bluuebunny/crossref_metadata_2025 huggingface dataset:
White Matter Abnormalities in Body Integrity Dysphoria
Authors: Saetta Gianluca , Ruddy Kathy , Zapparoli Laura , Gandola Martina , Salvato Gerardo , Sberna Maurizio , Bottini Gabriella , Brugger Peter , Lenggenhager Bigna
Published: August 2021

“Body integrity dysphoria” (BID) is a severe condition affecting non-psychotic individuals where a limb may be experienced as not being part of the body, despite normal anatomical development and intact sensorimotor functions. Limb amputation is desired for restoring their own identity. We previously demonstrated altered brain structural (gray matter) and functional connectivity in 16 men with a long-lasting and exclusive desire for left leg amputation. Here we aimed to identify in the same sample altered patterns of white matter structural connectivity. Fractional anisotropy (FA), derived from Diffusion Tensor Imaging data, was considered as a measure of structural connectivity. Results showed reduced structural connectivity of: i) the right superior parietal lobule (rSPL) with the right cuneus, superior occipital and posterior cingulate gyri ii) the pars orbitalis of the right middle frontal gyrus (rMFGOrb) with the putamen iii) the left middle temporal gyrus (lMTG) with the pars triangularis of the left inferior frontal gyrus. Increased connectivity was observed between the right paracentral lobule (rPLC) and the right caudate nucleus. By using a complementary method of investigation, we confirmed and extended previous results showing alterations in areas tuned to the processing of the sensorimotor representations of the affected leg (rPCL), and to higher-order components of bodily representation such as the body image (rSPL). Alongside this network for bodily awareness, other networks such as the limbic (rMFGOrb) and the mirror (lMTG) systems showed structural alterations as well. These findings consolidate current understanding of the neural correlates of BID, which might in turn guide diagnostics and rehabilitative treatments.
Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation
Authors: Habel Jennifer R , Chua Brendon Y , Kedzierski Lukasz , Selva Kevin J , Damelang Timon , Haycroft Ebene R , Nguyen Thi HO , Koay Hui-Fern , Nicholson Suellen , McQuilten Hayley , Jia Xiaoxiao , Allen Lilith F , Hensen Luca , Zhang Wuji , van de Sandt Carolien E , Neil Jessica A , Amanat Fatima , Krammer Florian , Wragg Kathleen , Juno Jennifer A , Wheatley Adam K , Tan Hyon-Xhi , Pell Gabrielle , Audsley Jennifer , Thevarajan Irani , Denholm Justin , Subbarao Kanta , Godfrey Dale I , Cheng Allen C , Tong Steven YC , Bond Katherine , Williamson Deborah A , James Fiona , Holmes Natasha E , Smibert Olivia C , Trubiano Jason A , Gordon Claire L , Chung Amy W , Whitehead Clare L , Kent Stephen J , Lappas Martha , Rowntree Louise C , Kedzierska Katherine
Published: August 2021

Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK cells, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4+and CD8+T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.
Soil inoculum identity and rate jointly steer microbiomes and plant communities in the field
Authors: Han Xu , Li Yingbin , Li Yuhui , Du Xiaofang , Li Bing , Li Qi , Bezemer T. Martijn
Published: August 2021

The importance of soil inoculation to engineer soil microbiomes and ultimately entire ecosystems is becoming widely acknowledged. Inoculation with soil from different ecosystems can induce directional changes in soil and plant communities and promote the restoration of degraded ecosystems. However, it is unknown how such inoculations influence the soil microbiome, how much inoculum is needed, and whether inocula collected from similar ecosystems will steer the microbiome in different directions. We conducted a three-year soil inoculation field experiment at a degraded grassland and used two different soil inocula both from grasslands with three inoculation rates. Our results show that inoculation with soil that originates from different donor grasslands steers the soil microbiome as well as the plant communities at the inoculated site which was a degraded grassland into different directions and that these effects were stronger with increasing amount of soil used to inoculate. Inoculation with upland meadow soil introduced more keystone genera and resulted in more complex biotic networks in the soil than inoculation with meadow steppe soil. Our experiment highlights that soil inoculation can steer soil microbiomes in the field and that the direction and speed of development depend on the origin and the amount of soil inoculum used.
A multiscale spatiotemporal model including a switch from aerobic to anaerobic metabolism reproduces succession in the early infant gut microbiota
Authors: Versluis David M. , Schoemaker Ruud , Looijesteijn Ellen , Muysken Daniël , Jeurink Prescilla V. , Paques Marcel , Geurts Jan M. W. , Merks Roeland M. H.
Published: August 2021

