bluuebunny/crossref_metadata_2025 huggingface dataset:
Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation
Authors: Li Yingju , Dewar Amanda , Kim Yeonsun , Dey Sudhansu K. , Sun Xiaofei
Published: August 2020

An early event after implantation is stromal cell transformation to decidual cells (decidualization) that support embryo development. In mice, this process begins at the antimesometrial (AM) pole with differentiation of stromal cells into epithelial-like cells (epithelioid cells) surrounding the implantation chamber. This is an avascular zone called the primary decidual zone (PDZ), and considered to function as a transient, size-dependent permeable barrier to protect the embryo from maternal circulating harmful agents, including immunoglobulins, immune cells, microorganisms and other noxious agents. This zone forms on day 5 afternoon and becomes fully established on day 6 with the loss of the crypt epithelium. The PDZ gradually degenerates with the appearance of the secondary decidual zone (SDZ) around the PDZ that peaks on day 8 in mice. Decidualization is critical for early pregnancy in mice and humans. We show that cannabinoid/endocannabinoid signaling influences decidualization in early pregnancy. Mice deficient in two major cannabinoid receptors, CB1 and CB2, show compromised PDZ. We found that angiogenic factors are dysregulated inCnr1-/-Cnr2-/-mice with defective PDZs, resulting in the abnormal presence of blood vessels and macrophages in this zone; disruption of the PDZ compromises pregnancy outcomes. Using anin vitrodecidualization model, we found thatCnr1levels increase in mouse stromal cells and human uterine fibroblast (Huf) cells undergoing decidualization and that limiting CB1 signaling in these cell types suppresses decidualizationin vitro. Since endothelial cells expressCnr2and decidual cells expressCnr1, we hypothesize that angiogenic events driven by CB2 are integrated with CB1 in decidual cells, leading to proper PDZ formation, a critical step for pregnancy success.
Differential expression of starch and sucrose metabolic genes linked to varying biomass yield inMiscanthushybrids
Authors: De Vega Jose J , Peel Ned , Purdy Sarah J , Hawkins Sarah , Donnison Iain , Dyer Sarah , Farrar Kerrie
Published: August 2020

Miscanthusis a commercial lignocellulosic biomass crop owing to its high biomass productivity and low chemical input requirements. InterspecificMiscanthushybrids with high biomass yield were shown to have low concentrations of starch and sucrose but high concentrations of fructose. We performed a transcriptional RNA-seq analysis between selectedMiscanthushybrids with contrasting values for these phenotypes to clarify how these phenotypes are genetically controlled. We observed that genes directly involved in the synthesis and degradation of starch and sucrose were down-regulated in high yieldingMiscanthushybrids. At the same time, glycolysis and export of triose phosphates were up-regulated in high yieldingMiscanthushybrids. Our results evidence a direct relationship between high expression of essential enzymatic genes in the starch and sucrose pathways, high starch concentrations, and lower biomass production. The strong interconnectivity between genotype, chemotype and agronomic traits opens the door to use the expression of well-characterised genes in the starch and sucrose pathway for the early selection of high biomass yielding genotypes from largeMiscanthuspopulations.
Temperature Effect on Polymerase Fidelity
Authors: Xue Yuan , Braslavsky Ido , Quake Stephen R.
Published: August 2020

The discovery of extremophiles helped enable the development of groundbreaking technology such as polymerase chain reaction. Temperature variation is often an essential step of these technology platforms, but the effect of temperature on the error rate of polymerases from different origins is under-explored. Here, we applied high-throughput sequencing to profile the error rates of DNA polymerases from psychrophilic, mesophilic, and thermophilic origins with single-molecule resolution. We found that reaction temperature substantially increases substitution and deletion error rates of psychrophilic and mesophilic DNA polymerases. Our motif analysis shows that the substitution error profiles cluster according to phylogenetic similarity of polymerases, not reaction temperature, thus suggesting that reaction temperature increases global error rate of polymerases independent of sequence context. Intriguingly, we also found that the DNA polymerase I of a psychrophilic bacteria exhibits higher polymerization activity than its mesophilic ortholog across all temperature ranges, including down to −19°C which is well below the freezing temperature of water. Our results provide a useful reference for how reaction temperature, a crucial parameter of biochemistry, can affect DNA polymerase fidelity in organisms adapted to a wide range of thermal environments.
Phenological displacement is uncommon among sympatric angiosperms
Authors: Park Daniel S. , Breckheimer Ian K. , Ellison Aaron M. , Lyra Goia M. , Davis Charles C.
Published: August 2020

Interactions between species can influence access to resources and successful reproduction. One possible outcome of such interactions is reproductive character displacement. Here, the similarity of reproductive traits – such as flowering time – among close relatives growing in sympatry differ more so than when growing apart. However, evidence for the overall prevalence and direction of this phenomenon, or the stability of such differences under environmental change, remains untested across large taxonomic and spatial scales. We apply data from tens of thousands of herbarium specimens to examine character displacement in flowering time across 110 animal-pollinated angiosperm species in the eastern USA. We demonstrate that the degree and direction of phenological displacement among co-occurring closely related species pairs varies tremendously. Overall, flowering time displacement in sympatry is not common. However, displacement is generally greater among species pairs that flower close in time, regardless of direction. We additionally identify that future climate change may alter the nature of phenological displacement among many of these species pairs. On average, flowering times of closely related species were predicted to shift further apart by the mid-21st century, which may have significant future consequences for species interactions and gene flow.
An elasticity-curvature illusion decouples cutaneous and proprioceptive cues in active exploration of soft objects
Authors: Xu Chang , Wang Yuxiang , Gerling Gregory J.
Published: August 2020

