone, task with nonpainful stimulations, and the strongest effort when painful stimulations were administered during the task.

Results:

Overall, the findings offered support to our hypotheses. As predicted, results showed that pain increased subjective task difficulty (P = 0.020). Moreover, most of the effort-related cardiovascular measures showed the expected pattern with the strongest reactivity when painful stimulations were administered during the task compared with the other conditions (p < 0.02).

Conclusion:

These results are first evidence that pain impacts mental effort assessed as cardiovascular reactivity. We discuss how such extra effort might be related to the persistent feeling of fatigue and behavioral disengagement frequently observed in patients with chronic pain.
Perception-driven dynamics of mimicry based on attractor field model
Authors: Brejcha Jindřich , Tureček Petr , Kleisner Karel
Published: April 2021

We provide a formal account of an interface that bridges two different levels of dynamic processes manifested by mimicry: prey–prey interactions and predators' perception. Mimicry is a coevolutionary process between an animate selective agent and at least two similar organisms selected by agent's perception-driven actions. Attractor field model explains perceived similarity of forms by noting that in both human and animal cognition, morphologically intermediate forms are more likely to be perceived as belonging to rare rather than abundant forms. We formalize this model in terms of predators' perception space deformation using numerical simulations and argue that the probability of confusion between similar species creates pressure on the perception space, which in turn leads to inflation of regions of perception space with high density of species representations. Such inflation causes increased discrimination between species by a predator, which implies that adaptive mimicry could initially emerge more easily among atypical species because they do not need the same level of similarity to the model. We provide a theoretical instrument to conceptualize interdependence between objective measurable matrices and perceived matrices of the same external reality. We believe that our framework leads to a more precise understanding of the evolution of mimicry.
Tissue tectonics and the multi-scale regulation of developmental timing
Authors: Busby Lara , Steventon Benjamin
Published: April 2021

Development encompasses processes that occur at multiple length scales, including gene-regulatory interactions, cell movements and reorganization, cell signalling and growth. It is essential that the timing of events in all of these different processes is coordinated to generate well-patterned tissues and organs. However, how the timing of intrinsic cell state changes is coordinated with events occurring at the multi-tissue and whole-organism level is unknown. Here, we argue that an important mechanism that accounts for the integration of timing across levels of organization is provided bytissue tectonics, i.e. how morphogenetic events driving tissue shape changes result in the relative displacement of signalling and responding tissues and coordinate developmental timing across scales. In doing so, tissue tectonics provides a mechanism by which the cell specification events intrinsic to cells can be modulated by the temporal exposure to extracellular signals. This exposure is in turn regulated by higher-order properties of the embryo, such as their physical properties, rates of growth and the combination of dynamic cell behaviours, impacting tissue morphogenesis. Tissue tectonics creates a downward flow of information from higher to lower levels of biological organization, providing an instance of downward causation in development.
The impact of COVID-19 upon the delivery of exercise services within cystic fibrosis clinics in the United Kingdom
Authors: Tomlinson Owen W , Saynor Zoe L , Stevens Daniel , Urquhart Don , Williams Craig A
Published: April 2021

The COVID-19 pandemic has resulted in unprecedent change to clinical practice. As the impact upon delivery of exercise services for people with cystic fibrosis (CF) in the UK was unknown, this was characterised via a national survey. In total, 31 CF centres participated. Principal findings included a significant reduction in exercise testing, and widespread adaptation to deliver exercise training using telehealth methods. Promisingly, 71% stated that they would continue to use virtual methods of engaging patients in future practice. This does, however, highlight a need to develop sustainable and more standardised telehealth services further to manage patients moving forwards.
A very simple model to account for the rapid rise of the British variant of SARS-CoV-2 in several countries and the world
Authors: Fort Hugo
Published: April 2021

Since its first detection in the UK in September 2020, a highly contagious version of the coronavirus, called the British variant or B.1.1.7 SARS-CoV-2 virus lineage, is rapidly spreading across several countries and becoming the dominant strain in the outbreak.