The human intestinal microbiota starts to form immediately after birth, and is important for the health of the host. During the first days facultatively anaerobic bacterial species generally dominate, such as Enterobacteriaceae. These are succeeded by strictly anaerobic species, particularly Bifidobacterium species. An early transition to Bifidobacterium species is associated with health benefits: for example, Bifidobacterium species repress growth of pathogenic competitors and modulate the immune response. Succession to Bifidobacterium is thought to be due to consumption of intracolonic oxygen present in newborns by facultative anaerobes, including Enterobacteriaceae. To study if oxygen depletion suffices for the transition to Bifidobacterium species, here we introduce a multiscale mathematical model that considers metabolism, spatial bacterial population dynamics and cross-feeding. Using publicly available metabolic network data from the AGORA collection, the model simulates ab initio the competition of strictly and facultatively anaerobic species in a gut-like environment under the influence of lactose and oxygen. The model predicts that individual differences in intracolonic oxygen in newborn infants can explain the observed individual variation in succession to anaerobic species, in particular Bifidobacterium species. Bifidobacterium species become dominant in the model by using the bifid shunt, which allows Bifidobacterium to switch to sub-optimal yield metabolism with fast growth at high lactose concentrations as predicted here using flux-balance analysis. The computational model thus allows us to test the internal plausibility of hypotheses for bacterial colonization and succession in the infant colon.

IMPORTANCE

The composition of the infant microbiota has a great impact on infant health, but its controlling factors are still incompletely understood. The frequently dominant anaerobic Bifidobacterium species benefit health, e.g., because they can keep harmful competitors under control and modulate the intestinal immune response. Controlling factors could include nutritional composition and intestinal mucus composition, as well as environmental factors, such as antibiotics. We introduce a modeling framework of a metabolically realistic intestinal microbial ecology in which hypothetical scenarios can be tested and compared. We present simulations that suggest that greater levels of intra-intestinal oxygenation more strongly delay the dominance of Bifidobacterium species, explaining the observed variety of microbial composition and demonstrating the use of the model for hypothesis generation. The framework allows us to test a variety of controlling factors, including intestinal mixing and transit time. Future versions will also include detailed modeling of oligosaccharide and mucin metabolism.
Defining the components of the miRNA156-SPL-miR172 aging pathway in pea and their expression relative to changes in leaf morphology
Authors: Vander Schoor J.K. , Hecht V. , Aubert G. , Burstin J. , Weller J.L.
Published: August 2021

The timing of developmental phase transitions is crucial for plant reproductive success, and two microRNAs (miRNA),miR156andmiR172, are implicated in the control of these changes, together with their respectiveSQUAMOSA promoter binding-like(SPL) andAPETALA2(AP2)-like targets. While their patterns of regulation have been studied in a growing range of species, to date they have not been examined in pea (Pisum sativum), an important legume crop and model species. We analysed the recently-released pea genome and defined ninemiR156, 21SPL, fourmiR172, and fiveAP2-likegenes. Phylogenetic analysis of theSPLgenes in pea,MedicagoandArabidopsisconfirmed the eight previously defined clades, and identified a ninth potentially legume-specificSPLclade in pea andMedicago. Among thePsSPL, 14 contain amiR156binding site and all fiveAP2-liketranscription factors in pea include amiR172binding site. Phylogenetic relationships, expression levels and temporal expression changes identifiedPsSPL2a/3a/3c/6b/9a/9b/13b/21, PsmiR156d/jandPsmiR172a/das the most likely of these genes to participate in phase change in pea. Comparisons with leaf morphology suggests that vegetative phase change is unlikely to be definitively marked by a change in leaflet number. In addition, the timing ofFTgene induction suggests that the shift from the juvenile to the adult vegetative phase may occur within fourteen days in plants grown under inductive conditions, and calls into question the contribution ofmiR172/AP2to the floral transition. This work provides the first insight into the nature of vegetative phase change in pea, and an important foundation for future functional studies.
Tracheal tube fusion inDrosophilainvolves release of extracellular vesicles from multivesicular bodies
Authors: Camelo Carolina , Körte Anna , Jacobs Thea , Luschnig Stefan
Published: August 2021