Our sense of touch helps us encounter the richness of our natural world. Across a myriad of contexts and repetitions, we have learned to deploy certain exploratory movements in order to elicit perceptual cues that are optimal and efficient. Such cues help us assess an object’s roughness, or stickiness, or as in this case, its softness. Leveraging empirical experiments combined with computational modeling of skin deformation, we develop a perceptual illusion for softness, or compliance, where small-compliant and large-stiff spheres are indiscriminable. The elasticity-curvature illusion, however, becomes readily discriminable when explored volitionally. This tactile illusion is unique because it naturally decouples proprioceptive cues from those involving identical, cutaneous contact attributes. Furthermore, the illusion sheds light into exactly how we explore soft objects, i.e., by volitionally controlling force, to optimally elicit and integrate proprioceptive cues amidst illusory cutaneous contact.
An Efficient Vector-based CRISPR/Cas9 System in anOreochromis mossambicusCell Line using Endogenous Promoters
Authors: Hamar Jens , Kültz Dietmar
Published: August 2020

CRISPR/Cas9 gene editing is effective in manipulating genetic loci in mammalian cell cultures and whole fish but efficient platforms applicable to fish cell lines are currently limited. Our initial attempts to employ this technology in fish cell lines using heterologous promoters or a ribonucleoprotein approach failed to indicate genomic alteration at targeted sites in a tilapia brain cell line (OmB). For potential use in a DNA vector approach, endogenous tilapia beta Actin (OmbAct), EF1 alpha (OmEF1a), and U6 (TU6) promoters were isolated. The strongest candidate promoter determined by EGFP reporter assay, OmEF1a, was used to drive constitutive Cas9 expression in a modified OmB cell line (Cas9-OmB1). Cas9-OmB1 cell transfection with vectors expressing gRNAs driven by the TU6 promoter achieved mutational efficiencies as high as 81% following hygromycin selection. Mutations were not detected using human and zebrafish U6 promoters demonstrating the phylogenetic proximity of U6 promoters as critical when used for gRNA expression. Sequence alteration to TU6 improved mutation rate and cloning efficiency. In conclusion, we report new tools for ectopic expression and a highly efficient, economical system for manipulation of genomic loci and evaluation of their causal relationship with adaptive cellular phenotypes by CRISPR/Cas9 gene editing in fish cells.
CIVET-Macaque: an automated pipeline for MRI-based cortical surface generation and cortical thickness in macaques
Authors: Lepage Claude , Wagstyl Konrad , Jung Benjamin , Seidlitz Jakob , Sponheim Caleb , Ungerleider Leslie , Wang Xindi , Evans Alan C. , Messinger Adam
Published: August 2020

The MNI CIVET pipeline for automated extraction of cortical surfaces and evaluation of cortical thickness fromin-vivohuman MRI has been extended for processing macaque brains. Processing is performed based on the NIMH Macaque Template (NMT), as the reference template, with the anatomical parcellation of the surface following the D99 and CHARM atlases. The modifications needed to adapt CIVET to the macaque brain are detailed. Results have been obtained using CIVET-macaque to process the anatomical scans of the 31 macaques used to generate the NMT and another 95 macaques from the PRIME-DE initiative. It is anticipated that the open usage of CIVET-macaque will promote collaborative efforts in data collection and processing, sharing, and automated analyses from which the non-human primate brain imaging field will advance.
Characterization of extracellular vesicles and synthetic nanoparticles with four orthogonal single-particle analysis platforms
Authors: Arab Tanina , Mallick Emily R. , Huang Yiyao , Dong Liang , Liao Zhaohao , Zhao Zezhou , Gololobova Olesia , Smith Barbara , Haughey Norman J. , Pienta Kenneth J. , Slusher Barbara S. , Tarwater Patrick M. , Tosar Juan Pablo , Zivkovic Angela M. , Vreeland Wyatt N. , Paulaitis Michael E. , Witwer Kenneth W.
Published: August 2020

We compared four orthogonal technologies for sizing, counting, and phenotyping of extracellular vesicles (EVs) and synthetic particles. The platforms were: single-particle interferometric reflectance imaging sensing (SP-IRIS) with fluorescence, nanoparticle tracking analysis (NTA) with fluorescence, microfluidic resistive pulse sensing (MRPS), and nanoflow cytometry measurement (NFCM). EVs from the human T lymphocyte line H9 (high CD81, low CD63) and the promonocytic line U937 (low CD81, high CD63) were separated from culture conditioned medium (CCM) by differential ultracentrifugation (dUC) or a combination of ultrafiltration (UF) and size exclusion chromatography (SEC) and characterized by transmission electron microscopy (TEM) and Western blot (WB). Mixtures of synthetic particles (silica and polystyrene spheres) with known sizes and/or concentrations were also tested. MRPS and NFCM returned similar particle counts, while NTA detected counts approximately one order of magnitude lower for EVs, but not for synthetic particles. SP-IRIS events could not be used to estimate particle concentrations. For sizing, SP-IRIS, MRPS, and NFCM returned similar size profiles, with smaller sizes predominating (per power law distribution), but with sensitivity typically dropping off below diameters of 60 nm. NTA detected a population of particles with a mode diameter greater than 100 nm. Additionally, SP-IRIS, MRPS, and NFCM were able to identify at least three of four distinct size populations in a mixture of silica or polystyrene nanoparticles. Finally, for tetraspanin phenotyping, the SP-IRIS platform in fluorescence mode was able to detect at least two markers on the same particle, while NFCM detected either CD81 or CD63. Based on the results of this study, we can draw conclusions about existing single-particle analysis capabilities that may be useful for EV biomarker development and mechanistic studies.
An acylsugar-deficientNicotiana benthamianastrain for aphid and whitefly research
Authors: Feng Honglin , Acosta-Gamboa Lucia , Kruse Lars H. , Tracy Jake D. , Chung Seung Ho , Nava Fereira Alba Ruth , Shakir Sara , Xu Hongxing , Sunter Garry , Gore Michael A. , Casteel Clare L. , Moghe Gaurav D. , Jander Georg
Published: August 2020