Here it is shown that a very simple evolutionary model, when including the latest available data from March 2021, can fit the observed change in frequency of B.1.1.7 for several countries, regions of countries and the whole world with a single parameter which is almost universal.
Protein-coding potential of RNAs measured by potentially translated island scores
Authors: Suenaga Yusuke , Kato Mamoru , Nagai Momoko , Nakatani Kazuma , Kogashi Hiroyuki , Kobatake Miho , Makino Takashi
Published: April 2021

Recent studies have identified numerous RNAs that are functionally both coding and noncoding. However, the sequence characteristics that determine bifunctionality remain largely unknown. In this study, we developed and tested a potentially translated island (PTI) score, defined as the occupancy of the longest open reading frame (ORF) among all putative ORFs. We found that this score correlated with translation, including noncoding RNAs. In bacteria and archaea, coding and noncoding transcripts had narrow distributions of high and low PTI scores, respectively, whereas those of eukaryotes showed relatively broader distributions, with considerable overlap between coding and noncoding transcripts. The extent of overlap positively and negatively correlated with the mutation rates of genomes and effective population sizes of species, respectively. These overlaps were significantly increased in threatened species. In macroevolution, the appearance of the nucleus and multicellularity seem to have influenced the overlap of PTI score distributions, so that the probability of the existence of bifunctional RNAs is increased in eukaryotes. In mammalian testes, we observed an enrichment of noncoding RNAs with high PTI scores, which are candidates for bifunctional RNAs. These results suggest that the decrease in population size and the emergence of testes in eukaryotic multicellular organisms allow for the stable existence of bifunctional RNAs, consequently increasing the probability of the birth of novel coding and non-coding RNAs.
Germline testing data validate inferences of mutational status for variants detected from tumor-only sequencing
Authors: Jalloul Nahed , Gomy Israel , Stokes Samantha , Gusev Alexander , Johnson Bruce E. , Lindeman Neal I. , Macconaill Laura , Ganesan Shridar , Garber Judy E. , Khiabanian Hossein
Published: April 2021

Structured Abstract

Background

Pathogenic germline variants (PGV) in cancer susceptibility genes are usually identified in cancer patients through germline testing of DNA from blood or saliva: their detection can impact patient treatment options and potential risk reduction strategies for relatives. PGV can also be identified, in tumor sequencing assays, often performed without matched normal specimens. It is then critical to determine whether detected variants are somatic or germline. Here, we evaluate the clinical utility of computational inference of mutational status in tumor-only sequencing compared to germline testing results.

Patients and Methods

Tumor-only sequencing data from 1,608 patients were retrospectively analyzed to infer germline-versus-somatic status of variants using an information-theoretic, gene-independent approach. Loss of heterozygosity (LOH) was also determined. The predicted mutational models were compared to clinical germline testing results. Statistical measures were computed to evaluate performance.

Results

Tumor-only sequencing detected 3,988 variants across 70 cancer susceptibility genes for which germline testing data were available. Our analysis imputed germline-versus-somatic status for >75% of all detected variants, with a sensitivity of 65%, specificity of 88%, and overall accuracy of 86% for pathogenic variants. False omission rate was 3%, signifying minimal error in misclassifying true PGV. A higher portion of PGV in known hereditary tumor suppressors were found to be retained with LOH in the tumor specimens (72%) compared to variants of uncertain significance (58%).

Conclusions

Tumor-only sequencing provides sufficient power to distinguish germline and somatic variants and infer LOH. Although accurate detection of PGV from tumor-only data is possible, analyzing sequencing data in the context of specimens’ tumor cell content allows systematic exclusion of somatic variants, and suggests a balance between type 1 and 2 errors for identification of patients with candidate PGV for standard germline testing. Our approach, implemented in a user-friendly bioinformatics application, facilities objective analysis of tumor-only data in clinical settings.

Highlights

Most pathogenic germline variants in cancer predisposition genes can be identified by analyzing tumor-only sequencing data.

Information-theoretic gene-independent analysis of common sequencing data accurately infers germline vs. somatic status.

A reasonable statistical balance can be established between sensitivity and specificity demonstrating clinical utility.

Pathogenic germline variants are more often detected with loss of heterozygosity vs. germline variants of uncertain significance.
Integrative Clinical and Molecular Characterization of Translocation Renal Cell Carcinoma
Authors: Bakouny Ziad , Sadagopan Ananthan , Ravi Praful , Metaferia Nebiyou Y. , Li Jiao , AbuHammad Shatha , Tang Stephen , Denize Thomas , Garner Emma R. , Gao Xin , Braun David A. , Hirsch Laure , Steinharter John A. , Bouchard Gabrielle , Walton Emily , West Destiny , Labaki Chris , Dudani Shaan , Gan Chun-Loo , Sethunath Vidyalakshmi , Carvalho Filipe LF. , Imamovic Alma , Ricker Cora , Vokes Natalie I. , Nyman Jackson , Park Jihye , Hirsch Michelle S. , Haq Rizwan , Lee Gwo-Shu Mary , McGregor Bradley A. , Chang Steven L. , Feldman Adam S. , Wu Catherine J. , McDermott David F. , Heng Daniel Y.C. , Signoretti Sabina , Van Allen Eliezer M. , Choueiri Toni K. , Viswanathan Srinivas R.
Published: April 2021

