bluuebunny/crossref_metadata_2025 huggingface dataset:
Unicellular associative conditioning: an interspecies analysis
Authors: Carrasco-Pujante Jose , Bringas Carlos , Malaina Iker , Fedetz Maria , Martínez Luis , Pérez-Yarza Gorka , Boyano María Dolores , Berdieva Mariia , Goodkov Andrew , I. López José , Knafo Shira , Fuente Ildefonso M. De la
Published: October 2020

The capacity to learn new systemic behaviour is a fundamental issue to understand the adaptive mechanisms involved in cellular evolution. We have recently observed, in a preliminary analysis, the emergence of conditioned behaviour in individual amoebae cells. In these experiments, cells were able to acquire new migratory conduct and remember it for long periods of their cellular cycle, forgetting it later on. Here, following a similar conceptual framework of Pavlov’s experiments, we have exhaustively studied the migration trajectories of more than 2000 individual cells belonging to three different species:Amoeba proteus, Metamoeba leningradensis, andAmoeba borokensis. Fundamentally, we have analysed several properties of conditioned cells, such as the intensity of the responses, the directionality persistence, the total distance traveled, the directionality ratio, the average speed, and the persistence times. We have observed that these three species can modify the systemic response to a specific stimulus by associative conditioning. Our main analysis shows that such new behaviour is very robust and presents a similar structure of migration patterns in the three species, which was characterized by the presence of conditioning for long periods, remarkable straightness in their trajectories and strong directional persistence. Our quantitative results, compared with other studies on complex cellular responses in bacteria, protozoa, fungus-like organisms and metazoans, allow us to conclude that cellular associative conditioning might be a widespread characteristic of unicellular organisms. This finding could be essential to understand some key evolutionary principles involved in increasing the cellular adaptive fitness to microenvironments.
Phylostems: a new graphical tool to investigate temporal signal of heterochronous sequences at various evolutionary scales
Authors: Doizy Anna , Prin Amaury , Cornu Guillaume , Chiroleu Frederic , Rieux Adrien
Published: October 2020

Molecular tip-dating of phylogenetic trees is a growing discipline that uses DNA sequences sampled at different points in time to co-estimate the timing of evolutionary events with rates of molecular evolution. Such inferences should only be performed when there is sufficient temporal signal within the analysed dataset. Hence, it is important for researchers to be able to test their dataset for the amount and consistency of temporal signal prior to any tip-dating inference. For this purpose, the most popular method considered to-date has been the “root-to-tip regression” which consist in fitting a linear regression of the number of substitutions accumulated from the root to the tips of a phylogenetic tree as a function of sampling times. The main limitation of the regression method, in its current implementation, relies in the fact that the temporal signal can only be tested at the whole-tree evolutionary scale.

To fill this methodological gap, we introduce phylostems, a new graphical and user-friendly tool developed to investigate temporal signal at every evolutionary scale of a phylogenetic tree.

Phylostems allows detecting withouta prioriwhether any subset of a tree would contain sufficient temporal signal for tip-based inference to be performed. We provide a “how to” guide by running phylostems on empirical datasets and supply guidance for results interpretation. Phylostems is freely available athttps://pvbmt-apps.cirad.fr/apps/phylostems.

Considering the impressive increase in availability and use of heterochronous datasets, we hope the new functionality provided by phylostems will help biologists to perform thorough tip-dating inferences.
Prevalence of COVID-19 in Adolescents and Youth Compared with Older Adults in States Experiencing Surges
Authors: Rumain Barbara T. , Schneiderman Moshe , Geliebter Allan
Published: October 2020

PURPOSE

There has been considerable controversy regarding susceptibility of adolescents (10-19 years) and youth (15-24 years) to COVID-19. However, a number of studies have reported that adolescents are significantly less susceptible than older adults. Summer 2020 provided an opportunity to examine data on prevalence since after months of lockdowns, with the easing of restrictions, people were mingling, leading to surges in cases.

METHODS

We examined data from six U.S. states experiencing surges in the number of cases to determine prevalence of COVID-19, and two other measures, related to prevalence in adolescents and youth as compared to older adults. The two other measures were: (Percentage of cases observed in a given age group) ÷ (percentage of cases expected based on population demographics); and percentage deviation, or [(% observed - % expected)/ % expected] x 100.

RESULTS

Prevalence of COVID-19 for adolescents and for youth was significantly greater than for older adults (p<.00001), as was percentage observed ÷ percentage expected (p<.005). The percentage deviation was significantly greater in adolescents/youth than in older adults (p < 0.00001) when there was an excess of observed cases over what was expected, and significantly less when observed cases were fewer than expected (p< 0.00001).