Nicotiana benthamianais used extensively as a platform for transient gene expression and as a model system for studying plant-virus interactions. However, many tobacco-feeding generalist herbivores, includingMyzus persicae(green peach aphid),Bemisia tabaci(whitefly),Macrosiphum euphorbiae(potato aphid),Heliothis virescens(tobacco budworm),Trichoplusia ni(cabbage looper), andHelicoverpa zea(corn earworm), grow poorly onN. benthamiana, limiting its utility for research on plant-insect interactions. Using CRISPR/Cas9, we generated knockout mutations in twoN. benthamianaacylsugar acyltransferases,ASAT1andASAT2, which contribute to the biosynthesis of insect-deterrent acylsucroses. Whereasasat1mutations reduced the abundance of two predominant acylsucroses,asat2mutations caused almost complete depletion of foliar acylsucroses. The tested hemipteran and lepidopteran species survived, gained weight, and/or reproduced significantly better onasat2mutant plants than on wildtypeN. benthamiana. Furthermore, bothasat1andasat2mutations reduced the water content and increased the temperature of leaves, indicating that foliar acylsucroses can protect against desiccation. Two experiments demonstrated the utility of theN. benthamiana asat2mutant line for insect bioassays. Transmission of turnip mosaic virus byM. persicaewas significantly improved by anasat2mutation. Tobacco rattle virus constructs were used for virus-induced gene silencing ofacetylcholinesterase,squalene synthase,toll-like receptor 7, andtubulin-specific chaperon Dgenes inB. tabaci, an experiment that would have been difficult with wild-typeN. benthamianadue to high insect mortality. Additionally, the absence of acylsugars inasat2mutant lines will simplify transient expression assays for the functional analysis of acylsugar biosynthesis genes from other Solanaceae.
Impairment of the Hif-1α regulatory pathway in Foxn1-deficient (Foxn1−/−) mice affects the skin wound healing process
Authors: Machcinska Sylwia , Kopcewicz Marta , Bukowska Joanna , Walendzik Katarzyna , Gawronska-Kozak Barbara
Published: August 2020

Hypoxia and hypoxia-regulated factors [e. g., hypoxia-inducible factor-1α (Hif-1α), factor inhibiting Hif-1α (Fih-1), thioredoxin-1 (Trx-1), aryl hydrocarbon receptor nuclear translocator 2 (Arnt-2)] have essential roles in skin wound healing. Using Foxn1−/−mice that can heal skin injuries in a unique scarless manner, we investigated the interaction between Foxn1 and hypoxia-regulated factors. The Foxn1−/−mice displayed impairments in the regulation of Hif-1α, Trx-1 and Fih-1 but not Arnt-2 during the healing process. An analysis of wounded skin showed that the skin of the Foxn1−/−mice healed in a scarless manner, displaying rapid re-epithelialization and an increase intransforming growth factor β(Tgfβ-3)andcollagen IIIexpression. Anin vitroanalysis revealed that Foxn1 overexpression in keratinocytes isolated from the skin of the Foxn1−/−mice led to reducedHif-1αexpression in normoxic but not hypoxic cultures and inhibitedFih-1expression exclusively under hypoxic conditions. These data indicate that in the skin, Foxn1 affects hypoxia-regulated factors that control the wound healing process and suggest that under normoxic conditions, Foxn1 is a limiting factor for Hif-1α.
A Review of Population Pharmacokinetic Studies of Levetiracetam
Authors: Li Zi-ran , Wang Chen-yu , Zhu Xiao , Jiao Zheng
Published: August 2020

Background

Levetiracetam has been widely used as a treatment option for different types of epilepsy in both adults and children. Because of its large between-subject variability, several population pharmacokinetic studies have been performed to identify its pharmacokinetic covariates, and thus facilitate individualised therapy.

Objective

The aim of this review was to provide a synopsis for population pharmacokinetic studies of levetiracetam and explore the identified influencing covariates.

Methods

We systematically searched the PubMed and Embase databases from inception to 30 June, 2020. The information on study designs, target population, model characteristics, and identified covariates was summarised. Moreover, the pharmacokinetic profiles were compared among neonates, children, and adults.