ABSTRACT

Translocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven byMiT/TFEgene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 tRCC patients identified across multiple genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart fromMiT/TFEfusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8+tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.
Exceptional ancient DNA preservation and fibre remains of a Sasanian saltmine sheep mummy in Chehrābād, Iran
Authors: Rossi Conor , Ruß-Popa Gabriela , Mattiangeli Valeria , McDaid Fionnuala , Hare Andrew J. , Davoudi Hossein , Laleh Haeedeh , Lorzadeh Zahra , Khazaeli Roya , Fathi Homa , Teasdale Matthew D. , A’ali Abolfazl , Stöllner Thomas , Mashkour Marjan , Daly Kevin G.
Published: April 2021

Mummified remains have long attracted interest as a potential source of ancient DNA. However, mummification is a rare process that requires an anhydrous environment to rapidly dehydrate and preserve tissue before complete decomposition occurs. We present the whole genome sequences of a ∼1600 year old naturally mummified sheep recovered from Chehrābād, a salt mine in northwestern Iran. Comparative analyses of published ancient sequences revealed remarkable DNA integrity of this mummy. Hallmarks of postmortem damage, fragmentation and hydrolytic deamination, are substantially reduced, likely due to the high-salinity of this taphonomic environment. Metagenomic analyses reflect the profound influence of high salt content on decomposition; its microbial profile is predominated by halophilic archaea and bacteria, possibly contributing to the preservation of this sample. Applying population genomic analyses we find consistent clustering of this sheep with Southwest Asian modern breeds, suggesting ancestry continuity. Genotyping of a locus influencing the woolly phenotype showed the existence of an ancestral “hairy” allele in this sheep, consistent with hair fibre imaging, further elucidating Sasanian-period animal husbandry.
CoolBox: A flexible toolkit for visual analysis of genomics data
Authors: Xu Weize , Zhong Quan , Lin Da , Li Guoliang , Cao Gang
Published: April 2021

We developed CoolBox, an open source toolkit for visual analysis of genomics data, which is highly compatible with the Python ecosystem, easy to use and highly customizable with a well-designed user interface. It can be used in various visualization situations like a Swiss army knife, for example, to produce high-quality genome track plots or fetch common used genomic data files with a Python script or command line, interactively explore genomic data within Jupyter environment or web browser. Moreover, owing to the highly extensible API design, users can customize their own tracks without difficulty, which can greatly facilitate analytical, comparative genomic data visualization tasks.
Does powder averaging remove dispersion bias in diffusion MRI diameter estimates within real 3D axonal architectures?
Authors: Andersson Mariam , Pizzolato Marco , Kjer Hans Martin , Skodborg Katrine Forum , Lundell Henrik , Dyrby Tim B.
Published: April 2021

Noninvasive estimation of axon diameter with diffusion MRI holds potential to investigate the dynamic properties of the brain network and pathology of neurodegenerative diseases. Recent methods use powder averaging to account for complex white matter architectures, such as fibre crossing regions, but these have not been validated for real axonal geometries. Here, we present 120 – 313μm long segmented axons from X-ray nano-holotomography volumes of a splenium and crossing fibre region of a vervet monkey brain. We show that the axons in the complex crossing fibre region, which contains callosal, association, and corticospinal connections, are larger and exhibit a wider distribution than those of the splenium region. To accurately estimate the axon diameter in these regions, therefore, sensitivity to a wide range of diameters is required. We demonstrate how theq-value,b-value, signal-to-noise ratio and the assumed intra-axonal parallel diffusivity influence the range of measurable diameters with powder average approaches. Furthermore, we show how Gaussian distributed noise results in a wider range of measurable diameter at highb-values than Rician distributed noise, even at high signal-to-noise ratios of 100. The number of gradient directions is also shown to impose a lower bound on measurable diameter. Our results indicate that axon diameter estimation can be performed with only fewb-shells, and that additional shells do not improve the accuracy of the estimate. Through Monte Carlo simulations of diffusion, we show that powder averaging techniques succeed in providing accurate estimates of axon diameter across a range of sequence parameters and diffusion times, even in complex white matter architectures. At sufficiently lowb-values, the acquisition becomes sensitive to axonal microdispersion and the intra-axonal parallel diffusivity shows time dependency at both in vivo and ex vivo intrinsic diffusivities.
Incorporating family history of disease improves polygenic risk scores in diverse populations
Authors: Hujoel Margaux L.A. , Loh Po-Ru , Neale Benjamin M. , Price Alkes L.
Published: April 2021