Extracellular vesicles (EVs) comprise diverse types of cell-released membranous structures that are thought to play important roles in intercellular communication. Despite extensive work on the formation and functions of EVs in cultured cells, studies of EVsin vivohave remained scarce. We report here that EVs are present in the developing lumen of tracheal tubes inDrosophilaembryos. We defined two distinct EV subpopulations, one of which contains the Munc13-4 homologue Staccato (Stac) and is spatially and temporally associated with tracheal tube fusion events. The formation of Stac-positive luminal EVs depends on the tip-cell-specific GTPase Arl3, which is also required for the formation of Stac-positive multivesicular bodies, suggesting that Stac-EVs derive from fusion of Stac-MVBs with the luminal membrane in tip cells during anastomosis formation. The GTPases Rab27 and Rab35 cooperate downstream of Arl3 to promote Stac-MVB formation and tube fusion. We propose that Stac-MVBs act as membrane reservoirs that facilitate tracheal lumen fusion in a process regulated by Arl3, Rab27, Rab35, and Stac/Munc13-4.
The SARS-CoV-2 Delta variant is poised to acquire complete resistance to wild-type spike vaccines
Authors: Liu Yafei , Arase Noriko , Kishikawa Jun-ichi , Hirose Mika , Li Songling , Tada Asa , Matsuoka Sumiko , Arakawa Akemi , Akamatsu Kanako , Ono Chikako , Jin Hui , Kishida Kazuki , Nakai Wataru , Kohyama Masako , Nakagawa Atsushi , Yamagishi Yoshiaki , Nakagami Hironori , Kumanogoh Atsushi , Matsuura Yoshiharu , Standley Daron M. , Kato Takayuki , Okada Masato , Fujimoto Manabu , Arase Hisashi
Published: August 2021

mRNA-based vaccines provide effective protection against most common SARS-CoV-2 variants. However, identifying likely breakthrough variants is critical for future vaccine development. Here, we found that the Delta variant completely escaped from anti-N-terminal domain (NTD) neutralizing antibodies, while increasing responsiveness to anti-NTD infectivity-enhancing antibodies. Although Pfizer-BioNTech BNT162b2-immune sera neutralized the Delta variant, when four common mutations were introduced into the receptor binding domain (RBD) of the Delta variant (Delta 4+), some BNT162b2-immune sera lost neutralizing activity and enhanced the infectivity. Unique mutations in the Delta NTD were involved in the enhanced infectivity by the BNT162b2-immune sera. Sera of mice immunized by Delta spike, but not wild-type spike, consistently neutralized the Delta 4+ variant without enhancing infectivity. Given the fact that a Delta variant with three similar RBD mutations has already emerged according to the GISAID database, it is necessary to develop vaccines that protect against such complete breakthrough variants.
Stretching and squeezing of neuronal log firing rate distribution by psychedelic and intrinsic brain state transitions
Authors: Dearnley Bradley , Dervinis Martynas , Shaw Melissa , Okun Michael
Published: August 2021

How psychedelic drugs change the activity of cortical neuronal populations and whether such changes are specific to transition into the psychedelic brain state or shared with other brain state transitions is not well understood. Here, we used Neuropixels probes to record from large populations of neurons in prefrontal cortex of mice given the psychedelic drug TCB-2. Drug ingestion significantly stretched the distribution of log firing rates of the population of recorded neurons. This phenomenon was previously observed across transitions between sleep and wakefulness, which suggested that stretching of the log-rate distribution can be triggered by different kinds of brain state transitions and prompted us to examine it in more detail. We found that modulation of the width of the log-rate distribution of a neuronal population occurred in multiple areas of the cortex and in the hippocampus even in awake drug-free mice, driven by intrinsic fluctuations in their arousal level. Arousal, however, did not explain the stretching of the log-rate distribution by TCB-2. In both psychedelic and naturally occurring brain state transitions, the stretching or squeezing of the log-rate distribution of an entire neuronal population reflected concomitant changes in two subpopulations, with one subpopulation undergoing a downregulation and often also stretching of its neurons’ log-rate distribution, while the other subpopulation undergoes upregulation and often also a squeeze of its log-rate distribution. In both subpopulations, the stretching and squeezing were a signature of a greater relative impact of the brain state transition on the rates of the slow-firing neurons. These findings reveal a generic pattern of reorganisation of neuronal firing rates by different kinds of brain state transitions.
Plasma Contains Ultra-short Single-stranded DNA in Addition to Nucleosomal cfDNA
Authors: Cheng Jordan , Morselli Marco , Huang Wei-Lun , Heo You Jeong , Pinheiro-Ferreira Thalyta , Li Feng , Wei Fang , Chia David , Jun Hua , Cole Kenneth , Su Wu-Chou , Pellegrini Matteo , Wong David TW
Published: August 2021