Results

Fourteen studies were included, among which 2 involved neonates, 4 involved children, 2 involved both children and adults, and 6 involved only adults. The median value of apparent clearance for children (0.074 [range: 0.038–0.079] L/h/kg) was higher than that for adults (0.054 [range: 0.039–0.061] L/h/kg). Body weight was found to significantly influence the apparent clearance and volume of distribution significantly, whereas renal function influenced the clearance. Likewise, co-administration with enzyme-inducing antiepileptic drugs (such as carbamazepine and phenytoin) increased the drug clearance by 9%–22%, whereas co-administration with valproate acid decreased it by 18.8%.

Conclusion

Levetiracetam dose regimen is dependent on the body size and renal function of patients. Further studies are needed to evaluate levetiracetam pharmacokinetics in neonates and pregnant women.

Key points

This review identifies weight, renal function, daily dose, and postmenstrual age as the covariates that most likely influence the levetiracetam (LEV) pharmacokinetics.

Children showed higher clearance per kilogram body weight than adults, indicating that a higher dosage is required for children per kilogram body weight.

Further PPK studies are needed to evaluate LEV pharmacokinetics in special populations such as pregnant women and neonates.
The prevalence and associated factors of adverse pregnancy outcomes among Afghan women in Iran; the possible impacts of domestic violence, poor mental health, housing issues, and food security
Authors: Dadras Omid , Nakayama Takeo , Kihara Mashiro , Kihara Masako-Ono , Seyedalinaghi Seyedahmad , Dadras Fateme
Published: August 2020

Backgrounds

Afghans are the largest refugee population in Iran and an estimated 2.5 million Afghans are living in the country. Although Afghan women constitute less than half of this population, they are young and at the childbearing ages. Evidence indicates lower rates of antenatal care and higher incidence of pregnancy complications in Afghan compared to Iranian women. In the present study, we aimed to explore the prevalence and associated sociodemographic factors of adverse pregnancy outcomes and examine the impact of intimate partner violence (IPV), food insecurity, poor mental health, and housing issues on pregnancy outcome in Afghan women living in Iran.

Methods

In July 2019, we enrolled 424 Afghan women aged 18-44 years old using the time-location sampling at three community health centers in the south region of Tehran province. The data was collected through face to face interviews using the researcher-developed questionnaire.

Results

More than half of Afghan women reported at least one pregnancy complication in their recent pregnancy. The results showed that illegal, illiterate, and unemployed Afghan women with lower socioeconomic status are more likely to experience adverse pregnancy outcomes. Furthermore, we observed lower prevalence of adverse pregnancy outcomes among legal immigrants with health insurance. It is also been found that food insecurity, poor antenatal care, IPV, and poor mental health could adversely impact the pregnancy outcome and we observed higher incidence of adverse outcomes among those suffering from these situations.

Conclusion

To our knowledge, this is the first study that explored the prevalence and associated factors of adverse pregnancy outcomes and the impact of intimate partner violence, food insecurity, poor mental health on pregnancy outcomes among Afghan women in Iran. Enhancing the psychosocial support and empowering Afghan women through expanding the social network and safety net should be a priority for the central government and international parties. Psychological counseling could be incorporated into routine maternity care for Afghan refugees. Access to free antenatal care is a right for all Afghan women and it could be facilitated by universal health insurance for all Afghans regardless of their legal status.
Discontinuity of the deadly infection rate for the COVID-19 pandemia due to lockdown measures
Authors: Vera Agustín Sabio
Published: August 2020

An asymmetric version of the classical Kermack-McKendrick description of an epidemic evolution is presented in terms of four independent parameters. This is enough to obtain an accurate description of the different stages of the COVID-19 pandemia in any country for the reported daily and total number of casualties due to the infection. The asymmetry accounts for lockdown effects introduced to reduce the impact of the epidemic outburst. A set of new variables allows for an analytic study of the evolution of the system before and after the lockdown measures are put in place. A continuous matching is possible for all variables in the system apart from the time dependence of the infection rate. An analytic expression is obtained for this discontinuity which is proposed as a good quantity to gauge the efficiency of the lockdown measures. A study of this variable for different countries is performed.
Impact of prenatal exome sequencing for fetal genetic diagnosis on maternal psychological outcomes and decisional conflict in a prospective cohort
Authors: Talati Asha N. , Gilmore Kelly L. , Hardisty Emily , Lyerly Anne D. , Rini Christine , Vora Neeta L.
Published: August 2020

Objective

To evaluate associations between prenatal trio exome sequencing (trio-ES) and psychological outcomes among women with an anomalous pregnancy.

Methods

Trio-ES study enrolling patients with major fetal anomaly and normal microarray. Women completed self-reported measures and free response interviews at two time points, pre- (1) and post- (2) sequencing. Pre-sequencing responses were compared to post-sequencing responses; post-sequencing responses were stratified by women who received trio-ES results that may explain fetal findings, secondary findings (medically actionable or carrier couple status), or negative results. Free responses were content analyzed.

Results

115 trios were enrolled. Of those, 41/115 (35.7%) received results from trio-ES, including 36 (31.3%) who received results that may explain the fetal phenotype. These women had greater post-sequencing distress compared to women who received negative results, including generalized distress (p=0.03) and test-related distress (p=0.2); they also had worse psychological adaptation to results (p=0.001). Genomic knowledge did not change from pre- to post-sequencing (p=0.51). Major themes from content analyses included closure, future pregnancy, altruism, anxiety, and gratitude.

Conclusions

Women show more distress after receiving trio-ES results compared to those who do not.
U.S. Field Hospitals: A Study on Public Health Emergency Response to COVID-19
Authors: Yuan Luorongxin , Sherryn Sherryn , Hu Peter , Chen Fenghao
Published: August 2020

With the number of confirmed COVID-19 cases rapidly growing in the U.S., many states are experiencing a shortage of hospital—especially ICU—beds. In addition to discharging non-critical patients, expanding local hospitals’ capacity as well as re-opening closed healthcare facilities, these states are actively building or converting public venues into field hospitals to fill the gap1. By studying these makeshift hospitals, we found that the states most severely impacted by the pandemic are fast at responding with the first wave of hospitals opening around the date of peak demand and the majority ready to use by the end of April. However, depending on the types of patients the field hospitals accept (COVID-19 vs. non-COVID-19) and how they are incorporated to local healthcare system, these field hospitals have utilization rate ranging from 100% to 0%. The field hospitals acting as alternative site to treat non-COVID-19 patients typically had low utilization rate and often faced the risk of COVID-19 outbreak in the facility. As overflow facilities, the field hospitals providing intensive care were highly relied on by local healthcare systems whereas the field hospitals dedicated to patients with mild symptoms often found it hard to fill the beds due to a combination of factors such as strict regulation on transferring patients from local hospitals, complication of health insurance discouraging health-seeking behavior, and effective public health measure to “flatten the curve” so that the additional beds were no longer needed.
Time-to-event estimation of birth prevalence trends: a method to enable investigating the etiology of childhood disorders including autism
Authors: MacInnis Alexander G.
Published: August 2020

An unbiased, widely accepted estimate of the rate of occurrence of new cases of autism over time would facilitate progress in understanding the causes of autism. The same may also apply to other disorders. While incidence is a widely used measure of occurrence, birth prevalence—the proportion of each birth year cohort with the disorder—is the appropriate measure for disorders and diseases of early childhood. Studies of autism epidemiology commonly speculate that estimates showing strong increases in rate of autism cases result from an increase in diagnosis rates rather than a true increase in cases. Unfortunately, current methods are not sufficient to provide a definitive resolution to this controversy. Prominent experts have written that it is virtually impossible to solve.

This paper presents a novel method, time-to-event birth prevalence estimation (TTEPE), to provide accurate estimates of birth prevalence properly adjusted for changing diagnostic factors. It addresses the shortcomings of prior methods. TTEPE is based on well-known time-to-event (survival) analysis techniques. A discrete survival process models the rates of incident diagnoses by birth year and age. Diagnostic factors drive the probability of diagnosis as a function of the year of diagnosis. TTEPE models changes in diagnostic criteria, which can modify the effective birth prevalence when new criteria take effect. TTEPE incorporates the development of diagnosable symptoms with age. General-purpose optimization software estimates all parameters, forming a non-linear regression. The paper specifies all assumptions underlying the analysis and explores potential deviations from assumptions and optional additional analyses.

A simulation study shows that TTEPE produces accurate parameter estimates, including trends in both birth prevalence and the probability of diagnosis in the presence of sampling effects from finite populations. TTEPE provides high power to resolve small differences in parameter values by utilizing all available data points.
Phenotyping the preterm brain: characterising individual deviations from normative volumetric development in two large infant cohorts
Authors: Dimitrova Ralica , Arulkumaran Sophie , Carney Olivia , Chew Andrew , Falconer Shona , Ciarrusta Judit , Wolfers Thomas , Batalle Dafnis , Cordero-Grande Lucilio , Price Anthony N. , Teixeira Rui PAG , Hughes Emer , Egloff Alexia , Hutter Jana , Makropoulos Antonios , Robinson Emma C. , Schuh Andreas , Vecchiato Katy , Steinweg Johannes K. , Macleod Russell , Marquand Andre F. , McAlonan Grainne , Rutherford Mary A. , Counsell Serena J. , Smith Stephen M. , Rueckert Daniel , Hajnal Joseph V. , O’Muircheartaigh Jonathan , Edwards A. David
Published: August 2020

The diverse cerebral consequences of preterm birth create significant challenges for understanding pathogenesis or predicting later outcome. Instead of focusing on describing effects common to the group, comparing individual infants against robust normative data offers a powerful alternative to study brain maturation. Here we used Gaussian process regression to create normative curves characterising brain volumetric development in 274 term-born infants, modelling for age at scan and sex. We then compared 89 preterm infants scanned at termequivalent age to these normative charts, relatingindividualdeviations from typical volumetric development to perinatal risk factors and later neurocognitive scores. To test generalisability, we used a second independent dataset comprising of 253 preterm infants scanned using different acquisition parameters and scanner. We describe rapid, non-uniform brain growth during the neonatal period. Inbothpreterm cohorts, cerebral atypicalities were widespread, often multiple, and varied highly between individuals. Deviations from normative development were associated with respiratory support, nutrition, birth weight, and later neurocognition, demonstrating their clinical relevance. Group-level understanding of the preterm brain disguise a large degree of individual differences. We provide a method and normative dataset that offer a more precise characterisation of the cerebral consequences of preterm birth by profiling theindividualneonatal brain.
Antigen-specific induction of CD4+CD8αα+intraepithelial T lymphocytes byBacteroidetesspecies
Authors: Bousbaine Djenet , Bhagchandani Preksha , London Mariya , Mimee Mark , Olesen Scott , Poyet Mathilde , Cheloha Ross W. , Sidney John , Ling Jingjing , Gupta Aaron , Lu Timothy K. , Sette Alessandro , Alm Eric J. , Mucida Daniel , Bilate Angelina M. , Ploegh Hidde L.
Published: August 2020

The microbiome contributes to the development and maturation of the immune system1–3In response to commensal bacteria, CD4+T cells can differentiate into distinct functional subtypes with regulatory or effector functions along the intestine. Peripherally-induced Foxp3+-regulatory T cells (pTregs) maintain immune homeostasis at the intestinal mucosa by regulating effector T cell responses against dietary antigens and microbes4. Similarly to pTregs, a subset of small intestine intraepithelial lymphocytes CD4+CD8αα+(CD4IELS) exhibit regulatory properties and promote tolerance against dietary antigens5. Development of CD4IELSfrom conventional CD4+T cells or from Treg precursors depends on the microbiota5,6. However, the identity of the microbial antigens recognized by CD4IELsremains unknown. We identified species belonging to theBacteroidetesphylum as commensal bacteria capable of generating CD4IELfrom naïve CD4+T cells expressing the pTreg transnuclear (TN) monoclonal TCR6as well as from polyclonal WT T cells. We found that β-hexosaminidase, a widely conserved carbohydrate-metabolizing enzyme in theBacteroidetesphylum, is recognized by TN T cells, which share their TCR specificity with CD4+T cells found in the intraepithelial compartment of polyclonal specific-pathogen-free (SPF) mice. In a mouse model of colitis, β-hexosaminidase-specific CD4IELsprovided protection from ulceration of the colon and weight loss. Thus, a single T cell clone can recognize a variety of abundant commensal bacteria and elicit a regulatory immune response at the intestinal epithelial surface.
Ventralis intermedius nucleus anatomical variability assessment by MRI structural connectivity
Authors: Ferreira Francisca , Akram Harith , Ashburner John , Zrinzo Ludvic , Zhang Hui , Lambert Christian
Published: August 2020

The ventralis intermedius nucleus (Vim) is centrally placed in the dentato-thalamo-cortical pathway (DTCp) and is a key surgical target in the treatment of severe medically refractory tremor. It is not visible on conventional MRI sequences; consequently, stereotactic targeting currently relies on atlas-based coordinates. This fails to capture individual anatomical variability, which may lead to poor long-term clinical efficacy. Probabilistic tractography, combined with known anatomical connectivity, enables localisation of thalamic nuclei at an individual subject level. There are, however, a number of confounds associated with this technique that may influence results.

Here we focused on an established method, using probabilistic tractography to reconstruct the DTCp, to identify the connectivity-defined Vim (cd-Vim)in vivo. Using 100 healthy individuals from the Human Connectome Project, our aim was to quantify cd-Vim variability across this population, measure the discrepancy with atlas-defined Vim (ad-Vim), and assess the influence of potential methodological confounds.

We found no significant effect of any of the confounds. The mean cd-Vim coordinate was located within 1.9 mm (left) and 2.1 mm (right) of the average midpoint and 4.9 mm (left) and 5.4 mm (right) from the ad-Vim coordinates. cd-Vim location was more variable on the right, which reflects hemispheric asymmetries in the probabilistic DTCp reconstructed. The superior cerebellar peduncle was identified as a potential source of artificial variance.

This work demonstrates significant individual anatomical variability of the cd-Vim that atlas-based approaches fail to capture. This variability was not related to any methodological confound tested. Lateralisation of cerebellar functions, such as speech, may contribute to the observed asymmetry. Tractography-based methods seem sensitive to individual anatomical variability that is missed by conventional neurosurgical targeting; These findings may form the basis for translational tools to improve efficacy and reduce side-effects of thalamic surgery for tremor.

Highlights

Connectivity-based Vim position varied markedly between subjects and from atlas-defined coordinates.

This positional variability was not related to any methodological confound tested.

Hemispheric asymmetry was observed in connectivity-based Vim position.

We hypothesise lateralization of cerebellar functions, such as language, may contribute to asymmetry.

Knowledge of Vim position variability could help inform neurosurgical planning in the management of tremor.
H3 K27M and EZHIP impede H3K27-methylation spreading by inhibiting allosterically stimulated PRC2
Authors: Jain Siddhant U. , Rashoff Andrew Q. , Krabbenhoft Samuel D. , Hoelper Dominik , Do Truman J. , Gibson Tyler J. , Lundgren Stefan M , Bondra Eliana R. , Deshmukh Shriya , Harutyunyan Ashot S. , Juretic Nikoleta , Jabado Nada , Harrison Melissa M. , Lewis Peter W.
Published: August 2020

Diffuse midline gliomas and posterior fossa type-A ependymomas contain the highly recurrent histone H3 K27M mutation and the H3 K27M-mimic EZHIP, respectively.In vitro, H3 K27M and EZHIP are competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity.In vivo, these proteins reduce overall H3K27me3 levels, however residual peaks of H3K27me3 remain at CpG islands through an unknown mechanism. Here, we report that EZHIP and H3 K27M preferentially interact with an allosterically activated form of PRC2in vivo. The formation of H3 K27M- and EZHIP-PRC2 complexes occurs at CpG islands containing H3K27me3 and impedes PRC2 and H3K27me3 spreading. While EZHIP is not found outside of placental mammals, we find that expression of human EZHIP reduces H3K27me3 inDrosophila melanogasterthrough a conserved molecular mechanism. Our results highlight the mechanistic similarities between EZHIP and H3 K27Min vivoand provide mechanistic insight for the retention of residual H3K27me3 in tumors driven by these oncogenes.
Astrocytes dystrophy in ageing brain parallels impaired synaptic plasticity
Authors: Popov Alexander , Brazhe Alexey , Denisov Pavel , Sutyagina Oksana , Lazareva Natalia , Verkhratsky Alexei , Semyanov Alexey
Published: August 2020

Little is known about age-dependent changes in structure and function of astrocytes and of the impact of these into the cognitive decline in the senescent brain. The prevalent view on age-dependent increase in reactive astrogliosis and astrocytic hypertrophy requires scrutiny and detailed analysis. Using two-photon microscopy in conjunction with 3D reconstruction, Sholl and volume fraction analysis we demonstrate a significant reduction in the number and the length of astrocytic processes, in astrocytic territorial domains and in astrocyte-to-astrocyte coupling in the aged brain. Probing physiology of astrocytes with patch-clamp and Ca2+imaging revealed deficits in K+and glutamate clearance, and spatiotemporal reorganization of Ca2+events in old astrocytes. These changes paralleled impaired synaptic long-term potentiation (LTP) in hippocampal CA1 in old mice. Our findings may explain astroglial mechanisms of age-dependent decline in learning and memory.
ADEP1 activated ClpP1P2 macromolecule ofLeptospira, an ideal Achilles’ heel to deregulate proteostasis and hamper the cell survival
Authors: Dhara Anusua , Hussain Md Saddam , Kanaujia Shankar Prasad , Kumar Manish
Published: August 2020

The caseinolytic protease (ClpP) complex inLeptospira interrogansis unusual in its functional activation. The genusLeptospirahas two ClpPs, ClpP1 and ClpP2, which transcribes independently, regardless it couples to form the active tetradecamer. Acyldepsipeptide (ADEP) antibiotic hampers the growth of numerous bacterial species by activating the target protein ClpP and dysregulating the physiological proteostasis within the cell.In vitroculture of theL. interrogansfortified with the ADEP impeded the spirochete growth accompanied by a more elongated morphology. The chemoactivation of the ClpP is conditional on the duration of the self-compartmentalization of each of the ClpP isoforms. The small extent (10 min) self-assembled ClpP1P2 revealed inhibition in the peptidase activity (7-fold) in the presence of the ADEP due to the self-cleavage of the ClpP subunits. On supplementation of the β-casein or bovine serum albumin, the peptidase activity of the ClpP1P2 (short-incubated) got enhanced by the ADEP, while the ClpP1P2 (long-incubated) activity was retained to the same level. ADEP can also switch on the ClpP1P2 from a strict peptidase into proteolytic machinery that discerns and degrades the unfolded protein substrates autonomous of the cognate chaperone ClpX. In consensus to the most prokaryotes with the multi ClpP variants, the computational prototype of the ClpP1P2 tertiary structure infers that the hydrophobic pocket wherein the ADEPs predominantly docks are present in the ClpP2 heptamer. Additionally, the dynamic light scattering and the site-directed mutagenesis of a catalytic serine residue in either of the ClpP isoforms proposes a second interaction site for the ADEP.
3D imaging and morphometry of the heart capillary system in spontaneously hypertensive rats and normotensive controls
Authors: Olianti Camilla , Costantini Irene , Giardini Francesco , Lazzeri Erica , Crocini Claudia , Ferrantini Cecilia , Pavone Francesco Saverio , Camici Paolo Guido , Sacconi Leonardo
Published: August 2020

Systemic arterial hypertension is a highly prevalent chronic disease associated with hypertensive cardiomyopathy. One important feature of this condition is remodelling of intramural small coronary arteries and arterioles. Here, we investigated the implications of this remodelling in the downstream vascular organization, in particular at the capillary level. We used Spontaneously Hypertensive Rats (SHR) exhibiting many features of the human hypertensive cardiomyopathy. We generated 3D high-resolution mesoscopic reconstructions of the entire network of SHR hearts combining gel-based fluorescent labelling of coronaries with a CLARITY-based tissue clearing protocol. We performed morphometric quantification of the capillary network over time to assess capillary diameter, linear density, and angular dispersion. In SHRs, we found significant remodelling of the capillary network density and dispersion. SHR capillary density is increased in both ventricles and at all ages, including before the onset of systemic hypertension. This result suggests that remodelling occurs independently from the onset of systemic hypertension and left ventricular hypertrophy. On the contrary, capillary angular dispersion increases with time in SHR. Consistently, our multi-modal imaging underlined a strong correlation between vascular dispersion and cellular disarray. Together our data show that 3D high-resolution reconstruction of the capillary network can unveil anatomic signatures in both physiological and pathological cardiac conditions, thus offering a reliable method for integrated quantitative analyses.
Failure to modulate reward prediction errors in declarative learning with theta (6 Hz) frequency transcranial alternating current stimulation
Authors: Ergo Kate , De Loof Esther , Debra Gillian , Pastötter Bernhard , Verguts Tom
Published: August 2020

Recent evidence suggests that reward prediction errors (RPEs) play an important role in declarative learning, but its neurophysiological mechanism remains unclear. Here, we tested the hypothesis that RPEs modulate declarative learning via theta-frequency oscillations, which have been related to memory encoding in prior work. For that purpose, we examined the interaction between RPE and transcranial Alternating Current Stimulation (tACS) in declarative learning. Using a between-subject (real versus sham stimulation group), single-blind stimulation design, 76 participants learned 60 Dutch-Swahili word pairs, while theta-frequency (6 Hz) tACS was administered over the medial frontal cortex (MFC). Previous studies have implied MFC in memory encoding. We replicated our previous finding of signed RPEs (SRPEs) boosting declarative learning; with larger and more positive RPEs enhancing memory performance. However, tACS failed to modulate the SRPE effect in declarative learning and did not affect memory performance. Bayesian statistics supported evidence for an absence of effect. Our study confirms a role of RPE in declarative learning, but also calls for standardized procedures in transcranial electrical stimulation.
Friendly-rivalry solution to the iteratedn-person public-goods game
Authors: Murase Yohsuke , Baek Seung Ki
Published: August 2020

Repeated interaction promotes cooperation among rational individuals under the shadow of future, but it is hard to maintain cooperation when a large number of error-prone individuals are involved. One way to construct a cooperative Nash equilibrium is to find a ‘friendly rivalry’ strategy, which aims at full cooperation but never allows the co-players to be better off. Recently it has been shown that for the iterated Prisoner’s Dilemma in the presence of error, a friendly rival can be designed with the following five rules: Cooperate if everyone did, accept punishment for your own mistake, punish defection, recover cooperation if you find a chance, and defect in all the other circumstances. In this work, we construct such a friendly-rivalry strategy for the iteratedn-person public-goods game by generalizing those five rules. The resulting strategy makes a decision with referring to the previousm= 2n− 1 rounds. A friendly-rivalry strategy inherently has evolutionary robustness in the sense that no mutant strategy has higher fixation probability in this population than that of neutral drift, and our evolutionary simulation indeed shows excellent performance of the proposed strategy in a broad range of environmental conditions.

Author summary

How to maintain cooperation among a number of self-interested individuals is a difficult problem, especially if they can sometimes commit error. In this work, we propose a strategy for the iteratedn-person public-goods game based on the following five rules: Cooperate if everyone did, accept punishment for your own mistake, punish others’ defection, recover cooperation if you find a chance, and defect in all the other circumstances. These rules are not far from actual human behavior, and the resulting strategy guarantees three advantages: First, if everyone uses it, full cooperation is recovered even if error occurs with small probability. Second, the player of this strategy always never obtains a lower long-term payoff than any of the co-players. Third, if the co-players are unconditional cooperators, it obtains a strictly higher long-term payoff than theirs. Therefore, if everyone uses this strategy, no one has a reason to change it. Furthermore, our simulation shows that this strategy will become highly abundant over long time scales due to its robustness against the invasion of other strategies. In this sense, the repeated social dilemma is solved for an arbitrary number of players.
A unique neurogenomic state emerges after aggressive confrontations in males of the fishBetta splendens
Authors: Vu Trieu-Duc , Iwasaki Yuki , Oshima Kenshiro , Nikaido Masato , Chiu Ming-Tzu , Okada Norihiro
Published: August 2020

Territorial defense involves frequent aggressive confrontations with competitors, but little is known about how brain-transcriptomic profiles change between individuals competing for territory establishment. Our previous study elucidated that brain-transcriptomic synchronization occurs in a pair-specific manner between two males of the fishBetta splendensduring fighting, reflecting a mutual assessment process between them at the level of gene expression. Here we evaluated how the brain-transcriptomic profiles of opponents change immediately after shifting their social status (i.e., the winner/loser has emerged) and 30 min after this shift. We showed that unique and carryover hypotheses can be adapted to this system, in which changes in the expression of certain genes are unique to different fighting stages and in which the expression patterns of certain genes are transiently or persistently changed across all fighting stages. Interestingly, the specificity of the brain-transcriptomic synchronization of a pair during fighting was gradually lost after fighting ceased, because of the decrease in the variance in gene expression across all individuals, leading to the emergence of a basal neurogenomic state. Strikingly, this unique state was more basal than the state that existed in the before-fighting group and resulted in the reduced and consistent expression of genes across all individuals. In spite of the consistent and basal overall gene expression in each individual in this state, expression changes for genes related to metabolism, learning and memory, and autism still differentiated losers from winners. The fighting system using maleB. splendensthus provides a promising platform for investigating neurogenomic states of aggression in vertebrates.

Author summary

Competitive interactions involve complex decision-making tasks that are shaped by mutual feedback between participants. When two animals interact, transcriptomes across their brains synchronize in a way that reflects how they assess and predict the other’s fighting ability and react to each other’s decisions. Here, we elucidated the gradual loss of brain-transcriptomic synchrony between interacting opponents after their interaction ceased, leading to the emergence of a basal neurogenomic state, in which the variations in gene expression were reduced to a minimum among all individuals. This basal neurogenomic state shares common characteristics with the hibernation state, which animals adopt to minimize their metabolic rates to cope with harsh environmental conditions. We demonstrated that this unique neurogenomic state, which is newly characterized in the present study, is composed of the expression of a unique set of genes, each of which was presumably minimally required for survival, providing a hypothesis that this state represents the smallest unit of neurogenomic activity for sustaining an active life.