Polygenic risk scores derived from genotype data (PRS) and family history of disease (FH) both provide valuable information for predicting disease risk, enhancing prospects for clinical utility. PRS perform poorly when applied to diverse populations, but FH does not suffer this limitation. Here, we explore methods for combining both types of information (PRS-FH). We analyzed 10 complex diseases from the UK Biobank for which family history (parental and sibling history) was available for most target samples. PRS were trained using all British individuals (N=409K), and target samples consisted of unrelated non-British Europeans (N=42K), South Asians (N=7K), or Africans (N=7K). We evaluated PRS, FH, and PRS-FH using liability-scaleR2, focusing on three well-powered diseases (type 2 diabetes, hypertension, depression) withR2> 0.05 for PRS and/or FH in each target population. Averaging across these three diseases, PRS attained average predictionR2of 5.8%, 4.0%, and 0.53% in non-British Europeans, South Asians, and Africans, confirming poor cross-population transferability. In contrast, PRS-FH attained average predictionR2of 13%, 12%, and 10%, respectively, representing a large improvement in Europeans and an extremely large improvement in Africans; for each disease and each target population, the improvement was highly statistically significant. PRS-FH methods based on a logistic model and a liability threshold model performed similarly when covariates were not included in predictions (consistent with simulations), but the logistic model outperformed the liability threshold model when covariates were included. In conclusion, including family history greatly improves the accuracy of polygenic risk scores, particularly in diverse populations.
A complex CTCF binding code defines TAD boundary structure and function
Authors: Chang Li-Hsin , Ghosh Sourav , Papale Andrea , Miranda Mélanie , Piras Vincent , Degrouard Jéril , Poncelet Mallory , Lecouvreur Nathan , Bloyer Sébastien , Leforestier Amélie , Holcman David , Noordermeer Daan
Published: April 2021

Topologically Associating Domains (TADs) compartmentalize vertebrate genomes into sub-Megabase functional neighbourhoods for gene regulation, DNA replication, recombination and repair1-10. TADs are formed by Cohesin-mediated loop extrusion, which compacts the DNA within the domain, followed by blocking of loop extrusion by the CTCF insulator protein at their boundaries11-20. CTCF blocks loop extrusion in an orientation dependent manner, with both experimental and in-silico studies assuming that a single site of static CTCF binding is sufficient to create a stable TAD boundary21-24. Here, we report that most TAD boundaries in mouse cells are modular entities where CTCF binding clusters within extended genomic intervals. Optimized ChIP-seq analysis reveals that this clustering of CTCF binding does not only occur among peaks but also frequently within those peaks. Using a newly developed multi-contact Nano-C assay, we confirm that individual CTCF binding sites additively contribute to TAD separation. This clustering of CTCF binding may counter against the dynamic DNA-binding kinetics of CTCF25-27, which urges a re-evaluation of current models for the blocking of loop extrusion21-23. Our work thus reveals an unanticipatedly complex code of CTCF binding at TAD boundaries that expands the regulatory potential for TAD structure and function and can help to explain how distant non-coding structural variation influences gene regulation, DNA replication, recombination and repair5,28-34.
Spontaneous modulations of high frequency cortical activity
Authors: Ono Hiroya , Sonoda Masaki , Silverstein Brian H. , Sonoda Kaori , Kubota Takafumi , Luat Aimee F. , Rothermel Robert , Sood Sandeep , Asano Eishi
Published: April 2021

Objective

We clarified the clinical and mechanistic significance of physiological modulations of high-frequency broadband cortical activity associated with spontaneous saccadic eye movements during a resting state.

Methods

We studied 30 patients who underwent epilepsy surgery following extraoperative electrocorticography and electrooculography recordings. We determined whether high-gamma activity at 70-110 Hzpreceding saccade onsetwould predict upcoming ocular behaviors. We assessed how accurately the model incorporating saccade-related high-gamma modulations would localize the primary visual cortex defined by electrical stimulation.