Plasma cell-free DNA is a widely used biomarker for diagnostic screening. We introduce uscfDNA-seq, a single-stranded cell-free DNA NGS pipeline, which bypasses previous limitations to reveal a novel population of ultrashort single-stranded cell-free DNA in plasma with a modal size of 50nt. This species of cfDNA aligns predominantly to the nuclear genome and could potentially be used for novel biomarker discovery.
Deep phylo-taxono genomics reveals Xylella as a variant lineage of plant associated Xanthomonas with Stenotrophomonas and Pseudoxanthomonas as misclassified relatives
Authors: Bansal Kanika , Kumar Sanjeet , Kaur Amandeep , Singh Anu , Patil Prabhu B.
Published: August 2021

Genus Xanthomonas is a group of phytopathogens which is phylogenetically related to Xylella, Stenotrophomonas and Pseudoxanthomonas following diverse lifestyles. Xylella is a lethal plant pathogen with highly reduced genome, atypical GC content and is taxonomically related to these three genera. Deep phylo-taxono-genomics reveals that Xylella is a variant Xanthomonas lineage that is sandwiched between Xanthomonas species. Comparative studies suggest the role of unique pigment and exopolysaccharide gene clusters in the emergence of Xanthomonas and Xylella clades. Pan genome analysis identified set of unique genes associated with sub-lineages representing plant associated Xanthomonas clade and nosocomial origin Stenotrophomonas. Overall, our study reveals importance to reconcile classical phenotypic data and genomic findings in reconstituting taxonomic status of these four genera.

Significance Statement

Xylella fastidiosa is a devastating pathogen of perennial dicots such as grapes, citrus, coffee, and olives. The pathogen is transmitted by an insect vector to its specific host wherein the infection leads to complete wilting of the plants. The genome of X. fastidiosa is extremely reduced both in terms of size (2Mb) and GC content (50%) when compared with its relatives such as Xanthomonas, Stenotrophomonas, and Pseudoxanthomonas that have higher GC content (65%) and larger genomes (5Mb). In this study, using systematic and in-depth genome-based taxonomic and phylogenetic criteria along with comparative studies, we assert the need of unification of Xanthomonas with its misclassified relatives (Xylella, Stenotrophomonas and Pseudoxanthomonas). Interestingly, Xylella revealed itself as a minor lineage embedded within two major Xanthomonas lineages comprising member species of different hosts.
Modeling movie-evoked human brain activity using motion-energy and space-time vision transformer features
Authors: Nishimoto Shinji
Published: August 2021

In this paper, the process of building a model for predicting human brain activity under video viewing conditions was described as a part of an entry into the Algonauts Project 2021 Challenge. The model was designed to predict brain activity measured using functional MRI (fMRI) by weighted linear summations of the spatiotemporal visual features that appear in the video stimuli (video features). Two types of video features were used: (1) motion-energy features designed based on neurophysiological findings, and (2) features derived from a space-time vision transformer (TimeSformer). To utilize the features of various video domains, the features of the TimeSformer models pre-trained using several different movie sets were combined. Through these model building and validation processes, results showed that there is a certain correspondence between the hierarchical representation of the TimeSformer model and the hierarchical representation of the visual system in the brain. The motion-energy features are effective in predicting brain activity in the early visual areas, while TimeSformer-derived features are effective in higher-order visual areas, and a hybrid model that uses motion energy and TimeSformer features is effective for predicting whole brain activity.
Vegetation memory effects and their association with vegetation resilience in global drylands
Authors: Kusch Erik , Davy Richard , Seddon Alistair W. R.
Published: August 2021

Abstract

Vegetation memory describes the effect of antecedent environmental and ecological conditions on the present ecosystem state and has been proposed as an important proxy for vegetation resilience. In particular, strong vegetation-memory effects have been identified in dryland regions, but the factors underlying the spatial patterns of vegetation memory remain unknown.

We aim to map the components and drivers of vegetation memory in dryland regions using state-of-the-art climate reanalysis data and refined approaches to identify vegetation-memory characteristics across dryland regions worldwide.

Using a framework which distinguishes between intrinsic and extrinsic ecological memory, we show that: (i) intrinsic memory is a much stronger component than extrinsic memory in the majority of dryland regions; and (ii) climate reanalysis data sets change the detection of extrinsic vegetation memory effects in some global dryland regions.

