bluuebunny/crossref_metadata_2025 huggingface dataset:
High-resolution ALMA and HST images of q1 Eri: an asymmetric debris disc with an eccentric Jupiter
Authors: Lovell J B , Marino S , Wyatt M C , Kennedy G M , MacGregor M A , Stapelfeldt K , Dent B , Krist J , Matrà L , Kral Q , Panić O , Pearce T D , Wilner D
Published: June 2021

We present Atacama Large Millimetre/sub-Millimetre Array (ALMA) 1.3 and 0.86 mm observations of the nearby (17.34 pc) F9V star q1 Eri (HD 10647, HR 506). This system, with age ∼1.4 Gyr, hosts a ∼2 au radial velocity planet and a debris disc with the highest fractional luminosity of the closest 300 FGK type stars. The ALMA images, with resolution ∼0${_{.}^{\prime\prime}}$5, reveal a broad (34–134 au) belt of millimetre emission inclined by 76.7 ± 1.0 degrees with maximum brightness at 81.6 ± 0.5 au. The images reveal an asymmetry, with higher flux near the south-west ansa, which is also closer to the star. Scattered light observed with the Hubble Space Telescope is also asymmetric, being more radially extended to the north-east. We fit the millimetre emission with parametric models and place constraints on the disc morphology, radius, width, dust mass, and scale height. We find that the south-west ansa asymmetry is best fitted by an extended clump on the inner edge of the disc, consistent with perturbations from a planet with mass $8\, M_{\oplus } {-} 11\, M_{\rm Jup}$ at ∼60 au that may have migrated outwards, similar to Neptune in our Solar system. If the measured vertical aspect ratio of h = 0.04 ± 0.01 is due to dynamical interactions in the disc, then this requires perturbers with sizes >1200 km. We find tentative evidence for a 0.86 mm excess within 10 au, $70{\pm }22\, \mu$Jy, that may be due to an inner planetesimal belt. We find no evidence for CO gas, but set an upper bound on the CO gas mass of 4 × 10−6 M⊕ ($3\sigma$), consistent with cometary abundances in the Solar system.
A force proportional to velocity squared derived from spacetime algebra
Authors: Hansen Steen H
Published: June 2021

The underlying geometry of spacetime algebra allows one to derive a force by contracting the relativistic generalization of angular momentum, M, with the mass-current, mω, where w is a proper 4-vector velocity. By applying this force to a cosmological object, a repulsive inverse distance-square law is found, which is proportional to the velocity dispersion squared of that structure. It is speculated if this finding may be relevant to the recent suggestion, that such a force may accelerate the expanding universe with no need for a cosmological constant.
Impact of the interplay between stemness features, p53 and pol iota on replication pathway choices
Authors: Ihle Michaela , Biber Stephanie , Schroeder Insa S , Blattner Christine , Deniz Miriam , Damia Giovanna , Gottifredi Vanesa , Wiesmüller Lisa
Published: June 2021

Using human embryonic, adult and cancer stem cells/stem cell-like cells (SCs), we demonstrate that DNA replication speed differs in SCs and their differentiated counterparts. While SCs decelerate DNA replication, differentiated cells synthesize DNA faster and accumulate DNA damage. Notably, both replication phenotypes depend on p53 and polymerase iota (POLι). By exploring protein interactions and newly synthesized DNA, we show that SCs promote complex formation of p53 and POLι at replication sites. Intriguingly, in SCs the translocase ZRANB3 is recruited to POLι and required for slow-down of DNA replication. The known role of ZRANB3 in fork reversal suggests that the p53–POLι complex mediates slow but safe bypass of replication barriers in SCs. In differentiated cells, POLι localizes more transiently to sites of DNA synthesis and no longer interacts with p53 facilitating fast POLι-dependent DNA replication. In this alternative scenario, POLι associates with the p53 target p21, which antagonizes PCNA poly-ubiquitination and, thereby potentially disfavors the recruitment of translocases. Altogether, we provide evidence for diametrically opposed DNA replication phenotypes in SCs and their differentiated counterparts putting DNA replication-based strategies in the spotlight for the creation of therapeutic opportunities targeting SCs.
Gull-inspired joint-driven wing morphing allows adaptive longitudinal flight control
Authors: Harvey C. , Baliga V. B. , Goates C. D. , Hunsaker D. F. , Inman D. J.
Published: June 2021

Birds dynamically adapt to disparate flight behaviours and unpredictable environments by actively manipulating their skeletal joints to change their wing shape. This in-flight adaptability has inspired many unmanned aerial vehicle (UAV) wings, which predominately morph within a single geometric plane. By contrast, avian joint-driven wing morphing produces a diverse set of non-planar wing shapes. Here, we investigated if joint-driven wing morphing is desirable for UAVs by quantifying the longitudinal aerodynamic characteristics of gull-inspired wing-body configurations. We used a numerical lifting-line algorithm (MachUpX) to determine the aerodynamic loads across the range of motion of the elbow and wrist, which was validated with wind tunnel tests using three-dimensional printed wing-body models. We found that joint-driven wing morphing effectively controls lift, pitching moment and static margin, but other mechanisms are required to trim. Within the range of wing extension capability, specific paths of joint motion (trajectories) permit distinct longitudinal flight control strategies. We identified two unique trajectories that decoupled stability from lift and pitching moment generation. Further, extension along the trajectory inherent to the musculoskeletal linkage system produced the largest changes to the investigated aerodynamic properties. Collectively, our results show that gull-inspired joint-driven wing morphing allows adaptive longitudinal flight control and could promote multifunctional UAV designs.
Tracing contacts to evaluate the transmission of COVID-19 from highly exposed individuals in public transportation
Authors: Ponte Caio , Carmona Humberto A. , Oliveira Erneson A. , Caminha Carlos , Lima Neto Antonio S. , Andrade José S. , Furtado Vasco
Published: June 2021

We investigate, through a data-driven contact tracing model, the transmission of COVID-19 inside buses during distinct phases of the pandemic in a large Brazilian city. From this microscopic approach, we recover the networks of close contacts within consecutive time windows. A longitudinal comparison is then performed by upscaling the traced contacts with the transmission computed from a mean-field compartmental model for the entire city. Our results show that the effective reproduction numbers inside the buses, Rebus, and in the city, Recity, followed a compatible behavior during the first wave of the local outbreak. Moreover, by distinguishing the close contacts of healthcare workers in the buses, we discovered that their transmission, Rehealth, during the same period, was systematically higher than Rebus. This result reinforces the need for special public transportation policies for highly exposed groups of people.
Development of low-cost serological immunoassay to detect antiviral antibodies to Sars-Cov-2 Spike protein
Authors: Peroni Luis Antonio , Toscaro Jessica , Canateli Camila , Lima Gabriel , Pagliarone Ana , Cardoso Elaine , Viana Renata , Borges Jessica Bassani , Lin-Wang Hui Tzu , Abboud Cely S. , Gun Carlos , Franchini Kleber , Bajgelman Marcio
Published: June 2021

Seroconversion to SARS-CoV-2 has been widely studied to evaluate infection spreading for epidemiological purpose, or even in studies of protective immunity in convalescent or vaccinated individuals. The viral particle has an envelope harboring the spike glycoprotein, which can be used as an antigen for assay development, to detect antiviral antibodies to SARS-CoV-2. Since several vaccines encode a spike subunit, the full length spike-based immunoassay should be a universal tool to evaluate seroconversion. In this manuscript, we propose a low-cost ELISA that can be used to detect antiviral IgG to SARS-CoV-2 in human serum.
Extended Invariant Information Clustering is Effective for Leave-One-Site-Out Cross-Validation in Resting State Functional Connectivity Modelling
Authors: Okamoto Naoki , Akama Hiroyuki
Published: June 2021

Herein, we propose a new deep neural network model based on invariant information clustering (IIC), proposed by Ji et al., to improve the modeling performance of the leave-one-site-out cross-validation (LOSO-CV) for a multi-source dataset. Our Extended IIC (EIIC) is a type of contrastive learning; however, unlike the original IIC, it is characterized by transfer learning with labeled data pairs, but without the need for a data augmentation technique. Each site in LOSO-CV is left out in turn from the remaining sites used for training and receives a value for modeling evaluation. We applied the EIIC to the resting state functional connectivity magnetic resonance imaging dataset of the Autism Brain Imaging Data Exchange. The challenging nature of brain analysis for autism spectrum disorder (ASD) can be attributed to the variability of subjects, particularly the rapid change in the neural system of children as the target ASD age group. However, EIIC demonstrated higher LOSO-CV classification accuracy for the majority of scanning locations than previously used methods. Particularly, with the adjustment of a mini-batch size, EIIC outperformed other classifiers with an accuracy >0.8 for the sites with highest mean age of the subjects. Considering its effectiveness, our proposed method might be promising for harmonization in other domains, owing to its simplicity and intrinsic flexibility. We are currently submitting this manuscript to Frontiers in Neuroinformatics.
The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour
Authors: Oliveira A. Sofia F. , Shoemark Deborah K. , Ibarra Amaurys Avila , Davidson Andrew D. , Berger Imre , Schaffitzel Christiane , Mulholland Adrian J.
Published: June 2021

The SARS-CoV-2 spike protein is the first contact point between the SARS-CoV-2 virus and host cells and mediates membrane fusion. Recently, a fatty acid binding site was identified in the spike (Toelzer et al. Science 2020). The presence of linoleic acid at this site modulates binding of the spike to the human ACE2 receptor, stabilizing a locked conformation of the protein. Here, dynamical-nonequilibrium molecular dynamics simulations reveal that this fatty acid site is coupled to functionally relevant regions of the spike, some of them far from the fatty acid binding pocket. Removal of a ligand from the fatty acid binding site significantly affects the dynamics of distant, functionally important regions of the spike, including the receptor-binding motif, furin cleavage site and fusion-peptide-adjacent regions. The results also show significant differences in behaviour between clinical variants of the spike: e.g. the D614G mutation shows a significantly different conformational response for some structural motifs relevant for binding and fusion. The simulations identify structural networks through which changes at the fatty acid binding site are transmitted within the protein. These communication networks significantly involve positions that are prone to mutation, indicating that observed genetic variation in the spike may alter its response to linoleate binding and associated allosteric communication.
Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Authors:   RECOVERY Collaborative Group, Horby Peter W , Pessoa-Amorim Guilherme , Staplin Natalie , Emberson Jonathan R , Campbell Mark , Spata Enti , Peto Leon , Brunskill Nigel J , Tiberi Simon , Chew Victor , Brown Thomas , Tahir Hasan , Ebert Beate , Chadwick David , Whitehouse Tony , Sarkar Rahuldeb , Graham Clive , Baillie J Kenneth , Basnyat Buddha , Buch Maya H , Chappell Lucy C , Day Jeremy , Faust Saul N , Hamers Raph L , Jaki Thomas , Juszczak Edmund , Jeffery Katie , Lim Wei Shen , Montgomery Alan , Mumford Andrew , Rowan Kathryn , Thwaites Guy , Mafham Marion , Haynes Richard , Landray Martin J
Published: June 2021

Background

Aspirin has been proposed as a treatment for COVID-19 on the basis of its antithrombotic properties.

Methods

In this randomised, controlled, open-label platform trial, several possible treatments were compared with usual care in patients hospitalised with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care plus 150mg aspirin once daily until discharge or usual standard of care alone using web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).

Findings

Between 01 November 2020 and 21 March 2021, 7351 patients were randomly allocated to receive aspirin and 7541 patients to receive usual care alone. Overall, 1222 (17%) patients allocated to aspirin and 1299 (17%) patients allocated to usual care died within 28 days (rate ratio 0·96; 95% confidence interval [CI] 0·89-1·04; p=0·35). Consistent results were seen in all pre-specified subgroups of patients. Patients allocated to aspirin had a slightly shorter duration of hospitalisation (median 8 vs. 9 days) and a higher proportion were discharged from hospital alive within 28 days (75% vs. 74%; rate ratio 1·06; 95% CI 1·02-1·10; p=0·0062). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (21% vs. 22%; risk ratio 0·96; 95% CI 0·90-1·03; p=0·23). Aspirin use was associated with an absolute reduction in thrombotic events of 0.6% (SE 0.4%) and an absolute increase in major bleeding events of 0.6% (SE 0.2%).

Interpretation

In patients hospitalised with COVID-19, aspirin was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death but was associated with a small increase in the rate of being discharged alive within 28 days.

Funding

UK Research and Innovation (Medical Research Council), National Institute of Health Research (Grant ref: MC_PC_19056), and the Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator.
Association between Preventive Measures against Workplace Infection and Preventive Behavior against Personal Infection
Authors: Kawasumi Mika , Nagata Tomohisa , Ando Hajime , Hino Ayako , Tateishi Seiichiro , Tsuji Mayumi , Matsuda Shinya , Fujino Yoshihisa , Mori Koji ,   for the CORoNaWork project
Published: June 2021

Objectives

To prevent the spread of coronavirus disease 2019 (COVID-19) infection, it is necessary for each individual to adopt infection prevention behavior. We investigated the effect of infection control measures implemented in the workplace on personal infection prevention behavior.

Methods

We conducted a self-administered questionnaire survey through the Internet from December 22 to 25, 2020, during which period COVID-19 was spreading. Among respondents aged 20 to 65 years (n=27,036), a total of 21,915 workers were included in the analysis after excluding self-employed workers (n=2,202), workers in small/home offices (n=377), and agriculture, forestry, and fisheries workers (n=212), etc., whose personal infection prevention behavior was almost the same as infection control measures taken in the workplace.

Results

The results showed that as the number of infection control measures in the workplace increased, implementation of infection prevention behavior by individuals also significantly increased. However, the relationship differed depending on the type of personal infection prevention behavior. Specifically, infection control measures against COVID-19 in the workplace may affect personal infection prevention behavior.

Conclusion

Implementation of infection control measures in the workplace appears to deepen personal understanding of infection prevention behaviors, and increases awareness of the importance of individual infection prevention behavior and its implementation by all individuals. These findings may be applicable not only to COVID-19 measures but also to responses to other emerging infections and seasonal influenza.
The missing pathway in current visuospatial processing models
Authors: Beyh Ahmad , Dell’Acqua Flavio , Cancemi Daniele , De Santiago Requejo Francisco , ffytche Dominic , Catani Marco
Published: June 2021

Visuospatial learning depends on the parahippocampal place area (PPA), a functionally heterogenous area which current visuospatial processing models place downstream from parietal cortex and only from area V4 of early visual cortex (EVC). However, evidence for anatomical connections between the PPA and other EVC areas is inconsistent, and these connections are not discussed in current models. Through a data-driven analysis based on diffusion MRI tractography, we present evidence that the PPA sits at the confluence of two white matter systems. The first conveys information from the retrosplenial complex to the anterior PPA and runs within the cingulum bundle. The second system connects all peripheral EVC areas to the posterior PPA and corresponds to the medial occipital longitudinal tract (MOLT), a novel white matter pathway distinct from the cingulum. Based on further functional connectivity analysis and meta-analytic data, we propose that the MOLT supports early stage encoding of visuospatial information by allowing direct reciprocal exchange between the PPA and EVC.
TheStreptochaetagenome and the evolution of the grasses
Authors: Seetharam Arun , Yu Yunqing , Belanger Sébastien , Clark Lynn G. , Meyers Blake C. , Kellogg Elizabeth A. , Hufford Matthew B.
Published: June 2021

In this work, we sequenced and annotated the genome ofStreptochaeta angustifolia, one of two genera in the grass subfamily Anomochlooideae, a lineage sister to all other grasses. The final assembly size is over 99% of the estimated genome size, capturing most of the gene space.Streptochaetais similar to other grasses in the structure of its fruit (a caryopsis or grain) but has peculiar flowers and inflorescences that are distinct from those in the outgroups and in other grasses. To provide tools for investigations of floral structure, we analyzed two large families of transcription factors, AP2-like and R2R3 MYBs, that are known to control floral and spikelet development in rice and maize among other grasses. Many of these are also regulated by small RNAs. Structure of the gene trees showed that the well documented whole genome duplication at the origin of the grasses (ρ) occurred before the divergence of the Anomochlooideae lineage from the lineage leading to the rest of the grasses (the spikelet clade) and thus that the common ancestor of all grasses probably had two copies of the developmental genes. However,Streptochaeta(and by inference other members of Anomochlooideae) has lost one copy of many genes. The peculiar floral morphology ofStreptochaetamay thus have derived from an ancestral plant that was morphologically similar to the spikelet-bearing grasses. We further identify 114 loci producing microRNAs and 89 loci generating phased, secondary siRNAs, classes of small RNAs known to be influential in transcriptional and post-transcriptional regulation of several plant functions.
A programmable pAgo nuclease with RNA target preference from the psychrotolerant bacteria Mucilaginibacter paludis
Authors: Li Wenqiang , Liu Yang , Wang Fei , Ma Lixin
Published: June 2021

Argonaute (Ago) proteins are programmable nuclease found in both eukaryotes and prokaryotes. Prokaryotic Argonaute proteins (pAgos) share a high degree of structural homology with eukaryotic Argonaute proteins (eAgos) and eAgos are considered to evolve from pAgos. However, the majority of studied pAgos prefer to cleave DNA targets, and eAgos exclusively cleave RNA targets. Here, we characterize a novel pAgo, MbpAgo, from psychrotolerant bacteria Mucilaginibacter paludis that can be programmed with DNA guides and prefers to cleave RNA targets rather than DNA targets. MbpAgo can be active at a wide range of temperatures (4-65°C). In comparison with previously studied pAgos, MbpAgo is able to utilize 16-nt long 5’phosphorylated and 5’hydroxylated DNA guides for efficient and precise cleavage and displays no obvious preference for the 5’end nucleotide of a guide. Furthermore, the cleavage efficiency can be regulated by mismatches in the central and 3’supplementary regions of the guide. MbpAgo can efficiently cleave highly-structured RNA targets using both 5’phosphorylated and 5’hydroxylated DNA guides in the presence of Mg2+ or Mn2+. In conclusion, we have demonstrated that MbpAgo is a unique programmable nuclease that has a strong preference for RNA targets, with great potential applications in the field of nucleic acid biotechnology.
Ssdp influences Wg expression and embryonic somatic muscle identity inDrosophila melanogaster
Authors: Poovathumkadavil Preethi , Da Ponte Jean-Philippe , Jagla Krzysztof
Published: June 2021

The somatic muscles of theDrosophilaembryo and larvae share structural and functional similarities with vertebrate skeletal muscles and serve as a powerful model for studying muscle development. Here we show that the evolutionarily conserved Ssdp protein is required for the correct patterning of somatic muscles. Ssdp is part of the conserved Chi/LDB-Ssdp (ChiLS) complex that is a core component of the conserved Wg/Wnt enhanceosome, which responds to Wg signals to regulate gene transcription.Ssdpshows isoform specific expression in developing somatic muscles and its loss of function leads to an aberrant somatic muscle pattern due to a deregulated muscle identity program.Ssdpmutant embryos fail to maintain adequate expression levels of muscle identity transcription factors and this results in aberrant muscle morphology, innervation, attachment and fusion. We also show that the epidermal expression of Wg is downregulated inSsdpmutants and that Ssdp interacts with Wg to regulate the properties of a subset of ventral muscles. Thus, our data unveil the dual contribution of Ssdp contribution to muscle diversification by regulating the expression of muscle-intrinsic identity genes and by interacting with the extrinsic factor, Wg. The knowledge gained here about Ssdp and its interaction with Wg could be relevant to vertebrate muscle development.
HSV-1 ICP22 is a selective viral repressor of cellular RNA polymerase II-mediated transcription elongation
Authors: Isa Nur F. , Bensaude Olivier , Aziz Nadiah C. , Murphy Shona
Published: June 2021

The Herpes Simplex Virus (HSV-1) immediate early protein ICP22 interacts with cellular proteins to inhibit host cell gene expression and promote viral gene expression. ICP22 inhibits phosphorylation of Ser2 of the RNA polymerase II (pol II) carboxyl-terminal domain (CTD) and productive elongation of pol II. Here we show that ICP22 affects elongation of pol II through both the early-elongation checkpoint and the poly(A)-associated elongation checkpoint on a protein-coding gene model. Coimmunoprecipitation assays using tagged ICP22 expressed in human cells and pulldown assays with recombinant ICP22 in vitro coupled with mass spectrometry identify transcription elongation factors, including P-TEFb, additional CTD kinases and the FACT complex as interacting cellular factors. Using a photoreactive amino acid incorporated into ICP22, we found that L191, Y230 and C225 crosslink to both subunits of the FACT complex in cells. Our findings indicate that ICP22 physically interacts with critical elongation regulators to inhibit transcription elongation of cellular genes, which may be vital for HSV-1 pathogenesis. We also show that the HSV viral activator, VP16 has a region of structural similarity to the ICP22 region that interacts with elongation factors, suggesting a model where VP16 competes with ICP22 to deliver elongation factors to viral genes.
Tuneable wide-field illumination and single-molecule photoswitching with a single MEMS mirror
Authors: Herdly Lucas , Janin Paul , Bauer Ralf , van de Linde Sebastian
Published: June 2021

Homogeneous illumination in single-molecule localization microscopy (SMLM) is key for the quantitative analysis of super-resolution images. Therefore, different approaches for flat-field illumination have been introduced as alternative to the conventional Gaussian illumination. Here, we introduce a single microelectromechanical systems (MEMS) mirror as a tuneable and cost-effective device for adapting wide-field illumination in SMLM. In flat-field mode the MEMS allowed for consistent SMLM metrics across the entire field of view. Employing single-molecule photoswitching, we developed a simple yet powerful routine to benchmark different illumination schemes on the basis of local emitter brightness and ON-state lifetime. Moreover, we propose that tuning the MEMS beyond optimal flat-field conditions enables to study the kinetics of photoswitchable fluorophores within a single acquisition.
Epithelial-mesenchymal plasticity through loss of CTCF motif accessibility and protein expression
Authors: Johnson Kelsey S. , Hussein Shaimaa , Chakraborty Priyanka , Muruganantham Arvind , Mikhail Sheridan , Gonzalez Giovanny , Song Shuxuan , Jolly Mohit Kumar , Toneff Michael J. , Benton Mary Lauren , Lin Yin C. , Taube Joseph H.
Published: June 2021

Epithelial-mesenchymal transition (EMT) and its reversal, mesenchymal-epithelial transition (MET) drive tissue reorganization critical for early development. In carcinomas, processing through EMT, MET or partial states promotes migration, invasion, dormancy, and metastatic colonization. As a reversible process, EMT is inherently regulated at epigenetic and epigenomic levels. To understand the epigenomic nature of reversible EMT and its partial states, we characterized chromatin accessibility dynamics, transcriptomic output, protein expression, and cellular phenotypes during stepwise reversible EMT. We found that the chromatin insulating protein machinery, including CTCF, is suppressed and re-expressed, coincident with broad alterations in chromatin accessibility, during EMT/MET and is lower in triple-negative breast cancer cell lines with EMT features. Through analysis of chromatin accessibility using ATAC-seq, we identify that early phases of EMT are characterized by enrichment for AP-1 family member binding motifs but also by diminished enrichment for CTCF binding motifs. Through loss-of-function analysis we demonstrate that suppression of CTCF alters cellular plasticity, facilitating entrance into a partial EMT state. These findings are indicative of a role of CTCF and chromatin reorganization for epithelial-mesenchymal plasticity.
Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study
Authors: Iida Megan A. , Farrell Kurt , Walker Jamie M. , Richardson Timothy E. , Marx Gabe , Bryce Clare H. , Purohit Dushyant , Ayalon Gai , Beach Thomas G. , Bigio Eileen H. , Cortes Etty , Gearing Marla , Haroutunian Vahram , McMillan Corey T. , Lee Eddie B. , Dickson Dennis , McKee Ann C. , Stein Thor D. , Trojanowski John Q. , Woltjer Randall L. , Kovacs Gabor G. , Kofler Julia K. , Kaye Jeffrey , White Charles L. , Crary John F.
Published: June 2021

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n=174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p=0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p=0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p<0.0001), but other features including ARTAG (p=0.03) and hippocampal atrophy (p=0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.
Tropical tree growth sensitivity to climate is driven by species intrinsic growth rate and leaf traits
Authors: Bauman David , Fortunel Claire , Cernusak Lucas A. , Bentley Lisa P. , McMahon Sean M. , Rifai Sami W. , Aguirre-Gutiérrez Jesús , Oliveras Imma , Bradford Matt , Laurance Susan G. W. , Delhaye Guillaume , Hutchinson Michael F. , Dempsey Raymond , McNellis Brandon E. , Santos-Andrade Paul E. , Ninantay-Rivera Hugo R. , Chambi Paucar Jimmy R. , Phillips Oliver L. , Malhi Yadvinder
Published: June 2021

A better understanding of how climate affects growth in tree species is essential for improved predictions of forest dynamics under climate change. Long-term climate averages (mean climate) and short-term deviations from these averages (anomalies) both influence tree growth, but the rarity of long-term data integrating climatic gradients with tree censuses has so far limited our understanding of their respective role, especially in tropical systems. Here, we combined 49 years of growth data for 509 tree species across 23 tropical rainforest plots along a climatic gradient to examine how tree growth responds to both climate means and anomalies, and how species functional traits mediate these tree growth responses to climate. We showed that short-term, anomalous increases in atmospheric evaporative demand and solar radiation consistently reduced tree growth. Drier forests and fast-growing species were more sensitive to water stress anomalies. In addition, species traits related to water use and photosynthesis partly explained differences in growth sensitivity to both long-term and short-term climate variations. Our study demonstrates that both climate means and anomalies shape tree growth in tropical forests, and that species traits can be leveraged to understand these demographic responses to climate change, offering a promising way forward to forecast tropical forest dynamics under different climate trajectories.
Host phenology can select for multiple stable parasite virulence strategies
Authors: MacDonald Hannelore , Brisson Dustin
Published: June 2021

Host phenology is an important driver of parasite transmission dynamics and evolution. Prior research has demonstrated that host phenology can drive monocyclic, obligate-killer parasites to evolve an intermediate virulence strategy where all parasites kill their host just before the season ends to limit the death of parasite progeny in the environment. The impact of host seasonality on parasites that are not constrained to a monocyclic life-cycle, however, cannot be inferred from these results. Here we present a mathematical model that demonstrates that many, but not all, seasonal host activity patterns support multiple evolutionarily stable parasite strategies (ESS), although these strategies cannot coexist in the same system. The specific monocyclic and polycyclic parasite evolutionarily stable strategies in each phenological pattern are interspersed with less-fit mono- and polycyclic strategies (evolutionary repellors). The ESS that dominates each system at equilibrium is a function of the strategy of the parasite introduced into the system. The results demonstrate that host phenology can, in theory, maintain diverse parasite strategies among isolated geographic locations.
Caenorhabditis elegans ETR-1/CELF has broad effects on the muscle cell transcriptome, including genes that regulate translation and neuroblast migration
Authors: Ochs Matthew E. , McWhirter Rebecca M. , Unckless Robert L. , Miller David M. , Lundquist Erik A.
Published: June 2021

Migration of neuroblasts and neurons from their birthplace is central to the formation of neural circuits and networks. ETR-1 is the Caenorhabditis elegans homolog of the CELF1 (CUGBP, ELAV-like family 1) RNA-processing factor involved in neuromuscular disorders. etr-1 regulates body wall muscle differentiation. Our previous work showed that etr-1 in muscle has a non-autonomous role in neuronal migration, suggesting that ETR-1 is involved in the production of a signal emanating from body wall muscle that controls neuroblast migration and that interacts with Wnt signaling. etr-1 is extensively alternatively-spliced, and we identified the viable etr-1(lq61) mutant, caused by a stop codon in alternatively-spliced exon 8 and only affecting etr-1 isoforms containing exon 8. We took advantage of viable etr-1(lq61) to identify potential RNA targets of ETR-1 in body wall muscle using a combination of fluorescence activated cell sorting (FACS) of body wall muscles from wild-type and etr-1(lq61) and subsequent RNA-seq. This analysis revealed genes whose splicing and transcript levels were controlled by ETR-1 exon 8 isoforms, and represented a broad spectrum of genes involved in muscle differentiation, myofilament lattice structure, and physiology. Genes with transcripts underrepresented in etr-1(lq61) included those involved in ribosome function and translation, similar to potential CELF1 targets identified in chick cardiomyocytes. This suggests that at least some targets of ETR-1 might be conserved in vertebrates, and that ETR-1 might generally stimulate translation in muscles. As proof-of-principle, a functional analysis of a subset of ETR-1 targets revealed genes involved in AQR and PQR neuronal migration. One such gene, lev-11/tropomyosin, requires ETR-1 for alternative splicing, and another, unc-52/perlecan, requires ETR-1 for the production of long isoforms containing 3’ exons. In sum, these studies identified gene targets of ETR-1/CELF1 in muscles, which included genes involved in muscle development and physiology, and genes with novel roles in neuronal migration.
Stratified Test Accurately Identifies Differentially Expressed Genes Under Batch Effects in Single-Cell Data
Authors: Liang Shaoheng , Liang Qingnan , Chen Rui , Chen Ken
Published: June 2021

Analyzing single-cell sequencing data from large cohorts is challenging. Discrepancies across experiments and differences among participants often lead to omissions and false discoveries in differentially expressed genes. We find that the Van Elteren test, a stratified version of the widely used Wilcoxon rank-sum test, elegantly mitigates the problem. We also modified the common language effect size to supplement this test, further improving its utility. On both simulated and real patient data we show the ability of Van Elteren test to control for false positives and false negatives. A comprehensive assessment using receiver operating characteristic (ROC) curve shows that Van Elteren test achieves higher sensitivity and specificity on simulated datasets, compared with nine state-of-the-art differential expression analysis methods. The effect size also estimates the differences between cell types more accurately.
Systematic reconstruction of the cellular trajectories of mammalian embryogenesis
Authors: Qiu Chengxiang , Cao Junyue , Li Tony , Srivatsan Sanjay , Huang Xingfan , Calderon Diego , Noble William Stafford , Disteche Christine M. , Spielmann Malte , Moens Cecilia B. , Trapnell Cole , Shendure Jay
Published: June 2021

Mammalian embryogenesis is characterized by rapid cellular proliferation and diversification. Within a few weeks, a single cell zygote gives rise to millions of cells expressing a panoply of molecular programs, including much of the diversity that will subsequently be present in adult tissues. Although intensively studied, a comprehensive delineation of the major cellular trajectories that comprise mammalian development in vivo remains elusive. Here we set out to integrate several single cell RNA-seq datasets (scRNA-seq) that collectively span mouse gastrulation and organogenesis. We define cell states at each of 19 successive stages spanning E3.5 to E13.5, heuristically connect them with their pseudo-ancestors and pseudo-descendants, and for a subset of stages, deconvolve their approximate spatial distributions. Despite being constructed through automated procedures, the resulting trajectories of mammalian embryogenesis (TOME) are largely consistent with our contemporary understanding of mammalian development. We leverage TOME to nominate transcription factors (TF) and TF motifs as key regulators of each branch point at which a new cell type emerges. Finally, to facilitate comparisons across vertebrates, we apply the same procedures to single cell datasets of zebrafish and frog embryogenesis, and nominate “cell type homologs” based on shared regulators and transcriptional states.
BROADLY NEUTRALIZING ANTI- HIV-1 ANTIBODIES DO NOT INHIBIT HIV-1 ENV-MEDIATED CELL-CELL FUSION
Authors: Düzgüneş Nejat , Yee Michael , Chau Deborah
Published: June 2021

PG9, PG16, PGT121, and PGT145 antibodies were identified from culture media of activated memory B-cells of an infected donor and shown to neutralize many HIV-1 strains. Since HIV-1 spreads via both free virions and cell-cell fusion, we examined the effect of the antibodies on HIV-1 Env-mediated cell-cell fusion. Clone69TRevEnv cells that express Env in the absence of tetracycline were labeled with Calcein-AM Green, and incubated with CD4+ SupT1 cells labeled with CellTrace™ Calcein Red-Orange, with or without antibodies. Monoclonal antibodies PG9, PG16, 2G12, PGT121, and PGT145 (at up to 50 μg/mL) had little or no inhibitory effect on fusion between HIV-Env and SupT1 cells. By contrast, Hippeastrum hybrid agglutinin completely inhibited fusion. Our results indicate that transmission of the virus or viral genetic material would not be inhibited by these broadly neutralizing antibodies. Thus, antibodies generated by HIV-1 vaccines should be screened for their inhibitory effect on Env-mediated cell-cell fusion.
Spatiotemporally flexible subnetworks reveal the quasi-cyclic nature of integration and segregation in the human brain
Authors: Strindberg Marika , Fransson Peter , Cabral Joana , Ådén Ulrika
Published: June 2021

Though the organization of functional brain networks is modular at its core, modularity does not capture the full range of dynamic interactions between individual brain areas nor at the level of subnetworks. In this paper we present a hierarchical model that represents both flexible and modular aspects of intrinsic brain organization across time by constructing spatiotemporally flexible subnetworks. We also demonstrate that segregation and integration are complementary and simultaneous events. The method is based on combining the instantaneous phase synchrony analysis (IPSA) framework with community detection to identify a small, yet representative set of subnetwork components at the finest level of spatial granularity. At the next level, subnetwork components are combined into spatiotemporally flexibly subnetworks where temporal lag in the recruitment of areas within subnetworks is captured. Since individual brain areas are permitted to be part of multiple interleaved subnetworks, both modularity as well as more flexible tendencies of connectivity are accommodated for in the model. Importantly, we show that assignment of subnetworks to the same community (integration) corresponds to positive phase coherence within and between subnetworks, while assignment to different communities (segregation) corresponds to negative phase coherence or orthogonality. Together with disintegration, i.e. the breakdown of internal coupling within subnetwork components, orthogonality facilitates reorganization between subnetworks. In addition, we show that the duration of periods of integration is a function of the coupling strength within subnetworks and subnetwork components which indicates an underlying metastable dynamical regime. Based on the main tendencies for either integration or segregation, subnetworks are further clustered into larger meta-networks that are shown to correspond to combinations of core resting-state networks. We also demonstrate that subnetworks and meta-networks are coarse graining strategies that captures the quasi-cyclic recurrence of global patterns of integration and segregation in the brain. Finally, the method allows us to estimate in broad terms the spectrum of flexible and/or modular tendencies for individual brain areas.
Natural resource funds for innovation in emerging countries: an assessment of the Chilean experience
Authors: Medina-Bueno José Luis , Guimón José , Cancino Christian A.
Published: June 2021

Purpose

This study aims to explore the institutional complexities associated with the design and implementation of a natural resource fund for innovation.

Design/methodology/approach

This study examines the case of Chile's Innovation Fund for Competitiveness by means of a historical approach building on interviews with key informants.

Findings

The proper functioning of a natural resource fund for innovation requires efficient institutional and operational structures, as well as strong coordination with innovation system actors. In particular, the case of Chile highlights the challenges inherent in adopting a regional approach when implementing this type of strategy, due to the institutional voids that hamper the role of regional governments in emerging countries.

Originality/value

Natural resource funds for innovation constitute a strategic mechanism for developing the innovative capabilities necessary to enhance the competitiveness of resource-rich emerging countries. This is one of the first studies addressing the institutional challenges involved in setting up this kind of fund in practice, focusing on one of the most relevant and longstanding examples from Latin America.
An analytic method for parameter extraction of InP HBTs small-signal model
Authors: Zhang Jincan , Liu Min , Wang Jinchan , Xu Kun
Published: June 2021

Purpose

High-speed Indium Phosphide (InP) HBTs have been widely used to design high-speed analog, digital and mixed-signal integrated circuits. The purpose of this study is to propose a new parameter extraction procedure for determining an improved T-topology small-signal equivalent circuit of InP heterojunction bipolar transistors (HBTs).

Design/methodology/approach

The alternating current crowding effect is considered through adding the intrinsic base capacitance in the small-signal equivalent circuit. All of the circuit parameters are extracted directly without using any approximation.

Findings

The extraction technique is more easily understood and clearer than other extraction methods, as the equations are derived from the S-parameters by peeling peripheral elements from small-signal models to get reduced ones and extracting each equivalent-circuit parameter using each equation.

Originality/value

To validate the presented parameter extraction technology, an n-p-n emitter-up InP HBT was analyzed adopting the method. Excellent agreement between measured and modeled S-parameters is obtained up to 40 GHz.
Memristive combinational logic circuits and stochastic computing implementation scheme
Authors: Li Tianshu , Duan Shukai , Liu Jun , Wang Lidan
Published: June 2021

Purpose

Stochastic computing which is an alternative method of the binary calculation has key merits such as fault-tolerant capability and low hardware cost. However, the hardware response time of it is required to be very fast due to its bit-wise calculation mode. While the complementary metal oxide semiconductor (CMOS) components are difficult to meet the requirements aforementioned. For this, the stochastic computing implementation scheme based on the memristive system is proposed to reduce the response time. The purpose of this paper is to provide the implementation scheme based memristive system for the stochastic computing.

Design/methodology/approach

The hardware structure of material logic based on the memristive system is realized according to the advantages of the memristor. After that, the scheme of NOT logic, AND logic and multiplexer are designed, which are the basic units of stochastic computing. Furthermore, a stochastic computing system based on memristive combinational logic is structured and its validity is verified successfully by operating a case.

Findings

The numbers of the elements of the proposed stochastic computing system are less than the conventional stochastic computing based on CMOS circuits.

Originality/value

The paper proposed a novel implementation scheme for stochastic computing based on the memristive systems, which are different from the conventional stochastic computing based on CMOS circuits.
How store managers’ employee climate perceptions affect frontline employee, customer and store performance outcomes: an examination in the small-store setting
Authors: Deitz George , Hansen John D. , DeCarlo Tom , Babakus Emin
Published: June 2021

Purpose

The purpose of this paper is to examine the effects of store managers’ employee climate perceptions on frontline employee (FLE), customer and store performance outcomes in the small-store setting.

Design/methodology/approach

This study derives the findings from a multi-source data set acquired in partnership with a North American-based retailer that includes survey responses from 1,133 store managers, 5,591 FLEs and 16,488 customers. This paper matches survey responses to corporate records and store sales and operations data.

Findings

This study finds that store managers’ employee climate perceptions affect FLEs both directly and indirectly, through store manager social support behaviors. This paper tests the boundary conditions for these findings by examining the moderating effects of store-level FLE tenure heterogeneity and competitive intensity. Study results provide partial support for the hypothesized relationships with regard to FLE tenure heterogeneity, but not competitive intensity.

Research limitations/implications

This research is subject to many of the limitations common to a survey-based study. While the use of one retailer provided opportunities to examine store-level performance data, future research would benefit by using a more expansive data set spanning several companies and industries. Moreover, as the current study was set in the small-store setting, future research should explore how store managers’ influence fluctuates depending on store size and the mechanisms through which organizational priorities flow through other management levels (e.g. department managers) in large retailers.

Practical implications

Study results provide managerial guidance regarding the implementation of an employee climate for the delivery of an enhanced customer experience and superior financial performance.

Originality/value

Although researchers have paid considerable attention to employees’ psychological and organizational climate perceptions, this study makes a unique contribution by examining the effects of store managers’ employee climate perceptions on FLE, customer and store-level outcomes.