CONCLUSIONS

Our results are contrary to previous findings that adolescents are less susceptible than older adults. The findings have implications for school re-openings. The age groups 10-19 and 15-24 are students in middle school, high school, college, and the first two years of professional/graduate school. The high prevalence in these age groups would argue against school re-openings in the near future.
Death by scientific method: Estimated mortality associated with the failure to conduct routine prospective cumulative systematic reviews in medicine and public health
Authors: Hahn Robert A. , Teutsch Steven M.
Published: October 2020

Failure to routinely assess the state of knowledge as new studies accumulate results in 1) non-use of effective interventions, 2) continued use of ineffective or harmful interventions, and 3) unnecessary research. We use a published cumulative meta-analysis of interventions to reduce the harms of acute myocardial infarctions (1966-1992), and applied population attributable risk to assess the mortality consequences of the failure to cumulatively assess the state of knowledge. Failure to use knowledge that would have been available with cumulative meta-analysis may have resulted in annual estimated mortality: 41,000 deaths from non-use of intravenous dilators, 35,000 deaths from non-use of aspirin, and 37,000 deaths annually from non-use of ß-blockers. Continued use of Class 1 anti-arrhythmic drugs, which would have been found to be harmful in 1981, resulted 39,000 deaths annually. Failure to routinely update the state knowledge can have large health consequences. The process of building knowledge and practice in medicine and public health needs fundamental revision.
Uncovering the mechanisms of real-world attentional control over the course of primary education
Authors: Turoman Nora , Tivadar Ruxandra I. , Retsa Chrysa , Maillard Anne M. , Scerif Gaia , Matusz Pawel J.
Published: October 2020

Schooling may shape children’s abilities to control their attention, but it is unclear if this impact extends from control over visual objects to encompass multisensory objects, which are more typical of everyday environments. We compared children across three primary school grades ([country] 1st, 3rd, and 5thgrade) on their performance on a game-like audio-visual attentional control task, while recording their EEG. Behavioral markers ofvisualattentional control were present from 3rdgrade (after 2 years of schooling), whereas multisensory attentional control was not detected in any group. However, multivariate whole-brain EEG analyses (‘electrical neuroimaging’) revealed stable patterns of brain activity that indexed both types of attentional control – visual control in all groups, and multisensory attentional control from 3rdgrade onwards. Multivariate EEG approaches can uncover otherwise undetectable mechanisms of attentional control over visual and multisensory objects and characterize how they differ at different educational stages.

Lay Abstract

We measured how visual and audiovisual distractors differ in capturing the attention of 1st- to 5th-graders while recording the children’s brain activity. Brain activity results showed that all children were sensitive to visual distraction, and from 3rdgrade onwards, children were also sensitive to audiovisual distraction. These results deepen our understanding of how school children control their attention in everyday environments, which are made up of information that stimulates multiple senses at a time.
SpecSeg: cross spectral power-based segmentation of neurons and neurites in chronic calcium imaging datasets
Authors: de Kraker Leander , Seignette Koen , Thamizharasu Premnath , van den Boom Bastijn J. G. , Pica Ildefonso Ferreira , Willuhn Ingo , Levelt Christiaan N. , van der Togt Chris
Published: October 2020

Imaging calcium signals in neurons of awake, behaving animals using single- or multi-photon microscopy facilitates the study of coding in large neural populations. Such experiments produce massive datasets requiring powerful methods to extract responses from hundreds of neurons. We present SpecSeg, a new open-source toolbox for 1) segmentation of regions of interest (ROIs) representing neuronal structures, 2) inspection and manual editing of ROIs, 3) neuropil correction and signal extraction and 4) matching of ROIs in sequential recordings. SpecSeg uses a novel method for ROI registration, based on temporal cross-correlations of low-frequency components derived by Fourier analysis, of each pixel with its neighbors. The approach is insightful and enables ROI detection around neurons or neurites. It works for single- (miniscope) and multi-photon microscopy data, eliminating the need for separate toolboxes. SpecSeg thus provides an efficient and user-friendly approach for analyzing calcium responses in neuronal structures imaged over prolonged periods of time.
Thermosensitivity of the voltage-dependent activation of calcium homeostasis modulator 1 (calhm1) ion channel
Authors: Jeon Young Keul , Choi Si Won , Kwon Jae Won , Woo Joohan , Choi Seong Woo , Kim Sang Jeong , Kim Sung Joon
Published: October 2020

Calcium homeostasis modulator 1 (calhm1) proteins form an outwardly rectifying nonselective ion channel having exceedingly slow kinetics and low sensitivity to voltage that is shifted by lowering extracellular Ca2+([Ca2+]e). Here we found that physiological temperature dramatically facilitates the voltage-dependent activation of the calhm1 current (Icalhm1); increased amplitude (Q10, 7-15) and fastened speed of activation. Also, the leftward shift of the half-activation voltage (V1/2) was similary observed in the normal and lower [Ca2+]e. Since calhm1 is highly expressed in the brain and taste cells, the thermosensitivity should be considered in their electrophysiology.
HIV-1 gp120 impairs spatial memory through CREB
Authors: Shrestha Jenny , Santerre Maryline , Allen Charles NS , Arjona Sterling P , Mukerjee Ruma , Park Jin , Bagashev Asen , Wang Ying , Kaul Marcus , Chin Jeannie , Sawaya Bassel E
Published: October 2020