Synthesis. Our study offers a global picture of the vegetation response to two climate forcing variables using satellite data, information which is potentially relevant for mapping components and properties of vegetation responses worldwide. However, the large differences in the spatial patterns in intrinsic vegetation memory in our study compared to previous analyses show the overall sensitivity of this component in particular to the initial choice of extrinsic forcing variables. As a result, we caution against using the oversimplified link between intrinsic vegetation-memory and vegetation recovery rates at large spatial scales.
Machine learning prediction of antiviral-HPV protein interactions for anti-HPV pharmacotherapy
Authors: Lin Hui-Heng , Zhang Qian-Ru , Kong Xiangjun , Zhang Liuping , Zhang Yong , Tang Yanyan , Xu Hongyan
Published: August 2021

Persistent infection with high-risk types Human Papillomavirus could cause diseases including cervical cancers and oropharyngeal cancers. Nonetheless, so far there is no effective pharmacotherapy for treating the infection from high-risk HPV types, and hence it remains to be a severe threat to the health of female. Based on drug repositioning strategy, we trained and benchmarked multiple machine learning models so as to predict potential effective antiviral drugs for HPV infection in this work. Through optimizing models, measuring models’ predictive performance using 182 pairs of antiviral-target interaction dataset which were all approved by the United States Food and Drug Administration, and benchmarking different models’ predictive performance, we identified the optimized Support Vector Machine and K-Nearest Neighbor classifier with high precision score were the best two predictors (0.80 and 0.85 respectively) amongst classifiers of Support Vector Machine, Random forest, Adaboost, Naïve Bayes, K-Nearest Neighbors, and Logistic regression classifier. We applied these two predictors together and successfully predicted 57 pairs of antiviral-HPV protein interactions from 864 pairs of antiviral-HPV protein associations. Our work provided good drug candidates for anti-HPV drug discovery. So far as we know, we are the first one to conduct such HPV-oriented computational drug repositioning study.
Reconstitution of surface lipoprotein translocation reveals Slam as an outer membrane translocon in Gram-negative bacteria
Authors: Huynh Minh Sang , Hooda Yogesh , Li Raina , Jagielnicki Maciej , Lai Christine Chieh-Lin , Moraes Trevor F
Published: August 2021

Surface lipoproteins (SLPs) are peripherally attached to the outer leaflet of the outer membrane in many Gram-negative bacteria, playing significant roles in nutrient acquisition and immune evasion in the host. While the factors that are involved in the synthesis and delivery of SLPs in the inner membrane are well characterized, the molecular machineries required for the movement of SLPs to the surface are still not fully elucidated. In this study, we investigated the translocation of a surface lipoprotein TbpB through a Slam1-dependent pathway. Using purified components, we developed an in vitro translocation assay where unfolded TbpB is transported through Slam1 containing proteoliposomes, confirming Slam1 as an outer membrane translocon. While looking to identify factors to increase translocation efficiency, we discovered the periplasmic chaperone Skp interacted with TbpB in the periplasm of Escherichia coli. The presence of Skp was found to increase the translocation efficiency of TbpB in the reconstituted translocation assays. A knockout of Skp in Neisseria meningitidis revealed that Skp is essential for functional translocation of TbpB to the bacterial surface. Taken together, we propose a pathway for surface destined lipoproteins, where Skp acts as a holdase for Slam-mediated TbpB translocation across the outer membrane.
Vapor cannabis exposure generationally affects male reproductive functions in mice
Authors: Shi Mingxin , Langholt Esther M. , Butler Logan C. , Harvey Madeleine E. , Wheeler Emma C. , Zhao Liang , MacLean James A. , Oh Yeongseok , Sabrowsky Emily , Yu Sue , Watson Shane , Davis Jon F. , Hayashi Kanako
Published: August 2021

This study was performed to examine whether vapor exposure to cannabis plant matter negatively impacts male reproductive functions and testis development in mice. Adult CD-1 male mice (F0) were exposed to air (control) or 200 mg of vaporized cannabis plant matter 3x/day over a 10 day period. Subsequently, F0 males were bred with drug naïve CD-1 females to generate F1 males, and F1 offspring were used to generate F2 males. Cannabis vapor exposure decreased sperm count and/or motility in F0 and F1 males and disrupted the progression of germ cell development, as morphometric analyses exhibited an abnormal distribution of the stages of spermatogenesis in F0 males. Although plasma levels of testosterone were not affected by cannabis exposure in any ages or generations of males, dysregulated steroidogenic enzymes, Cyp11a1 and Cyp19a1, were observed in F0 testis. In the neonatal testis from F1 males, while apoptosis was not altered, DNA damage and DNMT1, but not DNMT3A and DNMT3B, were increased in germ cells following cannabis exposure. In contrast, the alterations of DNA damage and DNMT1 expression were not observed in F2 neonatal males. These results suggest that cannabis vapor exposure generationally affects male reproductive functions, probably due to disruption of spermatogenesis in the developing testis.

GRAPHICAL ABSTRACT

HIGHLIGHTS

Cannabis vapor exposure to adult males impairs sperm counts, motility and spermatogenesis.

