bluuebunny/crossref_metadata_2025 huggingface dataset:
Localized accumulation of Xist RNA in X chromosome inactivation
Authors: Brockdorff Neil
Published: December 2019

The non-coding RNA Xist regulates the process of X chromosome inactivation, in which one of the two X chromosomes present in cells of early female mammalian embryos is selectively and coordinately shut down. Remarkably Xist RNA functions
in cis
, affecting only the chromosome from which it is transcribed. This feature is attributable to the unique propensity of Xist RNA to accumulate over the territory of the chromosome on which it is synthesized, contrasting with the majority of RNAs that are rapidly exported out of the cell nucleus. In this review I provide an overview of the progress that has been made towards understanding localized accumulation of Xist RNA, drawing attention to evidence that some other non-coding RNAs probably function in a highly analogous manner. I describe a simple model for localized accumulation of Xist RNA and discuss key unresolved questions that need to be addressed in future studies.
Identification of four unconventional kinetoplastid kinetochore proteins KKT22–25 in
Trypanosoma brucei
Authors: Nerusheva Olga O. , Ludzia Patryk , Akiyoshi Bungo
Published: December 2019

The kinetochore is a multi-protein complex that drives chromosome segregation in eukaryotes. It assembles onto centromere DNA and interacts with spindle microtubules during mitosis and meiosis. Although most eukaryotes have canonical kinetochore proteins, kinetochores of evolutionarily divergent kinetoplastid species consist of at least 20 unconventional kinetochore proteins (KKT1–20). In addition, 12 proteins (KKT-interacting proteins 1–12, KKIP1–12) are known to localize at kinetochore regions during mitosis. It remains unclear whether KKIP proteins interact with KKT proteins. Here, we report the identification of four additional kinetochore proteins, KKT22–25, in
Trypanosoma brucei
. KKT22 and KKT23 constitutively localize at kinetochores, while KKT24 and KKT25 localize from S phase to anaphase. KKT23 has a Gcn5-related
N
-acetyltransferase domain, which is not found in any kinetochore protein known to date. We also show that KKIP1 co-purifies with KKT proteins, but not with KKIP proteins. Finally, our affinity purification of KKIP2/3/4/6 identifies a number of proteins as their potential interaction partners, many of which are implicated in RNA binding or processing. These findings further support the idea that kinetoplastid kinetochores are unconventional.
The impact of sleep on eyewitness identifications
Authors: Morgan D. P. , Tamminen J. , Seale-Carlisle T. M. , Mickes L.
Published: December 2019

Sleep aids the consolidation of recently acquired memories. Evidence strongly indicates that sleep yields substantial improvements on recognition memory tasks relative to an equivalent period of wake. Despite the known benefits that sleep has on memory, researchers have not yet investigated the impact of sleep on eyewitness identifications. Eyewitnesses to crimes are often presented with a line-up (which is a type of recognition memory test) that contains the suspect (who is innocent or guilty) and fillers (who are known to be innocent). Sleep may enhance the ability to identify the guilty suspect and not identify the innocent suspect (i.e. discriminability). Sleep may also impact reliability (i.e. the likelihood that the identified suspect is guilty). In the current study, we manipulated the presence or the absence of sleep in a forensically relevant memory task. Participants witnessed a video of a mock crime, made an identification or rejected the line-up, and rated their confidence. Critically, some participants slept between witnessing the crime and making a line-up decision, while others remained awake. The prediction that participants in the sleep condition would have greater discriminability compared to participants in the wake condition was not supported. There were also no differences in reliability.
Stability and steady state of complex cooperative systems: a diakoptic approach
Authors: Greulich Philip , MacArthur Ben D. , Parigini Cristina , Sánchez-García Rubén J.
Published: December 2019

Cooperative dynamics are common in ecology and population dynamics. However, their commonly high degree of complexity with a large number of coupled degrees of freedom renders them difficult to analyse. Here, we present a graph-theoretical criterion, via a diakoptic approach (divide-and-conquer) to determine a cooperative system’s stability by decomposing the system’s dependence graph into its strongly connected components (SCCs). In particular, we show that a linear cooperative system is Lyapunov stable if the SCCs of the associated dependence graph all have non-positive dominant eigenvalues, and if no SCCs which have dominant eigenvalue zero are connected by a path.
Actin droplet machine
Authors: Adamatzky Andrew , Schnauß Jörg , Huber Florian
Published: December 2019

The actin droplet machine is a computer model of a three-dimensional network of actin bundles developed in a droplet of a physiological solution, which implements mappings of sets of binary strings. The actin bundle network is conductive to travelling excitations, i.e. impulses. The machine is interfaced with an arbitrary selected set ofkelectrodes through which stimuli, binary strings of lengthkrepresented by impulses generated on the electrodes, are applied and responses are recorded. The responses are recorded in a form of impulses and then converted to binary strings. The machine’s state is a binary string of lengthk: if there is an impulse recorded on theith electrode, there is a ‘1’ in theith position of the string, and ‘0’ otherwise. We present a design of the machine and analyse its state transition graphs. We envisage that actin droplet machines could form an elementary processor of future massive parallel computers made from biopolymers.
Monitor application of multi-electrochemical sensor in extracting bromine from seawater
Authors: Wang Qiujin , Wu Jianbo , Zhao Guochen , Huang Yuanfeng , Wang Zhen , Zheng Hao , Zhou Yifan , Ye Ying , Ghomashchi Reza
Published: December 2019