Results

The whole-brain level dynamic atlas demonstrated transient high-gamma suppression in the striatal region before saccade onset and high-gamma augmentation subsequently involving the widespread posterior brain regions. More intense striatal high-gamma suppression predicted the upcoming saccade directed to the ipsilateral side and lasting longer in duration. The bagged-tree-ensemble model demonstrated that intense saccade-related high-gamma modulations localized the visual cortex with an accuracy of 95%.

Conclusions

We successfully animated the neural dynamics supporting saccadic suppression, a principal mechanism minimizing the perception of blurred vision during rapid eye movements. The primary visual cortexper semay prepareactively in advancefor massive image motion expected during upcoming prolonged saccades.

Significance

Measuring saccade-related electrocorticographic signals may help localize the visual cortex and avoid misperceiving physiological high-frequency activity as epileptogenic.

Highlights

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The whole-brain level dynamic atlas animated spontaneous high gamma modulations associated with saccadic eye movements.

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Preceding high gamma activity in the striatal cortex predicted the direction and duration of the upcoming saccades.

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Saccade-related high-gamma modulations localized the stimulation-defined visual cortex with an accuracy of 95%.
Genetic deletion of interleukin-15 is not associated with major structural changes following experimental post-traumatic knee osteoarthritis in rats
Authors: Hadzic Ermina , Blackler Garth , Dupuis Holly , Renaud Stephen J , Appleton C. Thomas , Beier Frank
Published: April 2021

Post-traumatic Osteoarthritis (PTOA) is a degenerative joint disease, leading to articular cartilage breakdown, osteophyte formation, and synovitis, caused by an initial joint trauma. Pro-inflammatory cytokines increase catabolic activity and may perpetuate inflammation following joint trauma. Interleukin-15 (IL-15), a pro-inflammatory cytokine, is increased in OA patients, although its roles in OA pathophysiology are not well characterized.

IL-15 levels appear to correlate to self-reported pain levels, and polymorphisms in the IL-15 receptor alpha gene correlate to a 1.5-fold increase in OA symptoms. This could be due to IL-15 effects on the activity of proteinases, such as matrix metalloproteinases (MMP) −1, −3, and −7. Here we utilizedIl15deficient rats to examine the role of IL-15 in PTOA pathogenesis in an injury-induced model of OA. OA was surgically induced inIl15deficient rats and control wild-type rats to compare PTOA progression. Semi-quantitative scoring of the articular cartilage, subchondral bone, osteophyte size, and synovium was performed by two blinded observers. Analyses of articular cartilage damage, subchondral bone damage, and osteophyte formation revealed no significant difference betweenIl15deficient rats and wild-type rats following PTOA-induction. Similarly, synovitis scoring across 6 parameters found no significant difference between genetic variants. Overall, IL-15 does not appear to play a key role in the development of structural changes in this surgically-induced rat model of PTOA.
A computational model of typical and impaired reading: the role of visual processing
Authors: Chang Ya-Ning , Welbourne Stephen , Furber Steve , Ralph Matthew Lambon
Published: April 2021

Computational modelling has served as a powerful tool to advance our understanding of language processes by making theoretical ideas rigorously specified and testable (a form of “ open science” for theory building). In reading research, one of the most influential computational modelling frameworks is the triangle model of reading that characterises the mappings between orthography, phonology and semantics. Currently, most instantiations of the triangle modelling framework start the processes from orthographic levels which abstract away visual processing. Moreover, without visual processing, most models do not provide an opportunity to investigate visual-related dyslexia. To bridge this crucial gap, the present study extended the existing triangle models by implementing an additional visual input. We trained the model to learn to read from visual input without pre-defined orthographic representations. The model was assessed by reading tasks in both intact and after damage (to mimic acquire alexias). The simulation results demonstrated that the model was able to name word and nonwords as well as make lexical decisions. Damage to the visual, phonological or semantic components of the model resulted in the expected reading impairments associated with pure alexia, phonological dyslexia, and surface dyslexia, respectively. The simulation results demonstrated for the first time that both typical and neurologically-impaired reading including both central and peripheral dyslexia could be addressed in this extended triangle model of reading. The findings are consistent with the primary systems account.
JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation
Authors: Tavares Manuel , Khandelwal Garima , Mutter Joanne , Viiri Keijo , Beltran Manuel , Brosens Jan J. , Jenner Richard G.
Published: April 2021

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 (H3K27me3) to maintain repression of genes specific for other cell types and is essential for cell differentiation. In endometrial stromal sarcoma, the PRC2 subunit SUZ12 is often fused with the NuA4/TIP60 subunit JAZF1. Here, we show that JAZF1-SUZ12 dysregulates PRC2 composition, recruitment, histone modification, gene expression and cell differentiation. The loss of the SUZ12 N-terminus in the fusion protein disrupted interaction with the PRC2 accessory factors JARID2, EPOP and PALI1 and prevented recruitment of PRC2 from RNA to chromatin. In undifferentiated cells, JAZF1-SUZ12 occupied PRC2 target genes but gained a JAZF1-like binding profile during cell differentiation. JAZF1-SUZ12 reduced H3K27me3 and increased H4Kac at PRC2 target genes, and this was associated with disruption in gene expression and cell differentiation programs. These results reveal the defects in chromatin regulation caused by JAZF1-SUZ12, which may underlie its role in oncogenesis.
Characterization of a novel mesophilic CTP-dependent riboflavin kinase and rational engineering to create its thermostable homologs
Authors: Kumar Yashwant , Singh Reman Kumar , Hazra Amrita Brajagopal
Published: April 2021

Flavins play a central role in cellular metabolism as molecules that catalyze a wide range of oxidation-reduction reactions in living organisms. Several interesting variations in flavin biosynthesis exist among the domains of life, and the analysis of enzymes on this pathway have put forth many unique structural and mechanistic insights till date. The CTP-dependent riboflavin kinase in archaea is one such example - unlike most kinase enzymes that use adenosine triphosphate to conduct phosphorylation reactions, riboflavin kinases from archaea utilizes cytidine triphosphate (CTP) to phosphorylate riboflavin to produce flavin mononucleotide (FMN). In this study, we present the characterization of a new mesophilic archaeal riboflavin kinase homolog fromMethanococcus maripaludis(MmpRibK), which is linked closely in sequence to the previously characterized thermophilic homolog fromMethanocaldococcus jannaschii(MjRibK). We reconstitute the activity of the CTP-dependentMmpRibK, determine its kinetic parameters, and analyse the molecular factors that contribute to the uncommon properties of this class of enzymes. Specifically, we probe the flexibility ofMmpRibK andMjRibK under varying temperatures and the role of a metal ion for substrate binding and catalysis using molecular dynamics simulation and a series of experiments. Furthermore, based on the high degree of sequence similarity between the mesophilicMmpRibK and the thermophilicMjRibK, we use comparative analysis and site-directed mutagenesis to establish a set of the residues that are responsible for the thermostability of the enzyme without any loss in activity or substrate specificity. Our work contributes to the molecular understanding of flavin biosynthesis in archaea through the characterization of the first mesophilic CTP-dependent riboflavin kinase. Finally, it validates the role of salt bridges and rigidifying amino acid residues in imparting thermostability to enzymes, with implications in enzyme engineering and biotechnological applications.
Exploration of clinical breakpoint of Danofloxacin forGlaesserella parasuisin plasma and in PELF
Authors: Xu Zihui , Huang Anxiong , Luo Xun , Zhang Peng , Huang Lingli , Wang Xu , Mi Kun , Fang Shiwei , Huang Xiao , Li Jun , Yuan Zonghui , Hao Haihong
Published: April 2021

Background

To establish the clinical breakpoint (CBP) of danofloxacin toG. parasuis, three cutoff values, including epidemiological cutoff value (ECV), pharmacodynamic cutoff value (COPD) and clinical cutoff value (COCL), was obtained in the present study.

Methods

The ECV was calculated using ECOFFinder base on MIC distribution of 347G. parasuiscollected from disease pigs. The COPDwas established base onin vivoandex vivopharmacokinetic (PK) - pharmacodynamic (PD) modeling of danofloxacin both in plasma and pulmonary epithelial lining fluid (PELF) using Hill formula and Monte Carlo analysis. The COCLwas established based on the relationship between possibility of cure (POC) and MIC in the clinical trials using “WindoW” approach, nonlinear regression and CART analysis.

Results

The MIC50and MIC90of danofloxacin against 347G. parasuiswere 2 μg/mL and 8 μg/mL, respectively. The ECV value was set up as 8 μg/mL using ECOFFinder. Concentration-time curve of danofloxacin indicated a two-compartment model for PK analysis. The PK parameters of the maximum concentration (Cmax) and area under concentration-time curve (AUC) in PELF were 3.67 ± 0.25 μg/mL and 24.28 ± 2.70 h·μg/mL, higher than those in plasma (0.67 ± 0.01μg/mL and 4.47 ± 0.51 h·μg/mL). The peak time (Tmax) in plasma was 0.23 ± 0.07 h, shorter than that in PELF (1.61 ± 0.15 h). The COPDin plasma and PELF were 0.125 μg/mL and 0.5 μg/mL, respectively. The COCLcalculated by WindoW approach, nonlinear regression and CART analysis were 0.125∼4 μg/mL, 0.428 μg/mL and 0.56 μg/mL, respectively. The 0.5 μg/mL was selected as eligible COCL. The ECV is much higher than the COPDand COCL, and the clinical breakpoint based on data in plasma was large different with that of in PELF.

Conclusions

Our study firstly established three cutoff values of danofloxacin againstG. parasuis. It suggested that epidemiological danofloxacin-resistantG. parasuismay lead to the ineffective treatment by danofloxacin.

Importance

G. parasuis, a gram-negative respiratory pathogen, can colonize in the upper respiratory tract in swine and cause Glasser’s disease. As the abuse of antibiotics, antimicrobial resistantG. parasuisemerged in different degrees, which brought serious threat to global economy and public health. Danofloxacin in quinolones are one of the best choices for treatment ofG. parasuisinfection, because of their strong bactericidal activity and good absorption into blood and great distribution in the lung. However, the clinical breakpoint (CBP) for danofloxacin againstG. parasuishad not yet been established by clinical laboratory of standard Institute (CLSI) and European Commission of antimicrobial susceptibility testing (EUCAST). Our study firstly established three cutoff values of danofloxacin againstG. parasuis. It suggested that epidemiological danofloxacin-resistantG. parasuismay lead to the ineffective treatment by danofloxacin.
Modeling non-pharmaceutical interventions in the COVID-19 pandemic with survey-based simulations
Authors: Kaffai Marius , Heiberger Raphael H.
Published: April 2021

Governments around the globe use non-pharmaceutical interventions (NPIs) to curb the spread of coronavirus disease 2019 (COVID-19) cases. Making decisions under uncertainty, they all face the same temporal paradox: estimating the impact of NPIs before they have been implemented. Due to the limited variance of empirical cases, researcher could so far not disentangle effects of individual NPIs or their impact on different demographic groups. In this paper, we utilize large-scale agent-based simulations in combination with Susceptible-Exposed-Infectious-Recovered (SEIR) models to investigate the spread of COVID-19 for some of the most affected federal states in Germany. In contrast to other studies, we sample agents from a representative survey. Including more realistic demographic attributes that influence agents’ behavior yields accurate predictions of COVID-19 transmissions and allows us to investigate counterfactual “what-if” scenarios. Results show that quarantining infected people and exploiting industry-specific home office capacities are the most effective NPIs. Disentangling education-related NPIs reveals that each considered institution (kindergarten, school, university) has rather small effects on its own, yet, that combined openings would result in large increases in COVID-19 cases. Representative survey-characteristics of agents also allow us to estimate NPIs’ effects on different age groups. For instance, re-opening schools would cause comparatively few infections among the risk-group of people older than 60 years.
The contributions from the progenitor genomes of the mesopolyploid Brassiceae are evolutionarily distinct but functionally compatible
Authors: Hao Yue , Mabry Makenzie E. , Edger Patrick P. , Freeling Michael , Zheng Chunfang , Jin Lingling , VanBuren Robert , Colle Marivi , An Hong , Abrahams R. Shawn , Washburn Jacob D. , Qi Xinshuai , Barry Kerrie , Daum Christopher , Shu Shengqiang , Schmutz Jeremy , Sankoff David , Barker Michael S. , Lyons Eric , Pires J. Chris , Conant Gavin C.
Published: April 2021

The members of the tribe Brassiceae share a whole-genome triplication (WGT), and one proposed model for its formation is a two-step pair of hybridizations producing hexaploid descendants. However, evidence for this model is incomplete, and the evolutionary and functional constraints that drove evolution after the hexaploidy are even less understood. Here, we report a new genome sequence of Crambe hispanica, a species sister to most sequenced Brassiceae. Using this new genome and three others that share the hexaploidy, we traced the history of gene loss after the WGT using the Polyploidy Orthology Inference Tool (POInT). We confirm the two-step formation model and infer that there was a significant temporal gap between those two allopolyploidizations, with about a third of the gene losses from the first two subgenomes occurring before the arrival of the third. We also, for the 90,000 individual genes in our study, make parental subgenome assignments, inferring, with measured uncertainty, from which of the progenitor genomes of the allohexaploidy each gene derives. We further show that each subgenome has a statistically distinguishable rate of homoeolog losses. There is little indication of functional distinction between the three subgenomes: the individual subgenomes show no patterns of functional enrichment, no excess of shared protein–protein or metabolic interactions between their members, and no biases in their likelihood of having experienced a recent selective sweep. We propose a “mix and match” model of allopolyploidy, in which subgenome origin drives homoeolog loss propensities but where genes from different subgenomes function together without difficulty.
Genome-wide analysis of plant miRNA action clarifies levels of regulatory dynamics across developmental contexts
Authors: Ma Xiaoli , Denyer Tom , Javelle Marie , Feller Antje , Timmermans Marja C.P.
Published: April 2021

Development of complex organisms requires the delicate and dynamic spatiotemporal regulation of gene expression. Central to this are microRNAs (miRNAs). These mobile small RNAs offer specificity in conveying positional information and versatility in patterning the outcomes of gene expression. However, the parameters that shape miRNA output during development are still to be clarified. Here, we address this question on a genome-wide scale, using the maize shoot apex as a model. We show that patterns and levels of miRNA accumulation are largely determined at the transcriptional level, but are finessed post-transcriptionally in a tissue-dependent manner. The stem cell environments of the shoot apical meristem and vasculature appear particularly liable to this. Tissue-specific effects are also apparent at the level of target repression, with target cleavage products in the vasculature exceeding those of other tissues. Our results argue against a clearance mode of regulation purely at the level of transcript cleavage, leading us to propose that transcript cleavage provides a baseline level of target repression, onto which miRNA-driven translational repression can act to toggle the mode of target regulation between clearance and rheostat. Our data show how the inherent complexities of miRNA pathways allow the accumulation and activity of these small RNAs to be tailored in space and time to bring about the gene expression versatility needed during development.
The advanced treatment of hydrogen bonding in quantum crystallography
Authors: Malaspina Lorraine A. , Genoni Alessandro , Jayatilaka Dylan , Turner Michael J. , Sugimoto Kunihisa , Nishibori Eiji , Grabowsky Simon
Published: April 2021

Although hydrogen bonding is one of the most important motifs in chemistry and biology, H-atom parameters are especially problematic to refine against X-ray diffraction data. New developments in quantum crystallography offer a remedy. This article reports how hydrogen bonds are treated in three different quantum-crystallographic methods: Hirshfeld atom refinement (HAR), HAR coupled to extremely localized molecular orbitals and X-ray wavefunction refinement. Three different compound classes that form strong intra- or intermolecular hydrogen bonds are used as test cases: hydrogen maleates, the tripeptide L-alanyl-glycyl-L-alanine co-crystallized with water, and xylitol. The differences in the quantum-mechanical electron densities underlying all the used methods are analysed, as well as how these differences impact on the refinement results.
A high-throughput assembly of beam-shaping channel-cut monochromators for laboratory high-resolution X-ray diffraction and small-angle X-ray scattering experiments
Authors: Nadazdy Peter , Hagara Jakub , Mikulik Petr , Zaprazny Zdenko , Korytar Dusan , Majkova Eva , Jergel Matej , Siffalovic Peter
Published: April 2021

A four-bounce monochromator assembly composed of Ge(111) and Ge(220) monolithic channel-cut monochromators with V-shaped channels in a quasi-dispersive configuration is presented. The assembly provides an optimal design in terms of the highest transmittance and photon flux density per detector pixel while maintaining high beam collimation. A monochromator assembly optimized for the highest recorded intensity per detector pixel of a linear detector placed 2.5 m behind the assembly was realized and tested by high-resolution X-ray diffraction and small-angle X-ray scattering measurements using a microfocus X-ray source. Conventional symmetric and asymmetric Ge(220) Bartels monochromators were similarly tested and the results were compared. The new assembly provides a transmittance that is an order of magnitude higher and 2.5 times higher than those provided by the symmetric and asymmetric Bartels monochromators, respectively, while the output beam divergence is twice that of the asymmetric Bartels monochromator. These results demonstrate the advantage of the proposed monochromator assembly in cases where the resolution can be partially sacrificed in favour of higher transmittance while still maintaining high beam collimation. Weakly scattering samples such as nanostructures are an example. A general advantage of the new monochromator is a significant reduction in the exposure time required to collect usable experimental data. A comparison of the theoretical and experimental results also reveals the current limitations of the technology of polishing hard-to-reach surfaces in X-ray crystal optics.