Cannabis vapor exposure to F0 males causes reduced sperm counts in F1, but not in F2 males.

Plasma testosterone levels are not affected in F0, F1 and F2 males by cannabis exposure.

Cannabis increases DNA damage and the expression of DNA methyltransferase (DNMT) 1 in the F1 neonatal testis.
From complete cross-docking to partners identification and binding sites predictions
Authors: Dequeker Choé , Behbahani Yasser Mohseni , David Laurent , Laine Elodie , Carbone Alessandra
Published: August 2021

Proteins ensure their biological functions by interacting with each other. Hence, characterising protein interactions is fundamental for our understanding of the cellular machinery, and for improving medicine and bioengineering. Over the past years, a large body of experimental data has been accumulated on who interacts with whom and in what manner. However, these data are highly heterogeneous and sometimes contradictory, noisy, and biased.Ab initiomethods provide a means to a “blind” protein-protein interaction network reconstruction. Here, we report on a molecular cross-docking-based approach for the identification of protein partners. We applied it to a few hundred of proteins, and we systematically investigated the influence of several key ingredients, such as the size and quality of the interfaces and the scoring function. We achieved some significant improvement compared to previous works, and a very high discriminative power on some specific functional classes. In addition, we assessed the ability of the approach to account for protein surface multiple usages, and we compared it with a sequence-based deep learning method. This work may contribute to guiding the exploitation of the large amounts of protein structural models now available toward the discovery of unexpected partners and their complex structure characterisation.
Intra-host SARS-CoV-2 evolution in the gut of mucosally-infected Chlorocebus aethiops (African green monkeys)
Authors: Rowe Lori A. , Beddingfield Brandon J. , Goff Kelly , Killeen Stephanie Z. , Chirichella Nicole R. , Melton Alexandra , Roy Chad J. , Maness Nicholas J.
Published: August 2021

In recent months, several SARS-CoV-2 variants have emerged that enhance transmissibility and escape host humoral immunity. Hence, the tracking of viral evolutionary trajectories is clearly of great importance. Little is known about SARS-CoV-2 evolution in nonhuman primate models used to test vaccines and therapies and to model human disease. Viral RNA was sequenced from rectal swabs from Chlorocebus aethiops (African green monkeys) after experimental respiratory SARS-CoV-2 infection. Two distinct patterns of viral evolution were identified that were shared between all collected samples. First, mutations in the furin cleavage site that were initially present in the virus as a consequence of VeroE6 cell culture adaptation were subsequently lost in virus recovered in rectal swabs, confirming the necessity of this motif for viral infection in vivo. Three amino acid changes were also identified; ORF 1a S2103F, and spike D215G and H655Y, that were detected in rectal swabs from all sampled animals. These findings are demonstrative of intra-host SARS-CoV-2 evolution unique to this nonhuman primate species and may identify a host-adapted variant of SARS-CoV-2 that would be useful in future development of primate disease models.
Insights from the genomes of four diploid Camelina spp.
Authors: Martin Sara L. , Toro Beatriz Lujan , James Tracey , Sauder Connie A. , Laforest Martin
Published: August 2021

Plant evolution has been a complex process involving hybridization and polyploidization making understanding the origin and evolution of a plant’s genome challenging even once a published genome is available. The oilseed crop, Camelina sativa (Brassicaceae), has a fully sequenced allohexaploid genome with three unknown ancestors. To better understand which extant species best represent the ancestral genomes that contributed to C. sativa’s formation, we sequenced and assembled chromosome level draft genomes for four diploid members of Camelina: C. neglecta C. hispida var. hispida, C. hispida var. grandiflora and C. laxa using long and short read data scaffolded with proximity data. We then conducted phylogenetic analyses on regions of synteny and on genes described for Arabidopsis thaliana, from across each nuclear genome and the chloroplasts to examine evolutionary relationships within Camelina and Camelineae. We conclude that C. neglecta is closely related to C. sativa’s sub-genome 1 and that C. hispida var. hispida and C. hispida var. grandiflora are most closely related to C. sativa’s sub-genome 3. Further, the abundance and density of transposable elements, specifically Helitrons, suggest that the progenitor genome that contributed C. sativa’s sub-genome 3 maybe more similar to the genome of C. hispida var. hispida than that of C. hispida var. grandiflora. These diploid genomes show few structural differences when compared to C. sativa’s genome indicating little change to chromosome structure following allopolyploidization. This work also indicates that C. neglecta and C. hispida are important resources for understanding the genetics of C. sativa and potential resources for crop improvement.
Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height
Authors: Hattori Atsushi , Seki Atsuhito , Inaba Naoto , Nakabayashi Kazuhiko , Takeda Kazue , Tatsusmi Kuniko , Naiki Yasuhiro , Nakamura Akie , Ishiwata Keisuke , Matsumoto Kenji , Nasu Michiyo , Okamura Kohji , Michigami Toshimi , Katoh-Fukui Yuko , Umezawa Akihiro , Ogata Tsutomu , Kagami Masayo , Fukami Maki
Published: August 2021

