bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantification of the tradeoff between test sensitivity and test frequency in COVID-19 epidemic - a multi-scale modeling approach
Authors: Forde Jonathan E. , Ciupe Stanca M.
Published: February 2021

Control strategies that employ real time polymerase chain reaction (RT-PCR) tests for the diagnosis and surveillance of COVID-19 epidemic are inefficient in fighting the epidemic due to high cost, delays in obtaining results, and the need of specialized personnel and equipment for laboratory processing. Cheaper and faster alternatives, such as antigen and paper-strip tests, have been proposed. They return results rapidly, but have lower sensitivity thresholds for detecting virus. To quantify the effects of the tradeoffs between sensitivity, cost, testing frequency, and delay in test return on the overall course of an outbreak, we built a multi-scale immuno-epidemiological model that connects the virus profile of infected individuals with transmission and testing at the population level. We investigated various randomized testing strategies and found that, for fixed testing capacity, lower sensitivity tests with shorter return delays slightly flatten the daily incidence curve and delay the time to the peak daily incidence. However, compared with RT-PCR testing, they do not always reduce the cumulative case count at half a year into the outbreak. When testing frequency is increased to account for the lower cost of less sensitive tests, we observe a large reduction in cumulative case counts, from 57% to as low as 1.5% half a year into the outbreak and to 3.2% three years into the outbreak. The improvement is preserved even when the testing budget is reduced by one half or one third. Our results predict that surveillance testing that employs low-sensitivity tests at high frequency is an effective tool for epidemic control.
Celecoxib exhibits therapeutic potential in experimental model of hyperlipidaemia
Authors: Ekor Martins , Owusu Agyei Phyllis E. , Obese Ernest , Biney Robert P. , Henneh Isaac T. , Antwi-Adjei Meshack , Yahaya Ewura S. , Amoakohene Gordon , Akakpo Patrick K.
Published: February 2021

Hyperlipidaemia is a major risk factor for cardiovascular diseases, the leading cause of death globally. Celecoxib attenuated hypercholesterolemia associated with CCl4-induced hepatic injury in rats without improving liver function in our previous study. This present study investigated the lipid lowering potential of celecoxib in normal rats fed with coconut oil subjected to five deep-frying episodes. Male Sprague Dawley rats were randomly assigned to groups (n=6 rats/group) which received physiological saline (10 mL/kg), unheated coconut oil (UO, 10 mL/kg) or heated coconut oil (HO, 10 ml/kg) for 60 days. Groups that received HO were subsequently treated with either physiological saline, atorvastatin (25 mg/kg), celecoxib (5 mg/kg) or celecoxib (10 mg/kg) in the last fifteen days of the experiment. Rats were sacrificed 24 hours after last treatment and blood and tissue samples collected for analysis. HO consumption produced significant hyperlipidaemia and elevation in marker enzymes of hepatic function. Celecoxib ameliorated the hyperlipidaemia as shown by the significantly (P<0.05) lower total cholesterol, triglycerides, low and very low density lipoprotein in the celecoxib-treated rats when compared with HO-fed rats that received saline. Celecoxib also reduced (P<0.05) alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and liver weight of hyperlipidaemic rats. Similarly, hepatocellular damage and inflammation of the aorta associated with the hyperlipidaemia was significantly reversed by celecoxib. However, serum TNF-α and IL-6 did not change significantly between the various groups. Taken together, data from this study suggest that celecoxib may exert therapeutic benefit in hyperlipidaemia and its attendant consequences.
Intra-ocular dendritic cells are increased in HLA-B27 associated acute anterior uveitis
Authors: Kasper Maren , Heming Michael , Schafflick David , Li Xiaolin , Lautwein Tobias , zu Horste Melissa Meyer , Bauer Dirk , Walscheid Karoline , Wiendl Heinz , Loser Karin , Heiligenhaus Arnd , zu Horste Gerd Meyer
Published: February 2021

Uveitis describes a heterogeneous group of inflammatory eye diseases characterized by infiltration of leukocytes into the uveal tissues. HLA-B27-associated uveitis is a common subtype of uveitis and a prototypical ocular autoimmune disease. Local immune mechanisms driving human uveitis are poorly characterized mainly due to the limited available biomaterial and subsequent technical limitations.

Here, we provide the first high-resolution characterization of intraocular leukocytes in HLA-B27 positive and negative anterior uveitis and an infectious endophthalmitis control by combining single cell RNA-sequencing (scRNA-seq) with flow cytometry and low-input proteomics. Ocular cell infiltrates consisted primarily of lymphocytes in uveitis and of myeloid cells in infectious endophthalmitis. HLA-B27 positive uveitis exclusively featured an plasmacytoid and classical dendritic cells (cDC) infiltrate, and of plasma cells. Moreover, cDCs were central in predicted local cell-cell communication.

The data suggests a unique pattern of ocular leukocyte infiltration in HLA-B27 positive uveitis with relevance of particular dendritic cells.
Phase transitions may explain why SARS-CoV-2 spreads so fast and why new variants are spreading faster
Authors: Phillips J. C. , Moret Marcelo , Zebende Gilney F. , Chow Carson C.
Published: February 2021

The novel coronavirus SARS CoV-2 responsible for the COVID-19 pandemic and SARS CoV-1 responsible for the SARS epidemic of 2002-2003 share an ancestor yet evolved to have much different transmissibility and global impact1. A previously developed thermodynamic model of protein conformations predicted that SARS CoV-2 is very close to a thermodynamic critical point, which makes it highly infectious but also easily displaced by a spike-based vaccine because there is a tradeoff between transmissibility and robustness2. The model identified a small cluster of four key mutations of SARS CoV-2 that promotes much stronger viral attachment and viral spreading. Here we apply the model to two new strains (B.1.1.7 and B.1.351)3and predict, using no free parameters, how the new mutations can further enhance infectiousness.
Spatiotemporal heterogeneity of glioblastoma is dictated by microenvironmental interference
Authors: Ravi Vidhya M. , Will Paulina , Kueckelhaus Jan , Sun Na , Joseph Kevin , Salié Henrike , Ehr Jasmin von , Vollmer Lea , Benotmane Jasim K. , Neidert Nicolas , Follo Marie , Scherer Florian , Goeldner Jonathan M , Behringer Simon P. , Franco Pamela , Hofmann Ulrich G. , Fung Christian , Beck Jürgen , Sankowski Roman , Prinz Marco , Killmer Saskia , Bengsch Bertram , Walch Axel Karl , Delev Daniel , Schnell Oliver , Heiland Dieter Henrik
Published: February 2021

Glioblastomas are highly malignant tumors of the central nervous system. Evidence suggests that these tumors display large intra- and inter-patient heterogeneity hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies1–3. However, the source for dynamic reorganization of cellular states within their spatial context remains elusive. Here, we in-depth characterized glioblastomas by spatially resolved transcriptomics, metabolomics and proteomics. By deciphering exclusive and shared transcriptional programs across patients, we inferred that glioblastomas develop along defined neural lineages and adapt to inflammatory or metabolic stimuli reminiscent of reactive transformation in mature astrocytes. Metabolic profiling and imaging mass cytometry supported the assumption that tumor heterogeneity is dictated by microenvironmental alterations. Analysis of copy number variation (CNV) revealed a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. Deconvolution of age-dependent transcriptional programs in malignant and non-malignant specimens identified the aging environment as the major driver of inflammatory transformation in GBM, suggesting that tumor cells adopt transcriptional programs similar to inflammatory transformation in astrocytes. Glioblastoma stem cells implanted into human neocortical slices of varying age levels, independently confirmed that the ageing environment dynamically shapes the intratumoral heterogeneity towards reactive transcriptional programs. Our findings provide insights into the spatial architecture of glioblastoma, suggesting that both locally inherent tumor as well as global alterations of the tumor microenvironment shape its transcriptional heterogeneity. Global age-related inflammation in the human brain is driving distinct transcriptional transformation in glioblastomas, which requires an adjustment of the currently prevailing glioma models.
The type and source of reactive oxygen species influences the outcome of oxidative stress in cultured cells
Authors: Goffart Steffi , Tikkanen Petra , Michell Craig , Wilson Trevor , Pohjoismäki Jaakko L.O.
Published: February 2021

Oxidative stress can be modeled using various different experimental approaches, such as exposing the cells or organisms to oxidative chemicals. However, the actual effects of these chemicals, outside of the immediate measured effect, have attracted relatively little attention. We show here that three commonly used oxidants, menadione, potassium bromate and hydrogen peroxide, while known to function differently, also elicit different types of responses in cultured cells. While cells response to menadione and bromate exposure mainly by an integrated stress response, hydrogen peroxide has more indirect effects. Primary oxidative stress does not induce DNA repair or antioxidant defense mechanisms. However, cells with previous experience of oxidative stress show adaptive changes when the stress is renewed. Our results urge caution when comparing studies using different sources of oxidative stress or generalizing the findings of these studies to different tissue or oxidant types.
Temporal enhancement of cross-adaptation between density and size perception based on the theory of magnitude
Authors: Hisakata Rumi , Kaneko Hirohiko
Published: February 2021

The ability to estimate spatial extent is an important feature of the visual system. A previous study showed that perceived sizes shrank after adaptation to a dense texture and reported that this density–size aftereffect is modulated by the degree of density. In this study, we found that the aftereffect was also modulated by the temporal density of the adapting texture. The test stimuli were two circles, and the adapting stimulus had a dotted texture. The adapting texture refreshed every form 67ms to 500 ms, or not at all (static), during the adaptation. The results showed that the aftereffects from a refreshing stimulus were larger than those under the static condition. On the other hand, density adaptation lacked such enhancement. This result indicates that repetitive presentation of an adapting texture enhanced the density–size cross-aftereffect. The fact that density modulation occurs in both the spatial and temporal domains is consistent with the theory of magnitude, which assumes that the processing of the magnitude estimation of space, time, and numbers share a common cortical basis.
Targeted Memory Reactivation of Face-Name Learning Depends on Ample and Undisturbed Slow-Wave Sleep
Authors: Whitmore Nathan , Bassard Adrianna M. , Paller Ken A.
Published: February 2021

Face memory, including the ability to recall the name of a familiar person, is often crucial in social interactions, and like many other memory functions, it may rely on sleep. We investigated whether targeted memory reactivation during sleep could improve associative and perceptual aspects of face memory. Participants studied 80 face-name pairs, and then a subset of spoken names was presented unobtrusively during a daytime nap. This reactivation preferentially improved recall for those face-name pairs, as modulated by two factors related to sleep quality. That is, the memory benefit was positively correlated with the duration of stage N3 sleep (slow-wave sleep) and with the extent to which cues presented during SWS did not produce a sleep disruption indexed by increased alpha-band electroencephalographic activity in the 5 seconds after a cue. Follow-up analyses showed that a memory benefit from presenting spoken names during sleep was evident in participants with high amounts of SWS or with low amounts of sleep disruption. We conclude that sleep reactivation can strengthen memory for specific face-name associations and that the effectiveness of reactivation depends on uninterrupted N3 sleep.
Comparative analysis of Alzheimer’s disease knock-in model brain transcriptomes implies changes to energy metabolism as a causative pathogenic stress
Authors: Barthelson Karissa , Newman Morgan , Lardelli Michael
Published: February 2021

Energy production is the most fundamentally important cellular activity supporting all other functions, particularly in highly active organs such as brains. Here, we summarise transcriptome analyses of young adult (pre-disease) brains from a collection of eleven early-onset familial Alzheimer’s disease (EOfAD)-like and non-EOfAD-like mutations in three zebrafish genes. The one cellular activity consistently predicted as affected by only the EOfAD-like mutations is oxidative phosphorylation that produces most of the brain’s energy. All the mutations were predicted to affect protein synthesis. We extended our analysis to knock-in mouse models ofAPOEalleles and found the same effect for the late onset Alzheimer’s disease risk allele ɛ4. Our results support a common molecular basis for initiation of the pathological processes leading to both early and late onset forms of Alzheimer’s disease and illustrate the utility of both zebrafish and knock-in, single EOfAD mutation models for understanding the causes of this disease.
Evidence for a force favouring GC over AT at short intronic sites inDrosophila simulansandD. melanogaster
Authors: Jackson Ben , Charlesworth Brian
Published: February 2021

Population genetics studies often make use of a class of nucleotide site free from selective pressures in order to make inferences about population size changes or natural selection at other sites. If such neutral sites can be identified, they offer the opportunity to avoid any confounding effects of selection. Here we investigate evolution at putatively neutrally evolving short intronic sites in natural populations ofDrosophila melanogasterandD. simulans, in order to understand the properties of spontaneous mutations and the extent of GC-biased gene conversion in these species. Use of data on the genetics of natural populations is advantageous because it integrates information from large numbers of individuals over long timescales. In agreement with direct evidence from observations of spontaneous mutations inDrosophila, we find a bias in the spectrum of mutations towards AT basepairs. In addition, we find that this bias is stronger in theD. melanogasterlineage than theD. simulanslineage. The evidence for GC-biased gene conversion inDrosophilahas been equivocal. Here we provide evidence for a weak force favouring GC in both species, which is stronger inD. simulans.Some homologous short intronic sites have diverged in GC content between the two species, which may have been caused by lineage-specific changes in the extent to which different regions of the genome are subject to a GC (or AT)-favouring force.
Toxicity Profile of Artesunate in Rats and Dogs
Authors: Lang Johanna S.
Published: February 2021

Abstract

OBJECTIVES

The objectives of these studies were to investigate the toxicity, safety
and toxicokinetics of single and multiple doses of artesunate for injection
in rats and dogs.

METHODS

Sprague-Dawley rats and Beagle dogs were treated intravenously or
intramuscularly for 28 consecutive days with doses of up to 30 mg/kg
artesunate, evaluating toxicity, kinetics, genotoxicity, and cardiovascular
and central nervous safety parameters after single and 4-week repeated
administrations. Furthermore, respiratory parameters were evaluated after a
single intravenous administration in rats.

RESULTS

Artesunate was well tolerated with no mortality and only minor effects
on clinical pathology parameters. Following repeated intramuscular
administration, local reactions at the injection site became
evident.

CONCLUSIONS

The results obtained in these studies support the safe use of artesunate
in humans.

Subchronic data for repeated intravenous and intramuscular artesunate in
animals are available in the literature for a maximum duration of 14-days.
Published results of genotoxicity studies in
vitro in bacteria or cells of animal or human origin and
in vivo in animals are equivocal, with a
couple of negative results following oral administration and positive
results in human cells.

With the studies performed in rats and dogs for a treatment period of
28-days including measures of safety pharmacology, toxicokinetic evaluation
and in vivo genotoxicity data, a comparison of
toxicity and exposure of intravenous versus intramuscular artesunate for a
prolonged treatment period is possible, delivering important information,
when a decision between both routes has to be made for use in patients.
Results of the peripheral blood micronucleus assay in rats were positive,
suggesting genotoxic potential for the intravenous route of administration
of artesunate, what is, beside patients, likewise relevant for production
and health care personnel.
Ex vivoanticoagulants affect human blood platelet biomechanics with implications for high-throughput functional mechanophenotyping
Authors: Sachs Laura , Wesche Jan , Lenkeit Lea , Greinacher Andreas , Bender Markus , Otto Oliver , Palankar Raghavendra
Published: February 2021

Inherited platelet disorders affecting the human platelet cytoskeleton result in increased bleeding risk. However, deciphering their impact on cytoskeleton-dependent intrinsic biomechanics of platelets remains challenging and represents an unmet need from a diagnostic and prognostic perspective. It is currently unclear whetherex vivoanticoagulants used for the collection of peripheral blood impact the mechanophenotype of cellular components of blood. Using unbiased, high-throughput functional mechanophenotyping of single human platelets by deformability cytometry, we found thatex vivoanticoagulants are a critical pre-analytical variable that differentially influences platelet deformation, their size and functional response to agonists by altering the cytoskeleton. We applied our findings to characterize the functional mechanophenotype of platelets from a patient with Myosin Heavy Chain 9 (MYH9) related macrothrombocytopenia. Our data suggest that platelets fromMYH9p.E1841K mutation in humans affecting platelet non-muscle myosin heavy chain IIa (NMMHC-IIA) are biomechanically less deformable in comparison to platelets from healthy individuals.
Defining the Yeast Resistome throughin vitroEvolution and Whole Genome Sequencing
Authors: Ottilie Sabine , Luth Madeline R. , Hellemann Erich , Goldgof Gregory M. , Vigil Eddy , Kumar Prianka , Cheung Andrea L. , Song Miranda , Godinez-Macias Karla P. , Carolino Krypton , Yang Jennifer , Lopez Gisel , Abraham Matthew , Tarsio Maureen , LeBlanc Emmanuelle , Whitesell Luke , Schenken Jake , Gunawan Felicia , Patel Reysha , Smith Joshua , Love Melissa S. , Williams Roy M. , McNamara Case W. , Gerwick William H. , Ideker Trey , Suzuki Yo , Wirth Dyann F. , Lukens Amanda K. , Kane Patricia M. , Cowen Leah E. , Durrant Jacob D. , Winzeler Elizabeth A.
Published: February 2021

In vitroevolution and whole genome analysis were used to comprehensively identify the genetic determinants of chemical resistance in the model microbe,Saccharomyces cerevisiae. Analysis of 355 curated, laboratory-evolved clones, resistant to 80 different compounds, demonstrates differences in the types of mutations that are identified in selected versus neutral evolution and reveals numerous new, compound-target interactions. Through enrichment analysis we further identify a set of 137 genes strongly associated with or conferring drug resistance as indicated by CRISPR-Cas9 engineering. The set of 25 most frequently mutated genes was enriched for transcription factors and for almost 25 percent of the compounds, resistance was mediated by one of 100 independently derived, gain-of-function, single nucleotide variants found in 170-amino-acid domains in two Zn2C6transcription factors,YRR1andYRM1(p < 1x 10−100). This remarkable enrichment for transcription factors as drug resistance genes may explain why it is challenging to develop effective antifungal killing agents and highlights their important role in evolution.
A comprehensive fitness landscape model reveals the evolutionary history and future evolvability of eukaryoticcis-regulatory DNA sequences
Authors: Vaishnav Eeshit Dhaval , de Boer Carl G. , Yassour Moran , Molinet Jennifer , Fan Lin , Adiconis Xian , Thompson Dawn A. , Cubillos Francisco A. , Levin Joshua Z. , Regev Aviv
Published: February 2021

Mutations in non-codingcis-regulatory DNA sequences can alter gene expression, organismal phenotype, and fitness. Fitness landscapes, which map DNA sequence to organismal fitness, are a long-standing goal in biology, but have remained elusive because it is challenging to generalize accurately to the vast space of possible sequences using models built on measurements from a limited number of endogenous regulatory sequences. Here, we construct a sequence-to-expression model for such a landscape and use it to decipher principles ofcis-regulatory evolution. Using tens of millions of randomly sampled promoter DNA sequences and their measured expression levels in the yeastSacccharomyces cerevisiae, we construct a deep transformer neural network model that generalizes with exceptional accuracy, and enables sequence design for gene expression engineering. Using our model, we predict and experimentally validate expression divergence under random genetic drift and strong selection weak mutation regimes, show that conflicting expression objectives in different environments constrain expression adaptation, and find that stabilizing selection on gene expression leads to the moderation of regulatory complexity. We present an approach for detecting selective constraint on gene expression using our model and natural sequence variation, and validate it using observedcis-regulatory diversity across 1,011 yeast strains, cross-species RNA-seq from three different clades, and measured expression-to-fitness curves. Finally, we develop a characterization of regulatory evolvability, use it to visualize fitness landscapes in two dimensions, discover evolvability archetypes, quantify the mutational robustness of individual sequences and highlight the mutational robustness of extant natural regulatory sequence populations. Our work provides a general framework that addresses key questions in the evolution ofcis-regulatory sequences.
Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries
Authors: Zhang Xianonan , Shetty Mihir , Clemente Valentino , Linder Stig , Bazzaro Martina
Published: February 2021

Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A a member of the SWI/SNF chromatin remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells, however the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here we show that ARID1A-loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated to increase of C-myc and to increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide the for targeting mitochondrial activity in ARID1A-mutanted OCCCs.
RaptGen: A variational autoencoder with profile hidden Markov model for generative aptamer discovery
Authors: Iwano Natsuki , Adachi Tatsuo , Aoki Kazuteru , Nakamura Yoshikazu , Hamada Michiaki
Published: February 2021

Nucleic acid aptamers are generated by anin vitromolecular evolution method known as systematic evolution of ligands by exponential enrichment (SELEX). A variety of candidates is limited by actual sequencing data from an experiment. Here, we developed RaptGen, which is a variational autoencoder forin silicoaptamer generation. RaptGen exploits a profile hidden Markov model decoder to represent motif sequences effectively. We showed that RaptGen embedded simulation sequence data into low-dimension latent space dependent on motif information. We also performed sequence embedding using two independent SELEX datasets. RaptGen successfully generated aptamers from the latent space even though they were not included in high-throughput sequencing. RaptGen could also generate a truncated aptamer with a short learning model. We demonstrated that RaptGen could be applied to activity-guided aptamer generation according to Bayesian optimization. We concluded that a generative method by RaptGen and latent representation are useful for aptamer discovery. Codes are available athttps://github.com/hmdlab/raptgen.
Chromosome-level genome assembly of the horned-gall aphid,Schlechtendalia chinensis(Hemiptera: Aphididae: Erisomatinae)
Authors: Wei Hong-Yuan , Ye Yu-Xian , Huang Hai-Jian , Chen Ming-Shun , Yang Zi-Xiang , Chen Xiao-Ming , Zhang Chuan-Xi
Published: February 2021

The horned gall aphidSchlechtendalia chinensis, is an economically important insect that induces galls valuable for medicinal and chemical industries.S. chinensismanipulates its host plant to form well-organized horned galls during feeding. So far, more than twenty aphid genomes have been reported; however, all of those are derived from free-living aphids. Here we generated a high-quality genome assembly ofS. chinensis, representing the first genome sequence of a galling aphid. The final genome assembly was 280.43 Mb, with 97% of the assembled sequences anchored into thirteen chromosomes.S. chinensispresents the smallest aphid genome size among available aphid genomes to date. The contig and scaffold N50 values were 3.39 Mb and 20.58 Mb, respectively. The assembly included 96.4% of conserved arthropod and 97.8% of conserved Hemiptera single-copy orthologous genes based on BUSCO analysis. A total of 13,437 protein-coding genes were predicted. Phylogenomic analysis showed thatS. chinensisformed a single clade between theEriosoma lanigerumclade and the Aphidini+Macrosiphini aphid clades. In addition, salivary proteins were found to be differentially expressed whenS. chinensisunderwent host alternation, indicating their potential roles in gall formation and plant defense suppression. A total of 36 cytochrome P450 genes were identified inS. chinensis, considerably fewer compared to other aphids, probably due to its small host plant range. The high-qualityS. chinensisgenome assembly and annotation provide an essential genetic background for future studies to reveal the mechanism of gall formation and to explore the interaction between aphids and their host plants.
Social stratification without genetic differentiation at the site of Kulubnarti in Christian Period Nubia
Authors: Sirak Kendra A. , Fernandes Daniel M. , Lipson Mark , Mallick Swapan , Mah Matthew , Olalde Iñigo , Ringbauer Harald , Rohland Nadin , Hadden Carla S. , Harney Éadaoin , Adamski Nicole , Bernardos Rebecca , Broomandkhoshbacht Nasreen , Callan Kimberly , Ferry Matthew , Lawson Ann Marie , Michel Megan , Oppenheimer Jonas , Stewardson Kristin , Zalzala Fatma , Patterson Nick , Pinhasi Ron , Thompson Jessica C. , Gerven Dennis Van , Reich David
Published: February 2021

Nubia has been a corridor for the movement of goods, culture, and people between sub-Saharan Africa, Egypt, and West Eurasia since prehistory, but little is known about the genetic landscape of the region prior to the influence of the Islamic migrations that began in the late 1st millennium CE. We report genome-wide data for 66 individuals from the site of Kulubnarti (∼650–1000 CE), increasing the number of ancient individuals with genome-level data from the Nile Valley from three to 69. Our results shed light on the genetic ancestry of a Christian Period group and help to address a long-standing question about the relationships among people buried in two neighboring cemeteries who show skeletal evidence of differences in morbidity and mortality that are broadly suggestive of differences in social status. We find that the Kulubnarti Nubians were admixed with ∼43% Nilotic-related ancestry on average (individual proportions varied between ∼36-54%) and the remaining ancestry reflecting a West Eurasian-related gene pool likely introduced into Nubia through Egypt, but ultimately deriving from an ancestry pool like that found in the Bronze and Iron Age Levant. The admixed ancestry at Kulubnarti reflects interactions between genetically-distinct people in northeast Africa spanning almost a millennium, with West Eurasian ancestry disproportionately associated with females, highlighting the impact of female mobility in this region. We find no significant differences in ancestry among individuals from the two plausibly socially-stratified cemeteries at Kulubnarti, supporting hypotheses that the groups may have been socially divided but were not genetically distinct. We identify seven pairs of inter-cemetery relatives as close as second-degree, suggesting that any social divisions at Kulubnarti did not prevent mixing between groups. Present-day Nubians are not directly descended from the Christian Period people from Kulubnarti without additional admixture, attesting to the dynamic history of interaction that continues to shape the cultural and genetic landscape of Nubia.
Diversity and Function of Motile Ciliated Cell Types within Ependymal Lineages of the Zebrafish Brain
Authors: D’Gama Percival P. , Qiu Tao , Cosacak Mehmet Ilyas , Chong Yan Ling , Konac Ahsen , Hansen Jan Niklas , Ringers Christa , Hui Subhra P. , Olstad Emilie W. , Peng Ng Chee , Rayamajhi Dheeraj , Wachten Dagmar , Liebl David , Kikuchi Kazu , Kizil Caghan , Yaksi Emre , Roy Sudipto , Jurisch-Yaksi Nathalie
Published: February 2021

Motile cilia defects impair cerebrospinal fluid (CSF) flow, and can cause brain and spine disorders. To date, the development of ciliated cells, their impact on CSF flow and their function in brain and axial morphogenesis are not fully understood. Here, we have characterized motile ciliated cells within the zebrafish brain ventricles. We show that the ventricular surface undergoes significant restructuring through development, involving a transition from mono- to multiciliated cells (MCCs) driven by gmnc. MCCs are translationally polarized, co-exist with monociliated cells and generate directional flow patterns. Moreover, these ciliated cells have different developmental origins, and are genetically heterogenous with respect to expression of the Foxj1 family of ciliary master regulators. Finally, we show that cilia loss from specific brain regions or global perturbation of multiciliation does not affect overall brain or spine morphogenesis, but results in enlarged ventricles. Our findings establish that motile ciliated cells are generated by complementary and sequential transcriptional programs to support ventricular development.
A non-canonical role for glutamate decarboxylase 1 in cancer cell amino acid homeostasis, independent of the GABA shunt
Authors: Samborska Bozena , Griss Takla , Ma Eric H. , Jones Nicholas , Williams Kelsey S. , Sergushichev Alexey , Johnson Radia M. , Esaulova Ekaterina , Loginicheva Ekaterina , Flynn Breanna , Blagih Julianna , Artyomov Maxim N. , Jones Russell G. , Vincent Emma E.
Published: February 2021

Glutamate decarboxylase 1 (GAD1) is best known for its role in producing the neurotransmitter γ-amino butyric acid (GABA) as part of the “GABA shunt” metabolic pathway, an alternative mechanism of glutamine anaplerosis for TCA cycle metabolism (Yogeeswari et al., 2005). However, understanding of the metabolic function of GAD1 in non-neuronal tissues has remained limited. Here, we show that GAD1 supports cancer cell proliferation independent of the GABA shunt. Despite its elevated expression in lung cancer tissue, GAD1 is not engaged in the GABA shunt in proliferating non-small cell lung cancer (NSCLC) cells, but rather is required for regulating amino acid homeostasis. Silencing GAD1 promotes a broad deficiency in amino acid uptake, leading to reduced glutamine-dependent TCA cycle metabolism and defects in serum- and amino acid-stimulated mTORC1 activation. Mechanistically, GAD1 regulates amino acid uptake through ATF4-dependent amino acid transporter expression includingSLC7A5(LAT1), an amino acid transporter required for branched chain amino acid (BCAA) uptake. Overexpression of LAT1 rescues the proliferative and mTORC1 signalling defects of GAD1-deficient tumor cells. Our results, therefore, define a non-canonical role for GAD1, independent of its characterised role in GABA metabolism, whereby GAD1 regulates amino acid homeostasis to maintain tumor cell proliferation.
Midbrain dopamine neurons provide teaching signals for goal-directed navigation
Authors: Farrell Karolina , Lak Armin , Saleem Aman B
Published: February 2021

In naturalistic environments, animals navigate in order to harvest rewards. Successful goal-directed navigation requires learning to accurately estimate location and select optimal state-dependent actions. Midbrain dopamine neurons are known to be involved in reward value learning1–13. They have also been linked to reward location learning, as they play causal roles in place preference14,15and enhance spatial memory16–21. Dopamine neurons are therefore ideally placed to provide teaching signals for goal-directed navigation. To test this, we imaged dopamine neural activity as mice learned to navigate in a closed-loop virtual reality corridor and lick to report the reward location. Across learning, phasic dopamine responses developed to visual cues and trial outcome that resembled reward prediction errors and indicated the animal’s estimate of the reward location. We also observed the development of pre-reward ramping activity, the slope of which was modulated by both learning stage and task engagement. The slope of the dopamine ramp was correlated with the accuracy of licks in the next trial, suggesting that the ramp sculpted accurate location-specific action during navigation. Our results indicate that midbrain dopamine neurons, through both their phasic and ramping activity, provide teaching signals for improving goal-directed navigation.

Highlights

We investigated midbrain dopamine activity in mice learning a goal-directed navigation task in virtual reality

Phasic dopamine signals reflected prediction errors with respect to subjective estimate of reward location

A slow ramp in dopamine activity leading up to reward location developed over learning and was enhanced with task engagement

Positive ramp slopes were followed by improved performance on subsequent trials, suggesting a teaching role during goal-directed navigation
The IL-10GFP(VeRT-X) mouse strain is not suitable for the detection of IL-10 production by granulocytes during lung inflammation
Authors: Özkan Müge , Eskiocak Yusuf Cem , Wingender Gerhard
Published: February 2021

The clear and unequivocal identification of immune effector functions is essential to understand immune responses. The cytokine IL-10 is a critical immune regulator and was shown, for example, to limit pathology during various lung diseases. However, the clear identification of IL-10-producing cells is challenging and, therefore, reporter mouse lines were developed to facilitate their detection. Several such reporter lines utilize GFP, including the IL-10GFP(VeRT-X) reporter strain studied here. In line with previous reports, we found that this IL-10GFPline faithfully reports on the IL-10 production of lymphoid cells. However, we show that the IL-10GFPreporter is not suitable to analyse IL-10 production of myeloid cells during inflammations. During inflammation, the autofluorescence of myeloid cells increased to an extent that entirely masked the IL-10-specific GFP-signal. Our data illustrate a general and important technical caveat using GFP-reporter lines for the analysis of myeloid cells and suggest that previous reports on effector functions of myeloid cells using such GFP-based reporters might require re-evaluation.
Measuring the unknown: an estimator and simulation study for assessing case reporting during epidemics
Authors: Jarvis Christopher I , Gimma Amy , Finger Flavio , Morris Tim P , Thompson Jennifer A , Waroux Olivier le Polain de , Edmunds W John , Funk Sebastian , Jombart Thibaut
Published: February 2021

The fraction of cases reported, known as ‘reporting’, is a key performance indicator in an outbreak response, and an essential factor to consider when modelling epidemics and assessing their impact on populations. Unfortunately, its estimation is inherently difficult, as it relates to the part of an epidemic which is, by definition, not observed.

We introduce a simple statistical method for estimating reporting, initially developed for the response to Ebola in Eastern Democratic Republic of the Congo (DRC), 2018-2020. This approach uses transmission chain data typically gathered through case investigation and contact tracing, and uses the proportion of investigated cases with a known, reported infector as a proxy for reporting. Using simulated epidemics, we study how this method performs for different outbreak sizes and reporting levels. Results suggest that our method has low bias, reasonable precision, and despite sub-optimal coverage, usually provides estimates within close range (5-10%) of the true value.

Being fast and simple, this method could be useful for estimating reporting in real-time in settings where person-to-person transmission is the main driver of the epidemic, and where case investigation is routinely performed as part of surveillance and contact tracing activities.

Author summary

When responding to epidemics of infectious diseases, it is essential to estimate how many cases are not being reported. Unfortunately reporting, the proportion of cases actually observed, is difficult to estimate during an outbreak, as it typically requires large surveys to be conducted on the affected populations. Here, we introduce a method for estimating reporting from case investigation data, using the proportion of cases with a known, reported infector. We used simulations to test the performance of our approach by mimicking features of a recent Ebola epidemic in the Democratic Republic of the Congo. We found that despite some uncertainty in smaller outbreaks, our approach can be used to obtain informative ballpark estimates of reporting under most settings. This method is simple and computationally inexpensive, and can be used to inform the response to any epidemic in which transmission events can be uncovered by case investigation.
Invariant Differential Expression Analysis Reveals Mechanism of Cancer Resistance to Cell Cycle Inhibitors
Authors: Chatterjee Amit , Pandey Sonalisa , Danda Ravikanth , Ranjith Kumar R , Maheswari S , Khetan Vikas , Rishi Pukhraj , Ramaprabhu S , Elchuri Sailaja V , Sahoo Debashis
Published: February 2021

Retinoblastoma (RB) is a good model to study drug resistance to cell-cycle inhibitors because it is driven by mutations in the core components of cell-cycle, i.e, Rb gene. However, there is limited gene expression dataset in RB which has major reproducibility issues. We have developed invariant differential expression analysis (iDEA) that improves the state of the art in differential expression analysis (DEA). iDEA uses strong Boolean implication relationships in a large diverse human dataset GSE119087 (n = 25,955) to filter the noisy differentially expressed genes (DEGs). iDEA was applied to RB datasets and a gene signature was computed that led to prediction and mechanism of drug sensitivity. The prediction was confirmed using drugs-sensitive/resistant RB cell-lines and mouse xenograft models using CDC25 inhibitor NSC663284. iDEA improved reproducibility of differential expression across diverse retina/RB cohorts and RB cell-lines with different drug sensitivity (Y79/Weri vs NCC). Pathway analysis revealed WNT/β-catenin involved in distinguishing drug sensitivity to CDC25 inhibitor NSC663284. NSC663284 inhibited tumour cell proliferation in mouse xenograft model containing Y79 cells indicating novel therapeutic option in RB. Invariant differentially expressed genes (iDEGs) are robustly associated with outcome in diverse cancer datasets and supports for a fundamental mechanism of drug resistance.
Chromatin accessibility determines intron retention in a cell type-specific manner
Authors: Petrova Veronika , Song Renhua ,   DEEP Consortium, Nordström Karl J.V. , Walter Jörn , Wong Justin J.-L. , Armstrong Nicola J. , Rasko John E.J. , Schmitz Ulf
Published: February 2021

Dynamic intron retention (IR) in vertebrate cells is of widespread biological importance. Aberrant IR is associated with numerous human diseases including cancer. Despite consistent reports demonstrating intrinsic sequence features that predispose introns to become retained, conflicting findings about cell type-specific IR regulation demand a systematic analysis in a controlled experimental setting. We integrated matched transcriptomics and epigenetics data (including DNA methylation, nucleosome occupancy, histone modifications) from primary human myeloid and lymphoid cells. Using machine learning we trained two complementary models to determine the role of epigenetic factors in the regulation of IR. We show that increased chromatin accessibility contributes substantially to the retention of introns in a cell-specific manner. We also confirm that intrinsic characteristics of introns are key for them to evade splicing. With mounting reports linking pathogenic alterations to RNA processing, our findings may have profound implications for the design of therapeutic approaches targeting aberrant splicing.
Harmonised segmentation of neonatal brain MRI
Authors: Grigorescu Irina , Vanes Lucy , Uus Alena , Batalle Dafnis , Cordero-Grande Lucilio , Nosarti Chiara , David Edwards A. , Hajnal Joseph V. , Modat Marc , Deprez Maria
Published: February 2021

Deep learning based medical image segmentation has shown great potential in becoming a key part of the clinical analysis pipeline. However, many of these models rely on the assumption that the train and test data come from the same distribution. This means that such methods cannot guarantee high quality predictions when the source and target domains are dissimilar due to different acquisition protocols, or biases in patient cohorts. Recently, unsupervised domain adaptation (DA) techniques have shown great potential in alleviating this problem by minimizing the shift between the source and target distributions, without requiring the use of labelled data in the target domain. In this work, we aim to predict tissue segmentation maps onT2-weighted (T2w) magnetic resonance imaging (MRI) data of an unseen preterm-born neonatal population, which has both different acquisition parameters and population bias when compared to our training data. We achieve this by investigating two unsupervised DA techniques with the objective of finding the best solution for our problem. We compare the two methods with a baseline fully-supervised segmentation network and report our results in terms of Dice scores obtained on our ground truth test dataset. Moreover, we analyse tissue volumes and cortical thickness (CT) measures of the harmonised data on a subset of the population matched for gestational age (GA) at birth and postmenstrual age (PMA) at scan. Finally, we demonstrate the applicability of the harmonised cortical gray matter maps with an analysis comparing term and preterm-born neonates and a proof-of-principle investigation of the association between CT and a language outcome measure.
Heterogeneous interactions and polymer entropy decide organization and dynamics of chromatin domains
Authors: Kumari Kiran , Prakash J. Ravi , Padinhateeri Ranjith
Published: February 2021

Chromatin is known to be organized into multiple domains of varying sizes and compaction. While these domains are often imagined as static structures, they are highly dynamic and show cell-to-cell variability. Since processes such as gene regulation and DNA replication occur in the context of these domains, it is important to understand their organization, fluctuation and dynamics. To simulate chromatin domains, one requires knowledge of interaction strengths among chromatin segments. Here, we derive interaction strength parameters from experimentally known contact maps and use them to predict chromatin organization and dynamics. Taking two domains on the human chromosome as examples, we investigate its 3D organization, size/shape fluctuations, and dynamics of different segments within a domain, accounting for hydrodynamic effects. Considering different cell types, we quantify changes in interaction strengths and chromatin shape fluctuations in different epigenetic states. Perturbing the interaction strengths systematically, we further investigate how epigenetic-like changes can alter the spatio-temporal nature of the domains. Our results show that heterogeneous weak interactions are crucial in determining the organization of the domains. Computing effective stiffness and relaxation times, we investigate how perturbations in interactions affect the solid-like and liquid-like nature of chromatin domains. Quantifying dynamics of chromatin segments within a domain, we show how the competition between polymer entropy and interaction energy influence the timescales of loop formation and maintenance of stable loops.
Feature-based attention induces non-linearities in neuronal tuning and behavior during visual motion perception
Authors: Yoo Sang-Ah , Martinez-Trujillo Julio , Treue Stefan , Tsotsos John K. , Fallah Mazyar
Published: February 2021

Feature-based attention prioritizes the processing of the attended feature while strongly suppressing the processing of nearby ones. This creates a non-linearity or attentional suppressive surround predicted by the Selective Tuning model of visual attention. However, previously reported effects of feature-based attention on neuronal responses are linear, e.g., feature-similarity gain. Here, we investigated this apparent contradiction by neurophysiological and psychophysical approaches. Responses of motion direction-selective neurons in area MT/MST of monkeys were recorded during a motion task. When attention was allocated to a stimulus moving in the neurons preferred direction response tuning curves showed its minimum for directions 60-90 degrees away from the preferred direction, an attentional suppressive surround. This effect was modeled via the interaction of two Gaussian fields representing excitatory narrowly-tuned and inhibitory widely-tuned inputs into a neuron, with feature-based attention predominantly increasing the gain of inhibitory inputs. We further showed using a motion repulsion paradigm in humans that feature-based attention produces a similar non-linearity on motion discrimination performance. Our results link the gain modulation of neuronal inputs and tuning curves examined through the feature-similarity gain lens to the attentional impact on neural population responses predicted by the Selective Tuning model, providing a unified framework for the documented effects of feature-based attention on neuronal responses and behavior.