In this paper, a set of online measurement devices of multi-electrochemical sensor was investigated. Combined with industrial distributed control system, it was first applied in extracting bromine from seawater to realize the real-time adjustment of production process parameters. In the process of extracting bromine from seawater, the pH value of acidified raw brine, the addition amount of Cl
2
in the oxidation stage and the addition amount of SO
2
in the absorption stage are key parameters to control the whole production process. The multi-electrochemical sensor realized a rapid and high-throughput detection of the above parameters by integrating an all-solid-stage bromide ion selective electrode (Br-ISE), Eh electrode and pH electrode. The Br-ISE and the pH electrode were self-developed electrodes and the Pt electrode was Eh electrode. The pH electrode was used to control the addition amount of H
2
SO
4
during the acidification of the brine. The Eh electrode was used to control the addition amount of Cl
2
during the oxidation stage and the addition amount of SO
2
during the absorption stage. The Br-ISE was used to monitor the Br
−
concentration change in the raw brine. Results showed the optimum range of Eh in the oxidation stage and absorption stage of brine were 950–1000 mV and 580–610 mV, respectively. The application of multi-electrochemical sensor in industrial bromine production can realize real-time control of material addition and save the cost of production.
Photocatalytic inactivation ofEscherichia coliunder UV light irradiation using large surface area anatase TiO2quantum dots
Authors: Ahmed Faheem , Awada Chawki , Ansari Sajid Ali , Aljaafari Abdullah , Alshoaibi Adil
Published: December 2019

In this study, high specific surface areas (SSAs) of anatase titanium dioxide (TiO2) quantum dots (QDs) were successfully synthesized through a novel one-step microwave–hydrothermal method in rapid synthesis time (20 min) without further heat treatment. XRD analysis and HR-TEM images showed that the as-prepared TiO2QDs of approximately 2 nm size have high crystallinity with anatase phase. Optical properties showed that the energy band gap (Eg) of as-prepared TiO2QDs was 3.60 eV, which is higher than the standard TiO2band gap, which might be due to the quantum size effect. Raman studies showed shifting and broadening of the peaks of TiO2QDs due to the reduction of the crystallite size. The obtained Brunauer–Emmett–Teller specific surface area (381 m2g−1) of TiO2QDs is greater than the surface area (181 m2g−1) of commercial TiO2nanoparticles. The photocatalytic activities of TiO2QDs were conducted by the inactivation ofEscherichia coliunder ultraviolet light irradiation and compared with commercially available anatase TiO2nanoparticles. The photocatalytic inactivation ability ofE. coliwas estimated to be 91% at 60 µg ml−1for TiO2QDs, which is superior to the commercial TiO2nanoparticles. Hence, the present study provides new insight into the rapid synthesis of TiO2QDs without any annealing treatment to increase the absorbance of ultraviolet light for superior photocatalytic inactivation ability ofE. coli.
Physical properties and bonding quality of laminated veneer lumber produced with veneers peeled from small-diameter rubberwood logs
Authors: Khoo P. S. , Chin K. L. , H'ng P. S. , Bakar E. S. , Lee C. L. , Go W. Z. , Dahali R.
Published: December 2019

The peeling of small-diameter rubberwood logs from the current short-rotation practices undoubtedly will produce lower grade veneers compared to the veneers from conventional planting rotation. Hence, this raises the question of the properties of the produced laminated veneer lumber (LVL) from veneers peeled from small-diameter rubberwood logs using the spindleless lathe technology. Different thicknesses of rubberwood veneers was peeled from rubberwood logs with diameter less than 20 cm using a spindleless lathe. Three-layer LVLs were prepared using phenol formaldehyde (PF) adhesive and hot pressed at different temperatures. During the peeling of veneer, lathe checks as deep as 30–60% of the veneer thickness are formed. Owing to deeper lathe check on 3 mm rubberwood veneer, higher pressing temperature significantly increased the gluebond shear strength of the PF-bonded LVL. In addition, lathe check frequency was also shown to influence the bond strength. The presence of higher lathe check frequency on 2 mm veneer increased the wettability, thus facilitating optimum penetration of adhesive for stronger bonding. These findings stress the importance of measuring and considering the lathe check depth and frequency during the lamination process to get a better understanding of bonding quality in veneer-based products.
Influence of polydimethylsiloxane substrate stiffness on corneal epithelial cells
Authors: Masterton Sophia , Ahearne Mark
Published: December 2019

Many cell types are known to modulate their behaviour in response to changes in material stiffness; however, little is known about how stiffness affects corneal epithelial cells. This study aims to investigate the response of a corneal epithelial cell line to polydimethylsiloxane (PDMS) substrates with a range of Young's moduli from 10 to 1500 kPa. Cellular morphology, proliferation, differentiation and mechanobiology were examined. Cells grown on PDMS adopted the typical cobblestone morphology exhibited by the corneal epithelium. Proliferative markers pERK and Ki67 were higher in cells cultured on stiffer substrates compared with those on softer substrates. Material stiffness was also found to influence the cell phenotype with cells on stiffer substrates having higher cytokeratin 3 gene expression, a mature epithelial marker, while cells on softer substrates expressed more cytokeratin 14, a basal epithelial marker. Cells grown on softer substrates also displayed higher levels of focal adhesions and intermediate filaments compared with cells on stiff substrates. This research will aid in designing novel biomaterials for the culture and transplantation of corneal epithelial cells.
Modelling and analysing the coexistence of dual dilemmas in the proactive vaccination game and retroactive treatment game in epidemic viral dynamics
Authors: Kabir K. M. Ariful , Tanimoto Jun
Published: December 2019