Adult men are, on average, ∼13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.
A universal approach for integrating super large-scale single-cell transcriptomes by exploring gene rankings
Authors: Shen Hongru , Shen Xilin , Feng Mengyao , Wu Dan , Zhang Chao , Yang Yichen , Yang Meng , Hu Jiani , Liu Jilei , Wang Wei , Li Yang , Zhang Qiang , Yang Jilong , Chen Kexin , Li Xiangchun
Published: August 2021

Advancement in single-cell RNA sequencing leads to exponential accumulation of single-cell expression data. However, there is still lack of tools that could integrate these unlimited accumulation of single-cell expression data. Here, we presented a universal approachiSEEEKfor integrating super large-scale single-cell expression via exploring expression rankings of top-expressing genes. We developediSEEEKwith 13.7 million single-cells. We demonstrated the efficiency ofiSEEEKwith canonical single-cell downstream tasks on five heterogenous datasets encompassing human and mouse samples.iSEEEKachieved good clustering performance benchmarked against well-annotated cell labels. In addition,iSEEEKcould transfer its knowledge learned from large-scale expression data on new dataset that was not involved in its development.iSEEEKenables identification of gene-gene interaction networks that are characteristic of specific cell types. Our study presents a simple and yet effective method to integrate super large-scale single-cell transcriptomes and would facilitate translational single-cell research from bench to bedside.
Influence of condensation domains on activity and specificity of adenylation domains
Authors: Kranz Janik , Wenski Sebastian L. , Dichter Alexander A. , Bode Helge B. , Bozhüyük Kenan A. J.
Published: August 2021

Many clinically used natural products are produced by non-ribosomal peptide synthetases (NRPSs), which due to their modular nature should be accessible to modification and engineering approaches. While the adenylation domain (A) plays the key role in substrate recognition and activation, the condensation domain (C) which is responsible for substrate linkage and stereochemical filtering recently became the subject of debate - with its attributed role as a “gatekeeper” being called into question. Since we have thoroughly investigated different combinations of C-A didomains in a series of in vitro, in vivo, and in situ experiments suggesting an important role to the C-A interface for the activity and specificity of the downstream A domain and not the C domain as such, we would like to contribute to this discussion. The role of the C-A interface, termed ‘extended gatekeeping’, due to structural features of the C domains, can also be transferred to other NRPSs by engineering, was finally investigated and characterised in an in silico approach on 30 wild-type and recombinant C-A interfaces. With these data, we not only would like to offer a new perspective on the specificity of C domains, but also to revise our previously established NRPS engineering and construction rules.
Divergent effect of central incretin receptors inhibition in a rat model of sporadic Alzheimer’s disease
Authors: Barilar Jelena Osmanovic , Knezovic Ana , Homolak Jan , Perhoc Ana Babic , Salkovic-Petrisic Melita
Published: August 2021

The incretin system is an emerging new field that might provide valuable contributions to the research of both pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the role of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain as well as on the levels of these incretins, insulin and glucose, by inhibiting the central incretins’ receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer’s disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in the brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.
Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis
Authors: Jiang Limin , Yu Hui , Ness Scott , Mao Peng , Guo Fei , Tang Jijun , Guo Yan
Published: August 2021

Somatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer.Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1,747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.
Single Nucleotide Polymorphisms in the Bovine TLR2 Extracellular Domain Contribute to Breed and Species-Specific Innate Immune Functionality
Authors: BArtens Marie-Christine , Gibson Amanda , Etherington Graham John , di Palma Federica , Holder Angela , Werling Dirk , Willcocks Sam
Published: August 2021