HIV-associated neurocognitive disorders (HAND) remains an unsolved problem in the clinical management of HIV-1 carriers, because existing anti-retroviral therapy while suppressing viral replication, do not prevent neurocognitive impairment (e.g. spatial memory loss). HIV-1 gp120 protein has been proposed to contribute to HAND because it is shed by infected cells and the use of antibodies revealed its presence in cerebrospinal fluid (CSF) even in the combinatory antiretroviral therapy (cART) era. The cyclic AMP response element-binding protein (CREB) has long been known to be a star player in memory. CREB exerts its effect partially through regulating the genes for peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and brain-derived neurotrophic factor (BDNF). CREB, PGC-1α, and BDNF levels are low in the brains of patients with neurodegenerative diseases and a dearth of either protein is associated with cognitive decline. We have obtained data showing that gp120 contributes to neurodegeneration by altering CREB phosphorylation on serine residue 133 thus disrupting mitochondrial movement and synaptic plasticity leading to spatial memory loss. Inhibition of CREB function was also associated with a decrease of ATP levels and lower mitochondrial DNA copy numbers. Our data was validatedin vitro(primary mouse neurons and neuronal cell line, SH-SY5Y) andin vivo(gp120-tg mice and mice injected with gp120). The negative effect of gp120 was alleviated in cells and animals in the presence of Rolipram. Hence, we conclude that HIV-1 gp120 protein contributes to spatial memory impairment via inhibition of CREB protein activity.
selfRL: Two-Level Self-Supervised Transformer Representation Learning for Link Prediction of Heterogeneous Biomedical Networks
Authors: Wang Xiaoqi , Yang Yaning , Liao Xiangke , Li Lenli , Li Fei , Peng Shaoliang
Published: October 2020

Predicting potential links in heterogeneous biomedical networks (HBNs) can greatly benefit various important biomedical problem. However, the self-supervised representation learning for link prediction in HBNs has been slightly explored in previous researches. Therefore, this study proposes a two-level self-supervised representation learning, namely selfRL, for link prediction in heterogeneous biomedical networks. The meta path detection-based self-supervised learning task is proposed to learn representation vectors that can capture the global-level structure and semantic feature in HBNs. The vertex entity mask-based self-supervised learning mechanism is designed to enhance local association of vertices. Finally, the representations from two tasks are concatenated to generate high-quality representation vectors. The results of link prediction on six datasets show selfRL outperforms 25 state-of-the-art methods. In particular, selfRL reveals great performance with results close to 1 in terms of AUC and AUPR on the NeoDTI-net dataset. In addition, the PubMed publications demonstrate that nine out of ten drugs screened by selfRL can inhibit the cytokine storm in COVID-19 patients. In summary, selfRL provides a general frame-work that develops self-supervised learning tasks with unlabeled data to obtain promising representations for improving link prediction.
eDNA metabarcoding outperforms traditional fisheries sampling and reveals fine-scale heterogeneity in a temperate freshwater lake
Authors: Gehri Rebecca R , Larson Wesley A. , Gruenthal Kristen , Sard Nicholas , Shi Yue
Published: October 2020

Understanding biodiversity in aquatic systems is critical to ecological research and conservation efforts, but accurately measuring species richness using traditional methods can be challenging. Environmental DNA (eDNA) metabarcoding, which uses high-throughput sequencing and universal primers to amplify DNA from multiple species present in an environmental sample, has shown great promise for augmenting results from traditional sampling to characterize fish communities in aquatic systems. Few studies, however, have compared exhaustive traditional sampling with eDNA metabarcoding of corresponding water samples at a small spatial scale. We intensively sampled Boardman Lake (137 ha) in Michigan, USA from May to June in 2019 using gill and fyke nets and paired each net set with lake water samples collected in triplicate. We analyzed water samples using eDNA metabarcoding with 12S and 16S fish-specific primers and compared estimates of fish diversity among methods. In total, we set 60 nets and analyzed 180 1 L lake water samples. We captured a total of 12 fish species in our traditional gear and detected 40 taxa in the eDNA water samples, which included all the species observed in nets. The 12S and 16S assays detected a comparable number of taxa, but taxonomic resolution varied between the two genes. In our traditional gear, there was a clear difference in the species selectivity between the two net types, and there were several species commonly detected in the eDNA samples that were not captured in nets. Finally, we detected spatial heterogeneity in fish community composition across relatively small scales in Boardman Lake with eDNA metabarcoding, but not with traditional sampling. Our results demonstrated that eDNA metabarcoding was substantially more efficient than traditional gear for estimating community composition, highlighting the utility of eDNA metabarcoding for assessing species diversity and informing management and conservation.
dStripe: slice artefact correction in diffusion MRI via constrained neural network
Authors: Pietsch Maximilian , Christiaens Daan , Hajnal Joseph V , Tournier J-Donald
Published: October 2020

MRI scanner and sequence imperfections and advances in reconstruction and imaging techniques to increase motion robustness can lead to inter-slice intensity variations in Echo Planar Imaging. Leveraging deep convolutional neural networks as universal image filters, we present a data-driven method for the correction of acquisition artefacts that manifest as inter-slice inconsistencies, regardless of their origin. This technique can be applied to motion- and dropout-artefacted data by embedding it in a reconstruction pipeline. The network is trained in the absence of ground-truth data on, and finally applied to, the reconstructed multi-shell high angular resolution diffusion imaging signal to produce a corrective slice intensity modulation field. This correction can be performed in either motion-corrected or scattered source-space. We focus on gaining control over the learned filter and the image data consistency via built-in spatial frequency and intensity constraints. The end product is a corrected image reconstructed from the original raw data, modulated by a multiplicative field that can be inspected and verified to match the expected features of the artefact. In-plane, the correction approximately preserves the contrast of the diffusion signal and throughout the image series, it reduces interslice inconsistencies within and across subjects without biasing the data. We apply our pipeline to enhance the super-resolution reconstruction of neonatal multi-shell high angular resolution data as acquired in the developing Human Connectome Project.
Multivariate Meta-Analysis of Differential Principal Components underlying Human Primed and Naive-like Pluripotent States
Authors: Johnson Kory R. , Mallon Barbara S. , Fann Yang C. , Chen Kevin G.
Published: October 2020

The ground or naive pluripotent state of human pluripotent stem cells (hPSCs), which was initially established in mouse embryonic stem cells (mESCs), is an emerging and tentative concept. To verify this important concept in hPSCs, we performed a multivariate meta-analysis of major hPSC datasets via the combined analytic powers of percentile normalization, principal component analysis (PCA),t-distributed stochastic neighbor embedding (t-SNE), and SC3 consensus clustering. This vigorous bioinformatics approach has significantly improved the predictive values of the current meta-analysis. Accordingly, we were able to reveal various similarities between some naive-like hPSCs (NLPs) and their human and mousein vitrocounterparts. Moreover, we also showed numerous fundamental inconsistencies between diverse naive-like states, which are likely attributed to interlaboratory protocol differences. Collectively, our meta-analysis failed to provide global transcriptomic markers that support a bona fide human naive pluripotent state, rather suggesting the existence of altered pluripotent states under current naive-like growth protocols.
A predictive model of antibody binding in the presence of IgG-interacting bacterial surface proteins
Authors: Ahnlide Vibha Kumra , de Neergaard Therese , Sundwall Martin , Ambjörnsson Tobias , Nordenfelt Pontus
Published: October 2020

Many bacteria can interfere with how antibodies bind to their surfaces. This bacterial antibody targeting makes it challenging to predict the immunological function of bacteria-associated antibodies. The M and M-like proteins of group A streptococci exhibit IgGFc-binding regions, which they use to reverse IgG binding orientation depending on the host environment. Unraveling the mechanism behind these binding characteristics may identify conditions under which bound IgG can drive an efficient immune response. Here, we have developed a biophysical model for describing these complex protein-antibody interactions. We show how the model can be used as a tool for studying various IgG samples’ behaviour by performing in silico simulations and correlating this data with experimental measurements. Besides its use for mechanistic understanding, this model could potentially be used as a tool to predict the effect, as well as aid in the development of antibody treatments. We illustrate this by simulating how IgG binding in serum is altered as specified amounts of monoclonal or pooled IgG is added. Phagocytosis experiments link this altered antibody binding to a physiological function and demonstrate that it is possible to predict the effect of an IgG treatment with our model. Our study gives a mechanistic understanding of bacterial antibody targeting and provides a tool for predicting the effect of antibody treatments.
An organ-based multi-level model for glucose homeostasis: organ distributions, timing, and impact of blood flow
Authors: Herrgårdh Tilda , Li Hao , Nyman Elin , Cedersund Gunnar
Published: October 2020

Glucose homeostasis is the tight control of glucose in the blood. This complex control is important and not yet sufficiently understood, due to its malfunction in serious diseases like diabetes. Due to the involvement of numerous organs and sub-systems, each with their own intra-cellular control, we have developed a multi-level mathematical model, for glucose homeostasis, which integrates a variety of data. Over the last 10 years, this model has been used to insert new insights from the intra-cellular level into the larger whole-body perspective. However, the original cell-organ-body translation has during these years never been updated, despite several critical shortcomings, which also have not been resolved by other modelling efforts. For this reason, we here present an updated multi-level model. This model provides a more accurate sub-division of how much glucose is being taken up by the different organs. Unlike the original model, we now also account for the different dynamics seen in the different organs. The new model also incorporates the central impact of blood flow on insulin-stimulated glucose uptake. Each new improvement is clear upon visual inspection, and they are also supported by statistical tests. The final multi-level model describes >300 data points in >40 time-series and dose-response curves, resulting from a large variety of perturbations, describing both intra-cellular processes, organ fluxes, and whole-body meal responses. We hope that this model will serve as an improved basis for future data integration, useful for research and drug developments within diabetes.
Collagen fibre-mediated mechanical damage increases calcification of bovine pericardium for use in bioprosthetic heart valves
Authors: Whelan Alix , Williams Elizabeth , Fitzpatrick Emma , Murphy Bruce , Gunning Paul S. , O’Reilly David , Lally Caitríona
Published: October 2020

In cases of aortic stenosis, bioprosthetic heart valves (BHVs), with leaflets made from glutaraldehyde fixed bovine pericardium (GLBP), are often implanted to replace the native diseased valve. Widespread use of these devices, however, is restricted due to inadequate long-term durability owing specifically to premature leaflet failure. Mechanical fatigue damage and calcification remain the primary leaflet failure modes, where glutaraldehyde treatment is known to accelerate calcification. The literature in this area is limited, with some studies suggesting mechanical damage increases calcification and others that they are independent degenerative mechanisms. In this study, specimens which were non-destructively pre-sorted according to collagen fibre architecture and then uniaxially cyclically loaded until failure or 1 million cycles, were placed in anin-vitrocalcification solution. Measurements of percentage volume calcification demonstrated that the weakest specimen group (those with fibres aligned perpendicular to the load) had statistically significantly higher volumes of calcification when compared to those with a high fatigue life. Moreover, SEM imaging revealed that ruptured and damaged fibres presented binding sites for calcium to attach; resulting in more than 4 times the volume of calcification in fractured samples when compared to those which did not fail by fatigue. To the authors’ knowledge, this study quantifies for the first time, that mechanical damage drives calcification in commercial-grade GLBP and that this calcification varies spatially according to localised levels of damage. These findings illustrate that not only is calcification potential in GLBP exacerbated by fatigue damage, but that both failure phenomena are underpinned by the unloaded collagen fibre organisation. Consequently, controlling for GLBP collagen fibre architecture in leaflets could minimise the progression of these prevalent primary failure modes in patient BHVs.
The 55K SNP-Based Exploration of QTL for Spikelet Number Per Spike in a Tetraploid Wheat (Triticum turgidumL.) Population: Chinese Landrace ‘Ailanmai’ × Wild Emmer
Authors: Mo Ziqiang , Zhu Jing , Wei Jiatai , Zhou Jieguang , Xu Qiang , Tang Huaping , Mu Yang , Deng Mei , Jiang Qiantao , Liu Yaxi , Chen Guoyue , Wang Jirui , Qi Pengfei , Li Wei , Wei Yuming , Zheng Youliang , Lan Xiujin , Ma Jian
Published: October 2020

The spikelet number per spike (SNS) is a primary factor determining wheat yield. Common wheat breeding reduces the genetic diversity among elite germplasm resources, leading to a detrimental effect on future wheat production. It is, therefore, necessary to explore new genetic resources for SNS to increase wheat yield. A tetraploid landrace ‘Ailanmai’ × wild emmer wheat recombinant inbred line (RIL) population was used to construct a genetic map using the wheat 55K single nucleotide polymorphism (SNP) array. The linkage map containing 1150 bin markers with a total genetic distance of 2411.8 cM was obtained. Based on phenotypic data from eight environments and best linear unbiased prediction (BLUP) values, five quantitative trait loci (QTL) for SNS were identified, explaining 6.71-29.40% of the phenotypic variation. Two of them,QSns.sau-AM-2B.3andQSns.sau-AM-3B.2, were detected as the major and novel QTL. Their effects were further validated in two additional F2populations using tightly linked Kompetitive Allele-Specific PCR (KASP) markers. Potential candidate genes within the physical intervals of corresponding QTL were predicted to participate in inflorescence development and spikelet formation. Genetic associations between SNS and other agronomic traits were also detected and analyzed. This study demonstrates the feasibility of wheat 55K SNP array developed for common wheat in genetic mapping of tetraploid population and shows the potential application of wheat related species in wheat improvement programs.
EVQuant; high-throughput quantification and characterization of extracellular vesicle (sub)populations
Authors: Hartjes T.A. , Slotman J.A. , Vredenbregt M.S. , Dits N. , Van der Meel R. , Duijvesz D. , Kulkarni J.A. , French P.J. , Van Cappellen W.A. , Schiffelers R.M. , Houtsmuller A.B. , Jenster G.W. , Van Royen M.E.
Published: October 2020

Extracellular vesicles (EVs) reflect the cell of origin in terms of nucleic acids and protein content. They are found in biofluids and represent an ideal liquid biopsy biomarker source for many diseases. Unfortunately, clinical implementation is limited by available technologies for EV analysis. We have developed a simple, robust and sensitive microscopy-based high-throughput assay (EVQuant) to overcome these limitations and allow widespread use in the EV community. The EVQuant assay can detect individual immobilized EVs as small as 35 nm and determine their concentration in biofluids without extensive EV isolation or purification procedures. It can also identify specific EV subpopulations based on combinations of biomarkers and is used here to identify prostate-derived urinary EVs as CD9-/CD63+. Moreover, characterization of individual EVs allows analysis of their size distribution. The ability to identify, quantify and characterize EV (sub-)populations in high-throughput substantially extents the applicability of the EVQuant assay over most current EV quantification assays.
A comparison of cognitive-motor integration performance and resting state functional brain network connectivity in female athletes suggests intact motor network and visuomotor skill in those with a concussion history
Authors: Pierias Alanna E , Gorbet Diana E , Wojtowicz Magdalena , Prieur Andrea , Sergio Lauren
Published: October 2020

Structural neural changes following concussion are often not captured by standard imaging techniques. However, there is growing evidence that damage to white matter tracts and change in functional network connectivity may be observed following concussive injury. We investigated behavioural performance on a cognitive-motor integration (CMI) task in conjunction with alterations in resting state functional connectivity (rs-FC) in brain networks in a population of 30 female varsity athletes, with 16 having a previous history of concussion. Behavioural performance on accuracy, timing, and trajectory measures of a CMI task were assessed between the concussion history group and the control group. Rs-FC within the nodes of the Default Mode Network (DMN), Dorsal Attention Network (DAN), the Frontoparietal Network, and the Anterior Cerebellar Lobule Network, was assessed against performance scores on accuracy, timing, and trajectory measures. Main findings indicate no difference in behavioural performance between those with concussion history and those without, in contrast to previous findings in a group of primarily male varsity athletes. In addition, no difference in rs-FC was noted in correlation with behavioural performance scores on either accuracy, timing, or trajectory. These findings may suggest sex-related differences in performance on a CMI task, and a resiliency in both functional network connectivity and visuomotor skilled performance in varsity female athletes.
Assessment of two DNA extraction kits for profiling poultry respiratory microbiota from multiple sample types
Authors: Abundo Michael E.C. , Ngunjiri John M. , Taylor Kara J.M. , Ji Hana , Ghorbani Amir , Mahesh KC , Weber Bonnie P. , Johnson Timothy J. , Lee Chang-Won
Published: October 2020

Characterization of poultry microbiota is becoming increasingly important due to the growing need for microbiome-based interventions to improve poultry health and production performance. However, the lack of standardized protocols for sampling, sample processing, DNA extraction, sequencing, and bioinformatic analysis can hinder data comparison between studies. Here, we investigated how the DNA extraction process affects microbial community compositions and diversity metrics in different chicken respiratory sample types including choanal and tracheal swabs, nasal cavity and tracheal washes, and lower respiratory lavage. We did a side-by-side comparison of the performances of Qiagen DNeasy blood and tissue (BT) and ZymoBIOMICS DNA Miniprep (ZB) kits. In general, samples extracted with the BT kit yielded higher concentrations of total DNA while those extracted with the ZB kit contained higher numbers of bacterial 16S rRNA gene copies per unit volume. Therefore, the samples were normalized to equal amounts of 16S rRNA gene copies prior to sequencing. For each sample type, all predominant taxa detected in samples extracted with one kit were present in replicate samples extracted with the other kit and did not show significant differences at the class level. Furthermore, between-kit differences in alpha and beta diversity metrics were statistically indistinguishable. Therefore, both kits perform similarly with regard to 16S rRNA gene-based poultry microbiome analysis.
Clustering and erratic movement patterns of syringe-injected versus mosquito-inoculated malaria sporozoites underlie decreased infectivity
Authors: de Korne C.M. , Winkel B.M.F. , van Oosterom M.N. , Chevalley-Maurel S. , Houwing H.M. , Sijtsma J.C. , Baalbergen E. , Franke-Fayard B.M.D. , van Leeuwen F.W.B. , Roestenberg M.
Published: October 2020

Live attenuated malaria sporozoites are promising vaccine candidates, however, their efficacy critically depends on their capability to reach and infect the host liver. Administration via mosquito inoculation is by far the most potent method for inducing immunity, but highly unpractical. Here, we observed that intradermal syringe-injectedPlasmodium bergheisporozoites (syrSPZ) were three-fold less efficient in migrating to and infecting mouse liver compared to mosquito-inoculated sporozoites (msqSPZ). This was related to a clustered dermal distribution (2-fold decreased median distance betweensyrSPZ vsmsqSPZ) and, more importantly, a 1.4-fold significantly slower and more erratic movement pattern. These erratic movement patterns were likely caused by alteration of dermal tissue morphology (>15 μm intercellular gaps) due to injection pressure and may critically decrease sporozoite infectivity. These results suggest that novel microvolume-based administration technologies hold promise for replicating the success of mosquito-inoculated live attenuated sporozoite vaccines.
The genetic and linguistic structures of Abyssinians and their neighbor reveal the historical demographic dynamics and environmental adaptation in the African Horn region
Authors: Sertse Demissew , Mersha Tesfaye B. , Habtewold Jemaneh Z.
Published: October 2020

The African Horn region that includes the Abyssinian is one of the areas in the world that harbor high human genetic diversity manifesting past intermingling of people of different origins attributed to its geographic immediacy to the middle east and being historical trade and religio-cultural hub. Here, we performed a genetic structure analysis of linguistically differentiated populations of Ethiopia, South Sudan, and Somali. To get insight into the genetic landscape of the horn of Africa against the rest of the world, we leverage HapMap SNPs data from Utah residents with Northern and Western European ancestry (CEU), Maasai (MKK), and Yoruba (YRI) and analyzed for genetic admixture and diversity. The genetic and linguistic affiliations mismatch for most Cushitic and Semitic language speakers. The gradients of genetic variations among the different sub-populations within the region show gene-flow directions and past mass population movements. Ethiopians that predominately inhabited the central and northern Ethiopia harbored ~10-15% of CEU admixture. The African horn ancestral line contributed a total of ~20%, 5%, and 2% to MKK, YRI, and CEU, respectively. MKK showed a high genetic diversity comparable to the Ethiopian Cushitic, Semitic, and North Omotic language speakers. Allelic distribution frequencies among the populations at some outlier loci may also provide insight into the adaptations to critical environmental factors such as Malaria.
High-resolution mapping of the neutralizing and binding specificities of polyclonal rabbit serum elicited by HIV Env trimer immunization
Authors: Dingens Adam S. , Pratap Payal , Malone Keara , Hilton Sarah K. , Ketas Thomas , Cottrell Christopher A. , Overbaugh Julie , Moore John P. , Klasse P.J. , Ward Andrew B. , Bloom Jesse D.
Published: October 2020

Mapping the epitope specificities of polyclonal serum is critical to rational vaccine design. However, most high-resolution mapping approaches involve isolating and characterizing individual monoclonal antibodies, which incompletely defines the full polyclonal response. Here we use two complementary approaches to directly map the specificities of the neutralizing and binding antibodies of polyclonal anti-HIV-1 sera from rabbits immunized with BG505 Env SOSIP trimers. To map the neutralizing specificity, we used mutational antigenic profiling to determine how all amino-acid mutations in Env affected viral neutralization. To map the binding specificity, we used electron microscopy polyclonal epitope mapping (EMPEM) to directly visualize the Fabs in serum bound to Env trimers. Mutational antigenic profiling showed that the dominant neutralizing specificities were the C3/V5 and/or 241/289 glycan hole epitopes, which were generally only a subset of the more diverse binding specificities mapped with EMPEM. Additional differences between binding and neutralization reflected antigenicity differences between virus and soluble Env trimer. Further, mutational antigenic profiling was able to refine epitope specificity in residue-level detail directly from sera, revealing subtle differences across rabbits. Together, mutational antigenic profiling and EMPEM allow for a holistic view of the binding and neutralizing specificity of polyclonal sera and could be used to finely evaluate and guide vaccine design.
An H3-K9-me-independent binding of Swi6/HP1 to siRNA-DNA hybrids initiates heterochromatin assembly at cognate dg-dh repeats in Fission Yeast
Authors: Kumar Jyotsna , Haldar Swati , Gupta Neelima , Kumar Viney , Thakur Manisha , Chandradoss Keerthivasan Raanin , Ghose Debarghya , Dutta Dipak , Sandhu Kuljeet Singh , Singh Jagmohan
Published: October 2020

Canonically, heterochromatin formation in fission yeast and metazoans is initiated by di/trimethylation of histone H3 at lysine 9 position by the histone methyltransferase Suv39H1/Clr4, followed by binding of Swi6/HP1 to H3-K9-me2/me3 via its chromodomain. Subsequent self-association of Swi6/HP1 on adjacent nucleosomes or a cooperative interaction between Clr4 and Swi6/HP1 leads to folded heterochromatin structure. HP1 binding to RNA is shown to facilitate its localization at and assembly of heterochromatin in metazoans. Likewise, recruitment of Swi6/HP1 to centromere depends on the RNAi pathway in fission yeast; paradoxically, Swi6/HP1 is also thought to play a role in RNA turnover. Here we provide evidence in support of RNAi-independent recruitment of Swi6. We show that, apart from the low affinity binding to RNAs through its hinge domain, as already reported, Swi6/HP1 displays a hierarchy of increasing binding affinity through its chromodomain to the siRNAs corresponding to specific dg-dh repeats and even stronger binding to the cognate siRNA-DNA hybrids than to the siRNA precursors or general RNAs. Our results support a mechanism of recruitment of Swi6, which is dependent on its specific and high affinity binding to siRNA-DNA hybrid at the dg-dh repeats. This binding, which is independent of, albeit augmented by binding to H3-K9-Me2, leads to heterochromatin formation and silencing. We suggest that the net role of Swi6 in RNA physiology may be regulated by a balance between abundance and affinity of Swi6 towards heterochromatic and euchromatic RNAs and siRNAs.
Characterization of Constitutive macro-ER-phagy
Authors: Lipatova Zhanna , Gyurkovska Valeriya , Zhao Sarah F. , Segev Nava
Published: October 2020

Thirty percent of all cellular proteins are inserted into the endoplasmic reticulum (ER), which spans throughout the cytoplasm. Two well-established stress-induced pathways ensure quality control (QC) at the ER: ER-phagy and ER-associated degradation (ERAD), which shuttle cargo for degradation to the lysosome and proteasome, respectively. In contrast, not much is known about constitutive ER-phagy. We have previously reported that excess of integral-membrane proteins is delivered from the ER to the lysosome via autophagy during normal growth of yeast cells. Here, we characterize this pathway as constitutive ER-phagy. Constitutive and stress-induced ER-phagy share the basic macro-autophagy machinery including the conserved Atgs and Ypt1 GTPase. However, induction of stress-induced autophagy is not needed for constitutive ER-phagy to occur. Moreover, the selective receptors needed for starvation-induced ER-phagy, Atg39 and Atg40, are not required for constitutive ER-phagy and neither these receptors nor their cargos are delivered through it to the vacuole. As for ERAD, while constitutive ER-phagy recognizes cargo different from that recognized by ERAD, these two ER-QC pathways can partially substitute for each other. Because accumulation of membrane proteins is associated with disease, and constitutive ER-phagy players are conserved from yeast to mammalian cells, this process could be critical for human health.

Author Summary

Accumulation of excess proteins can lead to their aggregation, which in turn can cause multiple disorders, notably neurodegenerative disease. Nutritional and endoplasmic-reticulum (ER) stress stimulate autophagy and ER-associated degradation (ERAD) to clear excess and misfolded proteins, respectively. However, not much is known about clearance of excess proteins during normal growth. We have previously shown that excess integral-membrane proteins are cleared from the ER by macro-autophagy during normal growth of yeast cells. Here we characterize this pathway as constitutive ER-phagy. While this pathway shares machinery of core Atgs and autophagosomes with nutritional stress-induced ER-phagy, it differs from the latter: It is independent of the stress response and of receptors needed for stress-induced ER-phagy, and while stress-induced ER-phagy is not discriminatory, constitutive ER-phagy has specific cargos. However, when constitutive ER-phagy fails, machinery specific to stress-induced ER-phagy can process its cargo. Moreover, constitutive ER-phagy is also not dependent on ER-stress or the unfolded protein response (UPR) stimulated by this stress, although its failure elicits UPR. Finally, constitutive ER-phagy and ERAD can partially process each other’s cargo upon failure. In summary, constitutive ER-phagy, which clears excess integral-membrane proteins from the ER during normal growth does not require nutritional or ER stress for its function.
Heterochromatin Replication: Direct Interaction of DNA replication machinery with heterochromatin code writer Clr4/Suv39 and reader Swi6/HP1 inS. pombe
Authors: Saini Sharanjot , Arora Sumit , Bisht Kamlesh K. , Nakwal Nandni , Ahmed Shakil , Singh Jagmohan
Published: October 2020

The establishment of heterochromatin in fission yeast involves methyltransferase Clr4-mediated H3-Lys9 methylation, which is bound specifically by Swi6/HP1. However, the mechanism of propagation of heterochromatin through multiple cell divisions is not known. A role of DNA replication in propagating the heterochromatin is envisaged. Studies inS. pombehave indicated a direct interaction between DNA Polα and Swi6/HP1 and between DNA Polε and Rik1-Dos2 complex, suggesting a coupling between DNA replication and heterochromatin assembly. Here, we show that like DNA Polα, Polδ, which plays a role in both leading and lagging strand replication, also plays a role in silencing at mating type and centromere. We show that both the polymerases α and δ interact directly with both Clr4 and Swi6/HP1. Mutations in both the polymerases lead to decrease in H3-Lys9 methylation and Swi6 at the mating type and left outer repeats of centromeres I and II, with a reciprocal increase in their level at the central element,cnt, at all the three centromeres. These mutations also cause defects in chromosome segregation, recruitment of Cohesin and chromosome dynamics during mitosis and meiosis. Thus, our results indicate that a tight coordination between DNA replication machinery and propagation of the heterochromatin-specific epigenetic mark.
Mechanism of negative regulation of NF-κB by N4BP1
Authors: Shi Hexin , Sun Lei , Wang Ying , Liu Aijie , Zhan Xiaoming , Li Xiaohong , Tang Miao , Anderton Priscilla , Hildebrand Sara , Quan Jiexia , Ludwig Sara , Moresco Eva Marie Y. , Beutler Bruce
Published: October 2020

Many immune responses depend upon activation of NF-κB, a key transcription factor in the elicitation of a cytokine response. Here we demonstrate that N4BP1 inhibited TLR-dependent activation of NF-κB by interacting with the NF-κB signaling essential modulator (NEMO, also known as IκB kinase γ) to attenuate NEMO-NEMO dimerization or oligomerization. The UBA-like (ubiquitin associated-like) and CUE-like (ubiquitin conjugation to ER degradation) domains in N4BP1 mediated the interaction with the NEMO COZI domain. Bothin vitroand in mice,N4bp1deficiency specifically enhanced TRIF-independent (TLR2, TLR7, or TLR9-mediated), but not TRIF-dependent (TLR3 or TLR4-mediated), NF-κB activation leading to increased production of proinflammatory cytokines. In response to TLR4 or TLR3 activation, TRIF caused activation of caspase 8, which cleaved N4BP1 distal to residues D424 and D490 and abolished its inhibitory effect.N4bp1-/-mice also exhibited diminished numbers of T cells in the peripheral blood. Our work identifies N4BP1 as an inhibitory checkpoint protein that must be overcome to activate NF-κB, and a TRIF-initiated caspase 8-dependent mechanism by which this is accomplished.
Conditional targeting of phosphatidylserine decarboxylase to lipid droplets
Authors: Kumar Santosh , Chitraju Chandramohan , Farese Robert , Walther Tobias , Burd Christopher G.
Published: October 2020

Phosphatidylethanolamine is an abundant component of most cellular membranes whose physical and chemical properties modulate multiple aspects of organelle membrane dynamics. An evolutionarily ancient mechanism for producing phosphatidylethanolamine is to decarboxylate phosphatidylserine and the enzyme catalyzing this reaction, phosphatidylserine decarboxylase, localizes to the inner membrane of the mitochondrion. We characterize a second form of phosphatidylserine decarboxylase, termed PISD-LD, that is generated by alternative splicing of PISD pre-mRNA and localizes to lipid droplets and to mitochondria. Sub-cellular targeting is controlled by a common segment of PISD-LD that is distinct from the catalytic domain and is regulated by nutritional state. Growth conditions that promote neutral lipid storage in lipid droplets favors targeting to lipid droplets, while targeting to mitochondria is favored by conditions that promote consumption of lipid droplets. Depletion of both forms of phosphatidylserine decarboxylase impairs triacylglycerol synthesis when cells are challenged with free fatty acid, indicating a crucial role phosphatidylserine decarboxylase in neutral lipid storage. The results reveal a previously unappreciated role for phosphatidylserine decarboxylase in lipid droplet biogenesis.
Cortisone and cortisol break hydrogen-bonding rules to make a drug–prodrug solid solution
Authors: Verma Vivek , Bordignon Simone , Chierotti Michele R. , Lestari Monica , Lyons Kieran , Padrela Luis , Ryan Kevin M. , Lusi Matteo
Published: October 2020

Multidrug products enable more effective therapies and simpler administration regimens, provided that a stable formulation is prepared, with the desired composition. In this view, solid solutions have the advantage of combining the stability of a single crystalline phase with the potential of stoichiometry variation of a mixture. Here a drug–prodrug solid solution of cortisone and cortisol (hydrocortisone) is described. Despite the structural differences of the two components, the new phase is obtained both from solution and by supercritical CO2 assisted spray drying. In particular, to enter the solid solution, hydrocortisone must violate Etter's rules for hydrogen bonding. As a result, its dissolution rate is almost doubled.