The dynamics of a spreadable disease are largely governed by four factors: proactive vaccination, retroactive treatment, individual decisions, and the prescribing behaviour of physicians. Under the imposed vaccination policy and antiviral treatment in society, complex factors (costs and expected effects of the vaccines and treatments, and fear of being infected) trigger an emulous situation in which individuals avoid infection by the pre-emptive or
ex post
provision. Aside from the established voluntary vaccination game, we propose a treatment game model associated with the resistance evolution of antiviral/antibiotic overuse. Moreover, the imperfectness of vaccinations has inevitably led to anti-vaccine behaviour, necessitating a proactive treatment policy. However, under the excessively heavy implementation of treatments such as antiviral medicine, resistant strains emerge. The model explicitly exhibits a dual social dilemma situation, in which the treatment behaviour changes on a local time scale, and the vaccination uptake later evolves on a global time scale. The impact of resistance evolution and the coexistence of dual dilemmas are investigated by the control reproduction number and the social efficiency deficit, respectively. Our investigation might elucidate the substantial impacts of both vaccination and treatment in the framework of epidemic dynamics, and hence suggest the appropriate use of antiviral treatment.
Testing predictions of inclusive fitness theory in inbreeding relatives with biparental care
Authors: Gow Elizabeth A. , Arcese Peter , Dagenais Danielle , Sardell Rebecca J. , Wilson Scott , Reid Jane M.
Published: December 2019

Inclusive fitness theory predicts that parental care will vary with relatedness between potentially caring parents and offspring, potentially shaping mating system evolution. Systems with extra-pair paternity (EPP), and hence variable parent–brood relatedness, provide valuable opportunities to test this prediction. However, existing theoretical and empirical studies assume that a focal male is either an offspring's father with no inbreeding, or is completely unrelated. We highlight that this simple dichotomy does not hold given reproductive interactions among relatives, complicating the effect of EPP on parent–brood relatedness yet providing new opportunities to test inclusive fitness theory. Accordingly, we tested hierarchical hypotheses relating parental feeding rate to parent–brood relatedness, parent kinship and inbreeding, using song sparrows (Melospiza melodia) experiencing natural variation in relatedness. As predicted, male and female feeding rates increased with relatedness to a dependent brood, even controlling for brood size. Male feeding rate tended to decrease as paternity loss increased, and increased with increasing kinship and hence inbreeding between socially paired mates. We thereby demonstrate that variation in a key component of parental care concurs with subtle predictions from inclusive fitness theory. We additionally highlight that such effects can depend on the underlying social mating system, potentially generating status-specific costs of extra-pair reproduction.
Cultural linkage: the influence of package transmission on cultural dynamics
Authors: Yeh D. Justin , Fogarty Laurel , Kandler Anne
Published: December 2019

Many cultural traits are not transmitted independently, but together as a package. This can happen because, for example, media may store information together making it more likely to be transmitted together, or through cognitive mechanisms such as causal reasoning. Evolutionary biology suggests that physical linkage of genes (being on the same chromosome) allows neutral and maladaptive genes to spread by hitchhiking on adaptive genes, while the pairwise difference between neutral genes is unaffected. Whether packaging may lead to similar dynamics in cultural evolution is unclear. To understand the effect of cultural packages on cultural evolutionary dynamics, we built an agent-based simulation that allows links to form and break between cultural traits. During transmission, one trait and others that are directly or indirectly connected to it are transmitted together in a package. We compare variation in cultural traits between different rates of link formation and breakage and find that an intermediate frequency of links can lower cultural diversity, which can be misinterpreted as a signature of payoff bias or conformity. Further, cultural hitchhiking can occur when links are common.
Games academics play and their consequences: how authorship,h-index and journal impact factors are shaping the future of academia
Authors: Chapman Colin A. , Bicca-Marques Júlio César , Calvignac-Spencer Sébastien , Fan Pengfei , Fashing Peter J. , Gogarten Jan , Guo Songtao , Hemingway Claire A. , Leendertz Fabian , Li Baoguo , Matsuda Ikki , Hou Rong , Serio-Silva Juan Carlos , Chr. Stenseth Nils
Published: December 2019

Research is a highly competitive profession where evaluation plays a central role; journals are ranked and individuals are evaluated based on their publication number, the number of times they are cited and theirh-index. Yet such evaluations are often done in inappropriate ways that are damaging to individual careers, particularly for young scholars, and to the profession. Furthermore, as with all indices, people can play games to better their scores. This has resulted in the incentive structure of science increasingly mimicking economic principles, but rather than a monetary gain, the incentive is a higher score. To ensure a diversity of cultural perspectives and individual experiences, we gathered a team of academics in the fields of ecology and evolution from around the world and at different career stages. We first examine how authorship,h-index of individuals and journal impact factors are being used and abused. Second, we speculate on the consequences of the continued use of these metrics with the hope of sparking discussions that will help our fields move in a positive direction. We would like to see changes in the incentive systems, rewarding quality research and guaranteeing transparency. Senior faculty should establish the ethical standards, mentoring practices and institutional evaluation criteria to create the needed changes.
Single-cell visualization indicates direct role of sponge host in uptake of dissolved organic matter
Authors: Achlatis Michelle , Pernice Mathieu , Green Kathryn , de Goeij Jasper M. , Guagliardo Paul , Kilburn Matthew R. , Hoegh-Guldberg Ove , Dove Sophie
Published: December 2019

Marine sponges are set to become more abundant in many near-future oligotrophic environments, where they play crucial roles in nutrient cycling. Of high importance is their mass turnover of dissolved organic matter (DOM), a heterogeneous mixture that constitutes the largest fraction of organic matter in the ocean and is recycled primarily by bacterial mediation. Little is known, however, about the mechanism that enables sponges to incorporate large quantities of DOM in their nutrition, unlike most other invertebrates. Here, we examine the cellular capacity for direct processing of DOM, and the fate of the processed matter, inside a dinoflagellate-hosting bioeroding sponge that is prominent on Indo-Pacific coral reefs. Integrating transmission electron microscopy with nanoscale secondary ion mass spectrometry, we track
15
N- and
13
C-enriched DOM over time at the individual cell level of an intact sponge holobiont. We show initial high enrichment in the filter-feeding cells of the sponge, providing visual evidence of their capacity to process DOM through pinocytosis without mediation of resident bacteria. Subsequent enrichment of the endosymbiotic dinoflagellates also suggests sharing of host nitrogenous wastes. Our results shed light on the physiological mechanism behind the ecologically important ability of sponges to cycle DOM via the recently described sponge loop.
Temporally varying disruptive selection in the medium ground finch (Geospiza fortis)
Authors: Beausoleil Marc-Olivier , Frishkoff Luke O. , M'Gonigle Leithen K. , Raeymaekers Joost A. M. , Knutie Sarah A. , De León Luis F. , Huber Sarah K. , Chaves Jaime A. , Clayton Dale H. , Koop Jennifer A. H. , Podos Jeffrey , Sharpe Diana M. T. , Hendry Andrew P. , Barrett Rowan D. H.
Published: December 2019

Disruptive natural selection within populations exploiting different resources is considered to be a major driver of adaptive radiation and the production of biodiversity. Fitness functions, which describe the relationships between trait variation and fitness, can help to illuminate how this disruptive selection leads to population differentiation. However, a single fitness function represents only a particular selection regime over a single specified time period (often a single season or a year), and therefore might not capture longer-term dynamics. Here, we build a series of annual fitness functions that quantify the relationships between phenotype and apparent survival. These functions are based on a 9-year mark–recapture dataset of over 600 medium ground finches (Geospiza fortis) within a population bimodal for beak size. We then relate changes in the shape of these functions to climate variables. We find that disruptive selection between small and large beak morphotypes, as reported previously for 2 years, is present throughout the study period, but that the intensity of this selection varies in association with the harshness of environment. In particular, we find that disruptive selection was strongest when precipitation was high during the dry season of the previous year. Our results shed light on climatic factors associated with disruptive selection in Darwin's finches, and highlight the role of temporally varying fitness functions in modulating the extent of population differentiation.
Fine-scale appendage structure of the Cambrian trilobitomorphNaraoia spinosaand its ontogenetic and ecological implications
Authors: Zhai Dayou , Edgecombe Gregory D. , Bond Andrew D. , Mai Huijuan , Hou Xianguang , Liu Yu
Published: December 2019

Trilobitomorphs are a species-rich Palaeozoic arthropod assemblage that unites trilobites with several other lineages that share similar appendage structure. Post-embryonic development of the exoskeleton is well documented for some trilobitomorphs, especially trilobites, but little is known of the ontogeny of their soft parts, limiting understanding of their autecology. Here, we document appendage structure of the Cambrian naraoiid trilobitomorphNaraoia spinosaby computed microtomography, resulting in three-dimensional reconstructions of appendages at both juvenile and adult stages. The adult has dense, strong spines on the protopods of post-antennal appendages, implying a predatory/scavenging behaviour. The absence of such gnathobasic structures, but instead tiny protopodal bristles and a number of endopodal setae, suggests a detritus-feeding strategy for the juvenile. Our data add strong morphological evidence for ecological niche shifting by Cambrian arthropods during their life cycles. A conserved number of appendages across the sampled developmental stages demonstrates thatNaraoiaceased budding off new appendages by the mid-juvenile stage.
Description of Paenibacillus antri sp. nov. and Paenibacillus mesophilus sp. nov., isolated from cave soil
Authors: Narsing Rao Manik Prabhu , Dong Zhou-Yan , Kan Yu , Zhang Kun , Fang Bao-Zhu , Xiao Min , Kang Ying-Qian , Li Wen-Jun
Published: December 2019

Two Gram-positive, rod-shaped, motile, endospore-forming strains, SYSU K30003T and SYSU K30004T, were isolated from cave soil sampled in Xingyi County, Guizhou Province, south-west PR China. The 16S rRNA gene sequence results indicated that strains SYSU K30003T and SYSU K30004T had highest sequence similarities to

Paenibacillus thermoaerophilus

DSM 26310T (93.2 %) and Paenibacillus haemerocallicola KCTC 33185T (97.8 %), respectively. Optimum growth for both strains occurred at pH 7.0 and 37 °C. Both strains contained meso-2,6-diaminopimelic acid in their cell-wall peptidoglycan and MK-7 was the only isoprenoid quinone detected. The polar lipid profile of strain SYSU K30004T consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two aminophospholipids, an unidentified glycolipid, unidentified phospholipids and two unidentified polar lipids. The polar lipid profile of strain SYSU K30003T contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and an unidentified glycolipid. The major fatty acids (>5 %) of strain SYSU K30003T were anteiso-C15:0, C16 : 0, anteiso-C17 : 0 and iso-C16 : 0, while those of strain SYSU K30004T were anteiso-C15:0, C16:0, anteiso-C17 : 0, iso-C15 : 0, iso-C16:0 and iso-C17 : 0. The genome G+C contents of strains SYSU K30003T and SYSU K30004T were 59.0 and 53.6 mol%, respectively. The average nucleotide identity values between strains SYSU K30003T and SYSU K30004T and other closely related

Paenibacillus

members were below the cut-off level (95–96 %) for species identification. Based on the results of phenotypic, chemotaxonomic and genome analyses, strains SYSU K30003T and SYSU K30004T represent two novel species of the genus

Paenibacillus

, for which the names Paenibacillus antri sp. nov. and Paenibacillus mesophilus sp. nov. are proposed. The type strains are SYSU K30003T (=KCTC 33956T=CGMCC 1.13505T) and SYSU K30004T (=KCTC 33957T=CGMCC 1.13872T).
Using a genetic risk score to estimate the earliest age of Alzheimer’s disease-related physiologic change in Body Mass Index
Authors: Brenowitz Willa D. , Zimmerman Scott C. , Filshtein Teresa J. , Yaffe Kristine , Walter Stefan , Hoffmann Thomas J. , Jorgenson Eric , Whitmer Rachel A. , Glymour M. Maria
Published: December 2019

Objectives

Weight loss is common in the years before an Alzheimer’s disease (AD) diagnosis, likely due to changes in appetite and diet. The age at which this change in body mass index (BMI) emerges is unclear but may point to the earliest manifestations of AD, timing that may be important for identifying windows of intervention or risk reduction. We examined the association between AD genetic risk and cross-sectional BMI across adults in mid-to late-life as an innovative approach to determine the age at which BMI changes and may indicate preclinical AD.

Design

Observational study

Setting

UK Biobank

Participants

407,386 UK Biobank non-demented participants aged 39-70 with Caucasian genetic ancestry enrolled 2007-2010.

Main Outcome Measures

BMI (kg/m2) was constructed from height and weight measured during the initial visit. A genetic risk score for AD (AD-GRS) was calculated as a weighted sum of 23 genetic variants previously confirmed to be genome-wide significant predictors of AD (Z-scored). We evaluated whether the association of AD-GRS with BMI differed by age using linear regression with adjustment for sex and genetic ancestry, stratified by age grouping (40-60, 61+). We calculated the earliest age at which high AD-GRS predicted divergence in BMI compared to normal age-related BMI trends with linear and quadratic terms for age and interactions with AD-GRS.

Results

In 39-49 year olds, AD-GRS was not significantly associated with lower BMI (0.00 kg/m2 per SD in AD-GRS; 95%CI: -0.03,0.03). In 50-59 year olds AD-GRS was associated with lower BMI (-0.03 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.06,-0.01) and this association was stronger in 60-70 year olds (-0.09 kg/m2 per 1 SD in AD-GRS; 95%CI:-0.12,-0.07). Model-based BMI age-curves for people with high versus low AD-GRS scores began to diverge after age 47.

Interpretation

Genetic factors that increase AD risk begin to predict lower BMI in adults by age 50, with greater effect later in older ages. Weight loss may manifest as an early pathophysiologic change associated with AD.
Left frontal white matter links to rhythmic processing relevant to speech production
Authors: Bruffaerts Rose , Schaeverbeke Jolien , Grube Manon , Gabel Silvy , De Weer An-Sofie , Dries Eva , Van Bouwel Karen , Griffiths Timothy D , Sunaert Stefan , Vandenberghe Rik
Published: December 2019

Recent evidence suggests that a shared neurocomputational mechanism tracks the temporal structure of auditory input and speech output. We investigate the link between speech production and rhythmic abilities in 24 healthy controls and 23 patients with primary progressive aphasia, including 12 non-fluent variant patients (NFV) with apraxia of speech. Seventy-five percent of NFV cases displayed poorer rhythmic abilities. Rhythmic abilities and speech rhythm were significantly correlated in both controls and patients. Deformation-based morphometry and diffusion tensor imaging were used to identify white matter atrophy related to impaired rhythmic abilities in NFV. Left frontal white matter volume adjacent to the supplementary motor area (SMA) correlated with rhythmic abilities. Metrics of the left Aslant tract, which is typically damaged in NFV cases, also correlated with rhythmic abilities. Our results support the existence of a common temporal scaffolding mechanism structuring perceptual input and speech output. This mechanism partly explains abnormal speech in NFV.
Persistence of Anti-Zika Virus Immunoglobulin M Antibodies in Children with Microcephaly up to Four Years after Primary Infection
Authors: Campos Gubio S. , Carvalho Rejane H. , da Glória Teixeira Maria , Britto e Silva Giovanna F. , Rolo Carolina A. , Menezes Aline D. L. , Souza Rafael. R. M. , Sardi Silvia I.
Published: December 2019

Zika virus (ZIKV) is a member of the flaviviridae family of virus, considered to cause acute self-limited infection in adults, though it may lead to severe complications. It is believed that ZIKV infection elicit a classical viral immune reaction, with primary IgM antibody response and secondary IgG immunity. Persistence of IgM antibodies has been identified for other viruses belonging to the same family as ZIKV. We investigated, therefore, the presence of anti-ZIKV IgM antibodies in children with microcephaly born between January 2015 and November 2018, and their parents. We have detected persistence of IgM in 22% of children with microcephaly up to four years after primary infection. Long term IgM persistence have implications for the diagnosis of acute infection. More investigation is needed in order to correctly construe the significance of anti-ZIKV IgM persistence in the population in general, and in children with microcephaly in particular. The dynamics of IgM antibody responses against ZIKV must be known and understood to avoid misinterpretation of diagnosis for acute infection, re-infection and antibody persistence.
Discoidin domain receptor 2 drives melanoma drug resistance through AXL-dependent phenotype switching
Authors: Sala Margaux , Allain Nathalie , Jabouille Arnaud , Henriet Elodie , Abou-Ammoud Aya , Uguen Arnaud , Di-Tommaso Sylvaine , Dhourte Cyril , Raymond Anne-Aurélie , Dupuy Jean-William , Gerard Emilie , Dugot-Senant Nathalie , Rousseau Benoit , Merlio Jean-Phillipe , Pham-Ledart Anne , Vergier Béatrice , Moreau Violaine , Saltel Frédéric
Published: December 2019

Anti-BRAF plus anti-MEK are used as first-line treatment of patients with metastatic melanomas harboringBRAFV600E mutation. The main issue with targeted therapy is acquired cellular resistance. In 70% of acquired resistance, melanoma cells switch their phenotype and become more aggressive and invasive. The molecular signature of this phenotype is MITF low, AXL high associated with actin cytoskeleton reorganization. After this switch, resistant cells present an anarchic cell proliferation due to MAP kinase pathway hyper-activation. We demonstrate that resistant cell lines presenting phenotype switching overexpress DDR1 and DDR2. We show that DDR2 inhibition induces a decrease in AXL and reduces actin stress fiber formation. Once this phenotype switching is acquired, we report that both DDRs promotes tumor cell proliferation, but only DDR2 can over-activate the MAP kinase pathway in resistant invasive cellsin vitroandin vivo. Therefore, DDRs inhibition could be a promising strategy for countering this resistance mechanism.

Significance

Our results show that DDR2 is a relevant target in melanoma resistance. DDR2 is required at the beginning of resistance for melanoma cell phenotype switching to occur. After phenotype switching, DDRs promote tumor cell proliferation of resistant invasive melanoma cells, but only DDR2 is able to over-activate the MAP kinase pathway. We put forward dasatinib (a DDR inhibitor) as a potential second-line treatment after targeted dual therapy for resistant patients overexpressing DDRs.
Corollary Discharge Promotes a Sustained Motor State in a Neural Circuit for Navigation
Authors: Ji Ni , Venkatachalam Vivek , Rodgers Hillary , Hung Wesley , Kawano Taizo , Clark Christopher M. , Lim Maria , Alkema Mark J. , Zhen Mei , Samuel Aravinthan D.T.
Published: December 2019

Animals exhibit behavioral and neural responses that persist on longer time scales than transient or fluctuating stimulus inputs. Here, we report that C. elegans uses feedback from the motor circuit to a sensory processing interneuron to sustain its motor state during thermotactic navigation. By imaging circuit activity in behaving animals, we show that a principal postsynaptic partner of the AFD thermosensory neuron, the AIY interneuron, encodes both temperature and motor state information. By optogenetic and genetic manipulation of this circuit, we demonstrate that the motor state representation in AIY is a corollary discharge signal. RIM, an interneuron that is connected with premotor interneurons, is required for this corollary discharge. Ablation of RIM eliminates the motor representation in AIY, allows thermosensory representations to reach downstream premotor interneurons, and reduces the animal’s ability to sustain forward movements during thermotaxis. We propose that feedback from the motor circuit to the sensory processing circuit underlies a positive feedback mechanism to generate persistent neural activity and sustained behavioral patterns in a sensorimotor transformation.
Regulatory T cell expansion by a highly CD25-dependent IL-2 mutein arrests ongoing autoimmunity
Authors: Khoryati Liliane , Pham Minh Nguyet , Sherve McKenna , Kumari Swarnima , Cook Kevin , Pearson Josh , Bogdani Marika , Campbell Daniel J. , Gavin Marc A.
Published: December 2019

Interleukin-2 (IL-2) controls the homeostasis and function of regulatory T cells (Tregs) and defects in the IL-2 pathway contribute to multiple autoimmune diseases. Although recombinant IL-2 therapy has been efficacious in certain inflammatory conditions, the capacity for IL-2 to also activate inflammatory effector responses highlights the need for IL-2-based therapeutics with improved Treg-specificity. From a panel of rationally designed IL-2 variants, we identified IL-2 muteins with reduced potency and enhanced Treg-selectivity due to increased dependence on the IL-2-receptor component CD25. As an Fc-fused homodimer, the optimal Fc.IL-2 mutein induced selective Treg enrichment and reduced agonism of effector cells across a wide dose range. Furthermore, despite being a weaker agonist, overall Treg growth was greater and more sustained due to reduced receptor-mediated clearance of the Fc.IL-2 mutein compared to Fc-fused wild-type IL-2. Preferential Treg enrichment was also observed in the presence of activated pathogenic T cells in the autoimmune target organ, despite a loss of Treg-selectivity in an IL-2R-proximal response. These features allowed for extended resolution of spontaneous autoimmunity using infrequent dosing schedules. Thus, IL-2 muteins enable efficient, flexible, and targeted control of the autoimmune response.

One Sentence Summary

A CD25-dependent IL-2 mutein selectively expands regulatory T cells and provides potent and targeted control of autoimmunity.
Premature termination codon readthrough inDrosophilavaries in a developmental and tissue-specific manner
Authors: Chen Yanan , Sun Tianhui , Bi Zhuo , Ni Jian-Quan , Pastor-Pareja Jose C. , Javid Babak
Published: December 2019

Despite their essential function in terminating translation, readthrough of stop codons occurs more frequently than previously supposed. However, little is known about the regulation of stop codon readthrough by anatomical site and over the life cycle of animals. Here, we developed a set of reporters to measure readthrough inDrosophila melanogaster. A focused RNAi screen in whole animals identifiedupf1as a mediator of readthrough, suggesting that the stop codons in the reporters were recognized as premature termination codons (PTCs). We found readthrough rates of PTCs varied significantly throughout the life cycle of flies, being highest in older adult flies. Furthermore, readthrough rates varied dramatically by tissue and, intriguingly, were highest in fly brains, specifically neurons and not glia. This was not due to differences in reporter abundance or nonsense-mediated mRNA decay (NMD) surveillance between these tissues. Overall, our data reveal temporal and spatial variation of PTC-mediated readthrough in animals, and suggest that readthrough may be a potential rescue mechanism for PTC-harboring transcripts when the NMD surveillance pathway is inhibited.
ExpansionHunter Denovo: A computational method for locating known and novel repeat expansions in short-read sequencing data
Authors: Dolzhenko Egor , Bennett Mark F. , Richmond Phillip A. , Trost Brett , Chen Sai , van Vugt Joke J.F.A. , Nguyen Charlotte , Narzisi Giuseppe , Gainullin Vladimir G. , Gross Andrew , Lajoie Bryan , Taft Ryan J. , Wasserman Wyeth W. , Scherer Stephen W. , Veldink Jan H. , Bentley David R. , Yuen R K.C. , Bahlo Melanie , Eberle Michael A.
Published: December 2019

Expansions of short tandem repeats are responsible for over 40 monogenic disorders, and undoubtedly many more pathogenic repeat expansions (REs) remain to be discovered. Existing methods for detecting REs in short-read sequencing data require predefined repeat catalogs. However recent discoveries have emphasized the need for detection methods that do not require candidate repeats to be specified in advance. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide detection of REs. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference REs not discoverable via existing methods.

ExpansionHunter Denovo is freely available at https://github.com/Illumina/ExpansionHunterDenovo
Bacteriophages inhibit biofilms formed by multi-drug resistant bacteria isolated from septic wounds
Authors: Pallavali Roja Rani , Degati Vijaya Lakshmi , Durbaka Vijaya Raghava Prasad
Published: December 2019

Globally, indiscriminate use of antibiotics contributed to the development of antibiotic resistance by the majority of microbial pathogens. As an alternative to antibiotics, using bacteriophages as antibiofilm agents to tackle multi-drug resistant bacteria has gained importance in recent years. In the present study, we explored the ability of bacteriophages to inhibit biofilm formation under various conditions. Under dynamic condition (DR), wherein the medium is a renewal for every 12 h amount of biomass produced (0.74 ± 0.039), log10CFU count (6.3 ± 0.55) was highest when compared to other physical conditions tested. Biomass of biofilms produced byStaphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, andEscherichia colidrastically reduced when incubated for 2 or 4 h with bacteriophages vB_SAnS_SADP1, vB_PAnP_PADP4, vB_KPnM_KPDP1, and vB_ECnM_ECDP3 respectively at the time points tested (24, 48 and 72 h). Among the phages, vB_ECnM_ECDP3 effectively inhibited the biomass of biofilm when incubated for 2 h (0.35 ± 0.04, (44 %) (p < 0.0001) or 4 h (0.17 ± 0.015, (21.5%) (p<0.0001). Bacteriophages ofE. coli(vB_ECnM_ECDP3)P. aeruginosa(vB_PAnP_PADP4),K. pneumoniae(vB_KPnM_KPDP1) andS. aureus(vB_SAnS_SADP1) also significantly inhibited the biomass of biofilm formation as evidenced by Scanning Electron Microscopy and Confocal laser scanning microscopy.
The Use of GC-, Codon-, and Amino Acid-frequencies to Understand the Evolutionary Forces at a Genomic Scale
Authors: Elofsson Arne
Published: December 2019

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It is well known that the GC content varies enormously between organisms; this is believed to be caused by a combination of mutational preferences and selective pressure. Within coding regions, the variation of GC is more substantial in position three and smaller in position one and two. Less well known is that this variation also has an enormous impact on the frequency of amino acids as their codons vary in GC content. For instance, the fraction of alanines in different proteomes varies from 1.1% to 16.5%. In general, the frequency of different amino acids correlates strongly with the number of codons, the GC content of these codons and the genomic GC contents. However, there are clear and systematic deviations from the expected frequencies. Some amino acids are more frequent than expected by chance, while others are less frequent. A plausible model to explain this is that there exist two different selective forces acting on the genes; First, there exists a force acting to maintain the overall GC level and secondly there exists a selective force acting on the amino acid level. Here, we use the divergence in amino acid frequency from what is expected by the GC content to analyze the selective pressure acting on codon frequencies in the three kingdoms of life. We find four major selective forces; First, the frequency of serine is lower than expected in all genomes, but most in prokaryotes. Secondly, there exist a selective pressure acting to balance positively and negatively charged amino acids, which results in a reduction of arginine and negatively charged amino acids. This results in a reduction of arginine and all the negatively charged amino acids. Thirdly, the frequency of the hydrophobic residues encoded by a T in the second codon position does not change with GC. Their frequency is lower in eukaryotes than in prokaryotes. Finally, some amino acids with unique properties, such as proline glycine and proline, are limited in their frequency variation.
Improving Bacterial Ribosome Profiling Data Quality
Authors: Glaub Alina , Huptas Christopher , Neuhaus Klaus , Ardern Zachary
Published: December 2019

Ribosome profiling (RIBO-seq) in prokaryotes has the potential to facilitate accurate detection of translation initiation sites, to increase understanding of translational dynamics, and has already allowed detection of many unannotated genes. However, protocols for ribosome profiling and corresponding data analysis are not yet standardized. To better understand the influencing factors, we analysed 48 ribosome profiling samples from 9 studies on E. coli K12 grown in LB medium. We particularly investigated the size selection step in each experiment since the selection for ribosome-protected footprints (RPFs) has been performed at various read lengths. We suggest choosing a size range between 22-30 nucleotides in order to obtain protein-coding fragments. In order to use RIBO-seq data for improving gene annotation of weakly expressed genes, the total amount of reads mapping to protein-coding sequences and not rRNA or tRNA is important, but no consensus about the appropriate sequencing depth has been reached. Again, this causes significant variation between studies. Our analysis suggests that 20 million non rRNA/tRNA mapping reads are required for global detection of translated annotated genes. Further, we highlight the influence of drug induced ribosome stalling, causing bias at translation start sites. Drug induced stalling may be especially useful for detecting weakly expressed genes. These suggestions should improve both gene detection and the comparability of resulting ribosome profiling datasets.
Single-cell transcriptomics reveals diverse and complex gene expression alterations in human trisomy 18
Authors: Wang Jing , Chen Zixi , He Fei , Lee Trevor , Cai Wenjie , Chen Wanhua , Zhang Longbin , Miao Nan , Zeng Zhiwei , Hussain Ghulam , Guo Qiwei , Sun Tao
Published: December 2019

Trisomy 18, commonly known as Edward’s syndrome, is the second most common autosomal trisomy among live born neonates. Multiple tissues including cardiac, abdominal, and nervous systems are affected by an extra chromosome 18. To delineate the complexity of anomalies of trisomy 18, we analyzed amniotic fluid cells from two normal and three trisomy 18 samples using single-cell transcriptomics. We identified six cell groups, which function in major tissue development such as kidney, vasculature, and smooth muscle, and display significant alterations in gene expression detected by single-cell RNA-sequencing. Moreover, we demonstrated significant gene expression changes in previously proposed trisomy 18 critical regions, and identified three new regions such as 18p11.32, 18q11, 18q21.32, which are likely associated with trisomy 18 phenotypes. Our results indicate complexity of trisomy 18 at the gene expression level and reveal genetic reasoning of diverse phenotypes in trisomy 18 patients.
Multiscale criticality measures as general-purpose gauges of proper brain function
Authors: Fekete Tomer , Hinrichs Hermann , Sitt Jacobo Diego , Heinze Hans-Jochen , Shriki Oren
Published: December 2019

The brain is universally regarded as a system for processing information. If so, any behavioral or cognitive dysfunction should lend itself to depiction in terms of information processing deficiencies. Information is characterized by recursive, hierarchical complexity. The brain accommodates this complexity by a hierarchy of large/slow and small/fast spatiotemporal loops of activity. Thus, successful information processing hinges upon tightly regulating the spatiotemporal makeup of activity, to optimally match the underlying multiscale delay structure of such hierarchical networks. Reduced capacity for information processing will then be expressed as deviance from this requisite multiscale character of spatiotemporal activity. This deviance is captured by a general family of multiscale criticality measures (MsCr). We applied MsCr to MEG and EEG data in four telling degraded information processing scenarios: disorders of consciousness, mild cognitive impairment, schizophrenia and preictal activity. Consistently with our previous modeling work, MsCr measures systematically varied with information processing capacity. MsCr measures might thus be able to serve as general gauges of information processing capacity and, therefore, as normative measures of brain health.
Genetic dominance governs the evolution and spread of mobile genetic elements in bacteria
Authors: Rodríguez-Beltrán Jerónimo , Sørum Vidar , Toll-Riera Macarena , de la Vega Carmen , Peña-Miller Rafael , San Millán Alvaro
Published: December 2019

Mobile genetic elements (MGEs), such as plasmids, promote bacterial evolution through horizontal gene transfer (HGT). However, the rules governing the repertoire of traits encoded on MGEs remain unclear. In this study, we uncovered the central role of genetic dominance shaping genetic cargo in MGEs, using antibiotic resistance as a model system. MGEs are typically present in more than one copy per host bacterium and, as a consequence, genetic dominance favors the fixation of dominant mutations over recessive ones. Moreover, genetic dominance also determines the phenotypic effects of horizontally acquired MGE-encoded genes, silencing recessive alleles if the recipient bacterium already carries a wild-type copy of the gene. The combination of these two effects governs the catalogue of genes encoded on MGEs, dictating bacterial evolution through HGT.