Recent evidence suggests that several cattle breeds may be more resistant to infection with the zoonotic pathogen Mycobacterium bovis than others. Our data presented here suggests that the response to mycobacterial antigens varies in macrophages generated from Brown Swiss (BS) and Holstein Frisian (HF) cattle, two breeds belonging to the Bos taurus family. Whole genome sequencing of the Brown Swiss genome identified several potential candidate genes, in particular Toll-like Receptor-2 (TLR2) a pattern recognition receptor (PRR) that has previously been described to be involved in mycobacterial recognition. Further investigation revealed single nucleotide polymorphisms (SNP) in TLR2 that were identified between DNA isolated from cells of BS and HF cows. Interestingly, one specific SNP, H326Q, showed a different genotype frequency in two cattle subspecies, Bos taurus and Bos indicus. Cloning of the TLR2 gene and subsequent gene-reporter and chemokine assays revealed that this SNP, present in BS and Bos indicus breeds, resulted in a significantly higher response to mycobacterial antigens as well as tri-acylated lipopeptide ligands in general. Comparing wild-type and H326Q containing TLR2 responses, wild-type bovine TLR2 response showed clear, diminished mycobacterial antigen responses compared to human TLR2, however bovine TLR2 responses containing H326Q were found to be partially recovered compared to human TLR2. The creation of human:bovine TLR2 chimeras increased the response to mycobacterial antigens compared to the full-length bovine TLR2, but significantly reduced the response compared to the full-length human TLR2. Thus, our data, not only present evidence that TLR2 is a major PRR in the mammalian species-specific response to mycobacterial antigens, but furthermore, that there are clear differences between the response seen in different cattle breeds, which may contribute to their enhanced or reduced susceptibility to mycobacterial infection.
Differential gene expression reveals host factors for viral shedding variation in mallards (Anas platyrhynchos) infected with low-pathogenic avian influenza virus
Authors: Dolinski Amanda C. , Homola Jared J. , Jankowski Mark D. , Robinson John D. , Owen Jennifer C.
Published: August 2021

Intraspecific variation in pathogen shedding impacts disease transmission dynamics; therefore, understanding the host factors associated with individual variation in pathogen shedding is key to controlling and preventing outbreaks. In this study, ileum and bursa of Fabricius tissues of mallards (Anas platyrhynchos) infected with low-pathogenic avian influenza (LPAIV) were evaluated at various post-infection time points to determine genetic host factors associated with intraspecific variation in viral shedding. By analyzing transcriptome sequencing data (RNA-seq), we found that LPAIV-infected mallards do not exhibit differential gene expression compared to uninfected birds, but that gene expression was associated with viral shedding quantity early in the infection. In both tissues, immune genes were mostly up-regulated in higher shedding birds and had significant positive relationships with viral shedding. In the ileum, host genes involved in viral cell entry were down-regulated in low shedders one day post-infection (DPI), and host genes promoting viral replication were up-regulated in high shedders on two DPI. Our findings indicate that viral shedding is a key factor for gene expression differences in LPAIV-infected mallards, and the genes identified in this study could be important for understanding the molecular mechanisms driving intraspecific variation in pathogen shedding.
Dandelion pappus morphing is actuated by radially patterned material swelling
Authors: Seale Madeleine , Kiss Annamaria , Bovio Simone , Viola Ignazio Maria , Mastropaolo Enrico , Boudaoud Arezki , Nakayama Naomi
Published: August 2021

Plants can generate motion by absorbing and releasing water. Such motion often facilitates reproductive success through the dispersal of seeds and fruits or their self-burial into the soil. Asteraceae plants, such as the dandelion, often have a hairy pappus attached to their fruits to allow them to fly and in many cases, these can open and close depending on moisture levels to modify dispersal. Here we demonstrate the relationship between structure, composition and function of the underlying hygroscopic actuator. By investigating the structure and properties of the actuator cell walls we have identified the mechanism by which the dandelion pappus closes and developed a structural computational model that can capture observed pappus closing. This model was used to explore the contribution of differential material domains in the actuator function and the critical design features. We find that the actuator relies on the radial arrangement of vascular bundles and surrounding tissues including cortex and the floral podium around a central cavity. This allows heterogeneous swelling in a radially symmetric manner to co-ordinate precise movements of the pappus hairs attached at the upper flank. This actuator is a derivative of bilayer structures, but is radial and can synchronise the movement of a planar or lateral attachment. The simple, material-based mechanism presents a promising biomimetic potential in robotics and functional materials.
Extreme purifying selection against point mutations in the human genome
Authors: Dukler Noah , Mughal Mehreen R. , Ramani Ritika , Huang Yi-Fei , Siepel Adam
Published: August 2021

Genome sequencing of tens of thousands of humans has enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or “ultraselection” (λs), as the fractional depletion of rare single-nucleotide variants in target genomic sites relative to matched sites that are putatively free from selection, after controlling for local variation and neighbor-dependence in mutation rate. We show using simulations that λs is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find weak evidence in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3–0.5% of the human genome is ultraselected, implying ~0.3–0.4 lethal or nearly lethal de novo mutations per potential human zygote. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics.