bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimisation and Pre-clinical Demonstration of Temporal Diffusion Ratio for Imaging Restricted Diffusion
Authors: Warner William , Palombo Marco , Cruz Renata , Shemesh Noam , Jones Derek K. , Dell’Acqua Flavio , Ianus Andrada , Drobnjak Ivana
Published: July 2022

Temporal Diffusion Ratio (TDR) is a recently proposed dMRI technique (Dell’Acqua, 2019) which provides contrast between areas with restricted diffusion and areas either without restricted diffusion or with length scales too small for characterisation. Hence, it has a potential for mapping pore sizes, in particular large axon diameters or other cellular structures. TDR employs the signal from two dMRI acquisitions obtained with the same, large, b-value but with different diffusion times and gradient settings. TDR is advantageous as it employs standard acquisition sequences, does not make any assumptions on the underlying tissue structure and does not require any model fitting, avoiding issues related to model degeneracy. This work for the first time optimises the TDR diffusion sequences in simulation for a range of different tissues and scanner constraints. We extend the original work (which considers substrates containing cylinders) by additionally considering the TDR signal obtained from spherical structures, representing cell soma in tissue. Our results show that contrasting an acquisition with short gradient duration and short diffusion time with an acquisition with long gradient duration and long diffusion time improves the TDR contrast for a wide range of pore configurations. Additionally, in the presence of Rician noise, computing TDR from a subset (50% or fewer) of the acquired diffusion gradients rather than the entire shell as proposed originally further improves the contrast. In the last part of the work the results are demonstrated experimentally on rat spinal cord. In line with simulations, the experimental data shows that optimised TDR improves the contrast compared to non-optimised TDR. Furthermore, we find a strong correlation between TDR and histology measurements of axon diameter. In conclusion, we find that TDR has great potential and is a very promising alternative (or potentially complement) to model-based approaches for mapping pore sizes and restricted diffusion in general.

Highlights

Temporal Diffusion Ratio (TDR) 2-seq approach maps areas with restricted diffusion

Optimised gradient waveform pair is: long δ + low G and short δ + high G

If data is noisy calculating TDR using HARDI acquisition subsets increases accuracy

We demonstrate TDR for the first time pre-clinically in rat spinal cord

Pre-clinical TDR values are strongly correlated with axon diameter
Increased homozygosity due to endogamy results in fitness consequences in a human population
Authors: Swinford N.A. , Prall S.P. , Williams C.M. , Sheehama J. , Scelza B.A. , Henn B. M.
Published: July 2022

Recessive alleles have been shown to directly affect both human Mendelian disease phenotypes and complex traits like height. Pedigree studies also suggest that consanguinity results in increased childhood mortality and adverse health phenotypes, presumably through penetrance of recessive mutations. Here, we test whether the accumulation of homozygous, recessive alleles decreases reproductive success in a human population. We address this question among the Namibian Himba, an endogamous agro-pastoralist population, who until very recently practiced natural fertility. Using a sample of 681 individuals, we show that Himba exhibit elevated levels of “inbreeding”, calculated as the fraction of the genome in runs of homozygosity (FROH). Many individuals contain multiple long segments of ROH in their genomes, indicating that their parents had high kinship coefficients. However, we did not find evidence that this is explained by first-cousin consanguinity, despite a reported social preference for cross-cousin marriages. Rather, we show that elevated haplotype sharing in the Himba is due to a bottleneck, likely in the past 60 generations. We test whether increased recessive mutation load results in observed fitness consequences by assessing the effects of FROH on completed fertility in a cohort of post-reproductive women (n=69). We find that higher FROH is significantly associated with lower fertility among women who have had at least one child (p<0.006). Our data suggest a multi-locus genetic effect on fitness driven by the expression of deleterious recessive alleles, especially those in long ROH. However, these effects are not the result of consanguinity but rather elevated background identity by descent.
The Development of Sex Differences in Play in Wild White-Faced Capuchins (Cebus capucinus)
Authors: Winkler Sasha Lutz , Perry Susan Emily
Published: July 2022

Many mammalian species display sex differences in the frequency of play behavior, yet the animal literature includes few longitudinal studies of play, which are important for understanding the developmental timing of sex differences and the evolutionary functions of play. We analyzed social play, solitary play, and grooming using an 18-year dataset on 38 wild white-faced capuchin monkeys (Cebus capucinus) followed since infancy. Rates of each behavior were measured as the proportion of point samples taken during focal follows in which the individual engaged in each behavior. To determine sex differences in these rates, we ran a series of generalized linear mixed models, considering both linear and quadratic effects of age, and chose the optimal model for each of the three behavioral outcomes based on information criteria. Rates of both social play and solitary play decreased with age, with the exception of social play in males, which increased in the early juvenile period before decreasing. Male and female capuchins had different temporal patterns of social play, with males playing more than females during most of the juvenile period, but they did not display meaningful sex differences in solitary play rates. Additionally, males and females had different patterns of grooming over the lifespan: males participated in grooming at low rates throughout their lives, while adult females participated in grooming at much higher rates, peaking around age 11 years before declining. We suggest that male and female white-faced capuchins may adopt alternative social bonding strategies, including different developmental timing and different behaviors (social play for males versus grooming for females). Our results were consistent with two functional hypotheses of play, the practice and bonding hypotheses. This study demonstrates that play behavior may be critical for the development of sex-specific social strategies and emphasizes the importance of developmental perspectives on social behaviors.
Seasonality of host-seekingIxodes ricinusnymph abundance in relation to climate
Authors: Hoch Thierry , Madouasse Aurélien , Jacquot Maude , Wongnak Phrutsamon , Beugnet Fréderic , Bournez Laure , Cosson Jean-François , Huard Frédéric , Moutailler Sara , Plantard Olivier , Poux Valérie , René-Martellet Magalie , Vayssier-Taussat Muriel , Verheyden Hélène , Vourc’h Gwenaël , Chalvet-Monfray Karine , Agoulon Albert
Published: July 2022

There is growing concern about climate change and its impact on human health. Specifically, global warming could increase the probability of emerging infectious diseases, notably because of changes in the geographical and seasonal distributions of disease vectors such as mosquitoes and ticks. For example, the range ofIxodes ricinus, the most common and widespread tick species in Europe, is currently expanding northward and at higher altitudes. However, little is known about the seasonal variation in tick abundance in different climates. Seasonality ofI. ricinusis often based on expert opinions while field surveys are usually limited in time. Our objective was to describe seasonal variations inI. ricinusabundance under different climates. To this end, a seven-year longitudinal study, with monthly collections ofI. ricinushost-seeking nymphs, was carried out in France, in six locations corresponding to different climates. Tick data were log-transformed and grouped between years so as to obtain seasonal variations for a typical year. Daily average temperature was measured during the study period. Seasonal patterns of nymph abundance were established for the six different locations using linear harmonic regression. Model parameters were estimated separately for each location. Seasonal patterns appeared different depending on the climate considered. Western temperate sites showed an early spring peak, a summer minimum and a moderate autumn and winter abundance. More continental sites showed a later peak in spring, and a minimum in winter. The peak occurred in summer for the mountainous site, with an absence of ticks in winter. In all cases except the mountainous site, the timing of the spring peak could be related to the sum of degree days since the beginning of the year. Winter abundance was positively correlated to the corresponding temperature. Our results highlight clear patterns in the different sites corresponding to different climates, which allow further forecast of tick seasonality under changing climate conditions.
Preparing for the next Pandemic: Simulation-based Deep Reinforcement Learning to discover and test multimodal control of systemic inflammation using repurposed immunomodulatory agents
Authors: Cockrell Chase , Larie Dale , An Gary
Published: July 2022

Background

Preparation to address the critical gap in a future pandemic between non-pharmacological measures and the deployment of new drugs/vaccines requires addressing two factors: 1) finding virus/pathogen-agnostic pathophysiological targets to mitigate disease severity and 2) finding a more rational approach to repurposing existing drugs. It is increasingly recognized that acute viral disease severity is heavily driven by the immune response to the infection (“cytokine storm”). There exist numerous clinically available biologics that suppress various pro-inflammatory cytokines/mediators, but it is extremely difficult to identify clinically effective treatment regimens with these agents. We propose that this is a complex control problem that resists standard methods of developing treatment regimens and accomplishing this goal requires the application of simulation-based, model-free deep reinforcement learning (DRL) in a fashion akin to training successful game-playing artificial intelligences (AIs). This proof-of-concept study determines if simulated sepsis (e.g. infection-driven cytokine storm) can be controlled in the absence of effective antimicrobial agents by targeting cytokines for which FDA-approved biologics currently exist.

Methods

We use a previously validated agent-based model, the Innate Immune Response Agent-based Model (IIRABM), for control discovery using DRL. DRL training used a Deep Deterministic Policy Gradient (DDPG) approach with a clinically plausible control interval of 6 hours with manipulation of six cytokines for which there are existing drugs: Tumor Necrosis Factor (TNF), Interleukin-1 (IL-1), Interleukin-4 (IL-4), Interleukin-8 (IL-8), Interleukin-12 (IL-12) and Interferon-γ (IFNg).

Results

DRL trained an AI policy that could improve outcomes from a baseline mortality rate of 41% (= recovery rate of 59%) to one with a recovery rate of 82.3% over 42 days simulated time.

Discussion

The current proof-of-concept study demonstrates that significant disease severity mitigation can potentially be accomplished with existing anti-mediator drugs, but only through a multi-modal, adaptive treatment policy requiring implementation with an AI. While the actual clinical implementation of this approach is a projection for the future, the current goal of this work is to inspire the development of a research ecosystem that marries what is needed to improve the simulation models with the development of the sensing/assay technologies to collect the data needed to iteratively refine those models.
Introduction of a terminal electron sink in chloroplasts decreases leaf cell expansion associated to higher proteasome activity and lower endoreduplication
Authors: Arce Rocío C. , Mayta Martín L. , Melzer Michael , Hajirezaei Mohammad-Reza , Lodeyro Anabella F. , Carrillo Néstor
Published: July 2022

Foliar development involves successive phases of cell proliferation and expansion that determine the final leaf size, and is characterized by an early burst of reactive oxygen species (ROS) generated in the photosynthetic electron transport chain (PETC). Introduction of the alternative PETC acceptor flavodoxin in tobacco chloroplasts led to a reduction in leaf size associated to lower cell expansion, without affecting cell numbers per leaf. Proteomic analysis showed that components of the light-harvesting systems accumulated before electron-transport proteins, suggesting a mechanism for the early oxidative event. Flavodoxin expression did not affect biogenesis of the PETC but prevented ROS build-up through its function as electron sink. Mature leaves from flavodoxin-expressing plants were shown to contain higher levels of transcripts encoding components of the proteasome, a key negative modulator of organ size. Proteome profiling revealed that this differential accumulation initiated during expansion and led to increased proteasomal activity, whereas a proteasome inhibitor reverted the flavodoxin-dependent size phenotype. Cells expressing plastid-targeted flavodoxin displayed lower endoreduplication, also associated to decreased organ size. These results provide novel insights into the regulation of leaf growth by chloroplast-generated redox signals, and highlight the potential of alternative electron shuttles to investigate novel link(s) between photosynthesis and plant development.

Highlight

Modification of chloroplast redox status by expression of the cyanobacterial alternative electron sink flavodoxin decreased leaf cell expansion, which was associated with higher proteasome activity and lower endoreduplication.
Restoring local climate refugia to enhance the capacity for dispersal-limited species to track climate change
Authors: Backus Gregory A. , Clements Christopher F , Baskett Marissa L.
Published: July 2022

Climate refugia are areas where species can persist through climate change with little to no movement. Among the factors associated with climate refugia are high spatial heterogeneity, such that there is only a short distance between current and future optimal climates, as well as biotic or abiotic environmental factors which buffer against variability in time. However, climate refugia may be declining due to anthropogenic homogenization of environments and degradation of environmental buffers. To quantify the potential for restoration of refugia-like environmental conditions to increase population persistence under climate change, we simulated a population’s capacity to track increasing temperatures over time given different levels of spatial and temporal variability in temperature. To determine how species traits affected the efficacy of restoring heterogeneity, we explored an array of values for species’ dispersal ability, thermal tolerance, and fecundity. We found that species were more likely to persist in environments with higher local heterogeneity and lower environmental stochasticity. When simulating a management action that increased the local heterogeneity of a previously homogenized environment, species were more likely to persist through climate change, and population sizes were generally higher, but there was little effect with mild temperature change. The benefits of heterogeneity restoration were greatest for species with limited dispersal ability. In contrast, species with longer dispersal but lower fecundity were more likely to benefit from a reduction in environmental stochasticity than an increase in spatial heterogeneity. Our results suggest that restoring environments to refugia-like conditions could promote species’ persistence under climate change in addition to conservation strategies such as assisted migration, corridors, and increased protection.
Chemoproteomic identification of a dipeptidyl peptidase 4 (DPP4) homolog in Bacteroides thetaiotaomicron important for envelope integrity and fitness
Authors: Keller Laura J. , Nguyen Taylor H. , Liu Lawrence , Lakemeyer Markus , Gelsinger Danielle J. , Chanin Rachael , Ngo Nhi , Lum Kenneth M. , Faucher Franco , Ipock Phillip , Niphakis Micah J. , Bhatt Ami S. , O’Donoghue Anthony J. , Huang Kerwyn Casey , Bogyo Matthew
Published: July 2022

Serine hydrolases play important roles in signaling and human metabolism, yet little is known about the functions of these enzymes in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human protease dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Functional studies reveal that BT4193 is a true homolog of hDPP4 while the other is misannotated and is a proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and is inhibited by FDA-approved type 2 diabetes drugs that target hDPP4. Loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. Taken together, our findings suggest that serine hydrolases contribute to gut microbiota dynamics and may be off-targets for existing drugs that could cause unintended impact on the microbiota.
Mycobacterium leprae and host immune transcriptomic signatures for reactional states in leprosy
Authors: Das Madhusmita , David Diana , Horo Ilse , Van Hooij Anouk , Tió Coma Maria , Geluk Annemieke , Vedithi Sundeep Chaitanya
Published: July 2022

Background

Mycobacterium leprae transcriptomic and human host immune gene expression signatures that demonstrate a plausible association with type I (T1R) and type II reactions (T2R) aid in early diagnosis, prevention of nerve damage and consequent demyelinating neuropathy in leprosy. The aim of the study is to identify M. leprae and host-associated gene-expression signatures that are associated with reactional states in leprosy.

Methods

The differentially expressed genes from the whole transcriptome of M. leprae were determined using genome-wide hybridization arrays with RNA extracted from skin biopsies of 20 T1R, 20 T2R and 20 non reactional controls (NR). Additionally, human immune gene-expressions were profiled using RT2-PCR profiler arrays and real-time qPCRs.

Results

The RNA quality was optimal in 16 NR, 18 T1R and 19 T2R samples. Whole transcriptome expression array of these samples revealed significant overexpression of the genes that encode integral and intrinsic membrane proteins, hydrolases and oxidoreductases. In T1R lesional skin biopsy specimens, the top 10 over significantly upregulated genes are ML2064, ML1271, ML1960, ML122, ML2498, ML1996, ML2388, ML0429, ML2030 and ML0224 in comparison to NR. In T2R, genes ML2498, ML1526, ML0394, ML1960, ML2388, ML0429, ML0281, ML1847, ML1618 and ML1271 were significantly upregulated. We noted ML2664 was significantly upregulated in T1R and repressed in T2R. Conversely, we haven’t noted any genes upregulated in T2R and repressed in T1R. In both T1R and T2R, ML2388 was significantly overexpressed. This gene encodes a probable membrane protein and epitope prediction using Bepipred −2.0 revealed a distinct B-cell epitope. Overexpression of ML2388 was noted consistently across the reaction samples.

From the host immune gene expression profiles, genes for CXCL9, CXCL2, CD40LG, IL17A and CXCL11 were upregulated in T1R when compared to the NR. In T2R, CXCL10, CXCL11, CXCL9, CXCL2 and CD40LG were upregulated.

Conclusion

A gene set signature involving bacterial genes ML2388, ML2664, and host immune genes CXCL10 and IL-17A can be transcriptomic markers for reactional states in leprosy.
Parental education and occupation in relation to risk of childhood type 1 diabetes: nationwide cohort study
Authors: Ruiz Paz Lopez-Doriga , Tapia German , Bakken Inger J. , Håberg Siri E. , Gulseth Hanne L. , Skrivarhaug Torild , Joner Geir , Stene Lars C.
Published: July 2022

Background

Socioeconomic status in the risk of developing type 1 diabetes seems inconsistent. We investigated whether risk of childhood-onset type 1 diabetes differed by parental education or occupation in a nationwide cohort.

Methods

This cohort study included all children born in Norway from 1974 to 2013. In individually linked data from nationwide population registries following children born in Norway up to 15 years of age, we identified 4647 with newly diagnosed type 1 diabetes during 15,381,923 person-years of follow-up.

Results

Children of mothers with a master’s degree had lower risk of type 1 diabetes than children of mothers with completed upper secondary education only: adjusted incidence rate ratio, aIRR=0.81 95% confidence interval: 0.69 - 0.95). There was no difference between upper secondary and lower secondary maternal education (aIRR=0.98, 95% confidence interval 0.89-1.08). Paternal education was not significantly associated with type 1 diabetes. While maternal elementary occupation was associated with a lower risk of type 1 diabetes, specific maternal- or paternal occupations were not.

Conclusions

Our results suggested inverse U-shaped associations between maternal socioeconomic status and risk of type 1 diabetes. Non-linear associations be part of the reason why previous literature has been inconsistent.
The epidemiology of neuropathic pain: an analysis of prevalence and associated factors in UK Biobank
Authors: Baskozos Georgios , Hébert Harry L , Pascal Mathilde M V , Themistocleous Andreas C. , Macfarlane Gary J , Wynick David , Bennett David L H , Smith Blair H
Published: July 2022

Previous epidemiological studies of neuropathic pain have reported a range of prevalences and factors associated with the disorder. This study aimed to verify these characteristics in a large UK cohort. A cross sectional analysis was conducted of 148,828 UK Biobank participants who completed a detailed questionnaire on chronic pain. The Douleur Neuropathique en Quatre Questions (DN4) was used to distinguish between neuropathic pain (NeuP) and non-neuropathic pain (Non-NeuP) in participants with pain of at least 3 months’ duration. Participants were also identified with less than 3 months’ pain or without pain (NoCP). Binomial and multinomial regression were used to identify factors associated with NeuP compared to Non-NeuP and NoCP respectively. Chronic pain was present in 76,095 participants (51.1%). The overall prevalence of NeuP was 9.2% (13,744/148,828). NeuP was significantly associated with worse health-related quality of life, having a manual or personal service type occupation and younger age compared to NoCP. As expected NeuP was associated with diabetes and neuropathy, but also other pains (pelvic, post-surgical and migraine) and musculoskeletal disorders (rheumatoid arthritis, osteoarthritis and fibromyalgia). Additionally, NeuP was associated with pain in the limbs and greater pain intensity and higher BMI compared to Non-NeuP. Female gender was associated with NeuP when compared to NoCP, whilst male gender was associated with NeuP when compared to Non-NeuP. This is the largest epidemiological study of neuropathic pain to date. The results confirm that the disorder is common in the general population and is associated with a higher health impact than non-neuropathic pain.
Kick the wheels: radiograph-negative ankle injuries in bicycle-spoke accidents
Authors: Laumer Susanne JM , van Kooten Lottie , Barten Dennis G , van Osch Frits HM , Drees Marion MWE , Lekx Anita W
Published: July 2022

Introduction

Bicycle spoke injuries (BSIs) in children are notorious for the presence of Salter Harris type 1 (SH1) fractures. Most patients are therefore treated with cast immobilization. However, the actual prevalence of SH1 following a BSI is unknown. In this study, we aimed to describe a cohort with radiograph-negative BSIs and to identify possible clinical predictors for SH1 which might be useful for adequate risk assessment.

Methods

A retrospective cohort study was performed, including all children ≤12 years visiting our Emergency Department (ED) with a BSI. Patients without radiographic evidence of a fracture were classified as low or high level of suspicion of SH1. Multivariate logistic regression analysis was used to identify independent predictors of a high level of suspicion of SH1.

Results

In total, 323 patients were included. Ninety-three patients (29%) had a proven fracture; 230 patients were radiograph-negative at first presentation. Of these, 166 patients (72%) were treated with cast immobilization. At follow-up, 32 patients (13.9%) were classified as high level of suspicion of SH1. No clinical variables were found to be predictive for SH1. Local tenderness at the lateral malleolus was associated with a high level of suspicion of SH1, however, this was not statistically significant (OR 2.89, p-value 0.057).

Conclusion

Although BSIs with radiograph-negative ankle injuries are generally treated with cast immobilization, in this cohort only 13.9% had a high level of suspicion of SH1. Lateral malleolus tenderness was associated with a high level of suspicion of SH1 injury, but none of the clinical variables had a significant predictive value.
Release of the pre-assembled naRNA-LL37 composite DAMP re-defines neutrophil extracellular traps (NETs) as intentional DAMP webs
Authors: Bork Francesca , Greve Carsten L. , Youn Christine , Chen Sirui , Wang Yu , Nasri Masoud , Focken Jule , Scheurer Jasmin , Engels Pujan , Dubbelaar Marissa , Hipp Katharina , Schittek Birgit , Bugl Stefanie , Löffler Markus W. , Skokowa Julia , Archer Nathan K. , Weber Alexander N.R.
Published: July 2022

Neutrophil extracellular traps (NETs) are a key antimicrobial feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs), the primary human leukocyte population. NETs trap and kill microbes but have also been linked to inflammation, e.g. atherosclerosis, arthritis or psoriasis by unknown mechanisms. We here characterize naRNA (NET-associated RNA), as a new canonical, abundant, and unexplored inflammatory NET component. naRNA, upon release by NET formation, drove further NET formation in naïve PMN, and induced macrophage and keratinocyte activation via TLR8 in humans and Tlr13 in mice, in vitro and in vivo. Importantly, in vivo naRNA strongly drove skin inflammation, whereas genetic ablation of RNA sensing drastically ameliorated psoriatic skin inflammation. Rather than accidentally assembling with LL37 on the NET, naRNA was intracellularly pre-associated in resting neutrophils as a ‘composite DAMP’, thus highlighting NET formation as a DAMP release process. This re-defines sterile NETs as an intentionally inflammatory agent, signaling and amplifying neutrophil activation. Moreover, in the many conditions previously linked to NETs and extracellular RNA, TLR-mediated naRNA sensing emerges as both potential cause and new intervention target.

Graphical abstract

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zFACE: Facial Analytics from a Coordinate Extrapolation System for Developing Zebrafish
Authors: Maili Lorena , Ruiz Oscar E. , Kahan Philip , Larson Stephen T. , Hashmi S. Shahrukh , Hecht Jacqueline T. , Eisenhoffer George T.
Published: July 2022

Facial development requires a complex and coordinated series of cellular events, that when perturbed, can lead to structural birth defects. A standardized quantitative approach to quickly assess morphological changes could address how genetic or environmental inputs lead to differences in facial development. Here we report on a method to rapidly analyze craniofacial development in zebrafish embryos that combines a simple staining and mounting paradigm withFacialAnalytics based on aCoordinateExtrapolation system, termed zFACE. Confocal imaging of frontal/rostral mounted embryos generates high-resolution images to capture facial structures and morphometric data is quantified based on a coordinate system that assesses 26 anatomical landmarks present at defined times in development. The semi-automated analysis can be applied to embryos at different stages of development and quantitative morphometric data can detect subtle phenotypic variation. Shape analysis can also be performed with the coordinate data to inform on global changes in facial morphology. We applied this new approach to show that loss ofsmarca4ain developing zebrafish leads to craniofacial anomalies, microcephaly and alterations in brain morphology. These changes are characteristic of humans with Coffin-Siris syndrome (CSS), a rare genetic disorder associated with mutations inSMARCA4that is defined by anomalies in head size, intellectual disabilities and craniofacial abnormalities. We observed thatsmarca4ais expressed in craniofacial tissues and our multivariate analysis facilitated the classification ofsmarca4amutants based on changes in specific phenotypic characteristics. Together, our approach provides a way to rapidly and quantitatively assess the impact of genetic alterations on craniofacial development in zebrafish.
Cell type directed design of synthetic enhancers
Authors: Taskiran Ibrahim Ihsan , Spanier Katina I. , Christiaens Valerie , Mauduit David , Aerts Stein
Published: July 2022

Transcriptional enhancers act as docking stations for combinations of transcription factors and thereby regulate spatiotemporal activation of their target genes. A single enhancer, of a few hundred base pairs in length, can autonomously and independently of its location and orientation drive cell-type specific expression of a gene or transgene. It has been a long-standing goal in the field to decode the regulatory logic of an enhancer and to understand the details of how spatiotemporal gene expression is encoded in an enhancer sequence. Recently, deep learning models have yielded unprecedented insight into the enhancer code, and well-trained models are reaching a level of understanding that may be close to complete. As a consequence, we hypothesized that deep learning models can be used to guide the directed design of synthetic, cell type specific enhancers, and that this process would allow for a detailed tracing of all enhancer features at nucleotide-level resolution. Here we implemented and compared three different design strategies, each built on a deep learning model: (1) directed sequence evolution; (2) directed iterative motif implanting; and (3) generative design. We evaluated the function of fully synthetic enhancers to specifically target Kenyon cells in the fruit fly brain using transgenic animals. We then exploited this concept further by creating “dual-code” enhancers that target two cell types, and minimal enhancers smaller than 50 base pairs that are fully functional. By examining the trajectories followed during state space searches towards functional enhancers, we could accurately define the enhancer code as the optimal strength, combination, and relative distance of TF activator motifs, and the absence of TF repressor motifs. Finally, we applied the same three strategies to successfully design human enhancers. In conclusion, enhancer design guided by deep learning leads to better understanding of how enhancers work and shows that their code can be exploited to manipulate cell states.
The highly conserved RNA-binding specificity of nucleocapsid protein facilitates the identification of drugs with broad anti-coronavirus activity
Authors: Fan Shaorong , Sun Wenju , Fan Ligang , Wu Nan , Sun Wei , Ma Haiqian , Chen Siyuan , Li Zitong , Li Yu , Zhang Jilin , Yan Jian
Published: July 2022

The binding of SARS-CoV-2 nucleocapsid (N) protein to both the 5′- and 3′-ends of genomic RNA has different implications arising from its binding to the central region during virion assembly. However, the mechanism underlying selective binding remains unknown. Herein, we performed the high-throughput RNA-SELEX (HTR-SELEX) to determine the RNA-binding specificity of the N proteins of various SARS-CoV-2 variants as well as other β-coronaviruses and showed that N proteins could bind two unrelated sequences, both of which were highly conserved across all variants and species. Interestingly, both these sequence motifs are virtually absent from the human transcriptome; however, they exhibit a highly enriched, mutually complementary distribution in the coronavirus genome, highlighting their varied functions in genome packaging. Our results provide mechanistic insights into viral genome packaging, thereby increasing the feasibility of developing drugs with broad-spectrum anti-coronavirus activity by targeting RNA binding by N proteins.
The compact genome of the spongeOopsacas minuta(Hexactinellida) is lacking key metazoan core genes
Authors: Santini Sébastien , Schenkelaars Quentin , Jourda Cyril , Duschene Marc , Belahbib Hassiba , Rocher Caroline , Selva Marjorie , Riesgo Ana , Vervoort Michel , Leys Sally P. , Kodjabachian Laurent , Le Bivic André , Borchiellini Carole , Claverie Jean-Michel , Renard Emmanuelle
Published: July 2022

Background

Bilaterian animals today represent 99% of animal biodiversity. Elucidating how bilaterian hallmarks emerged is a central question of animal evo-devo and evolutionary genomics. Studies of non-bilaterian genomes have suggested that the ancestral animal already possessed a diversified developmental toolkit, including some pathways required for bilaterian body plans. Comparing genomes within the early branching metazoan Porifera phylum is key to identify which changes and innovations contributed to the successful transition towards bilaterians.

Results

Here, we report the first whole genome comprehensive analysis of a glass sponge,Oopsacas minuta, a member of theHexactinellida. Studying this class of sponge is evolutionary relevant because it differs from the three otherPoriferaclasses in terms of development, tissue organization, ecology and physiology. AlthoughO. minutadoes not exhibit drastic body simplifications, its genome is among the smallest animal genomes sequenced so far, surprisingly lacking several metazoan core genes (including Wnt and several key transcription factors). Our study also provided the complete genome of the symbiotic organism dominating the associated microbial community: a newThaumarchaeotaspecies.

Conclusions

The genome of the glass spongeO. minutadiffers from all other available sponge genomes by its compactness and smaller number of predicted proteins. The unexpected losses of numerous genes considered as ancestral and pivotal for metazoan morphogenetic processes most likely reflect the peculiar syncytial organization in this group. Our work further documents the importance of convergence during animal evolution, with multiple emergences of sponge skeleton, electrical signaling and multiciliated cells.
Anoxic age as a new tool to predict biogeochemical consequences of oxygen depletion in lakes
Authors: LaBrie Richard , Hupfer Michael , Lau Maximilian P.
Published: July 2022

Lake deoxygenation is of growing concern because it threatens ecosystem services delivery. Complete deoxygenation, anoxia, is projected to prolong and expand in lakes, promoting the production or release of nutrients, greenhouse gases and metals from water column and the sediments. Accumulation of these compounds cannot be easily predicted thus hindering our capacity to forecast the ecological consequences of global changes on aquatic ecosystems. Here, we used lakes Arendsee and Mendota monitoring data to develop a novel metric, anoxic age, characterizing lake hypolimnetic anoxia. Anoxic age explained, as a single predictor, 44% to 58% of the variation for ammonium, soluble reactive phosphorus and a dissolved organic matter fluorophore. Anoxic age could be modelled using only two oxygen profiles and lake bathymetry, making it an easily applicable tool to interpret and extrapolate biogeochemical data. This novel metric thus has the potential to transform widely available oxygen profiles into an ecologically meaningful variable.

Scientific Significance Statement

Oxygen depletion in deep water layers of lakes is of growing concern as it expands due to eutrophication and climate change. Anoxia is deleterious to benthic invertebrates and fishes, enables the production of potent greenhouse gases and releases stored phosphorus from sediments, among others. However, quantitatively forecasting the consequences of anoxia remains a challenge. Here, we developed a novel metric, anoxic age, which may be derived from oxygen profiles to predict end-of-summer concentration of various water chemical parameters. We argue that all by-products of anaerobic microbial metabolism should be related to anoxic age as they are released or processed continuously during anoxia. We believe that anoxic age can be used to predict the ecological consequences of temporally and spatially growing anoxia.
cloneMap: a R package to visualise clonal heterogeneity
Authors: Frankell Alexander M , Colliver Emma , Mcgranahan Nicholas , Swanton Charles
Published: July 2022

Genomic evolution and clonal heterogeneity in the soma are widespread and are involved in various pathologies with devastating consequences to human health, most prominently in neoplasia. Tools to interrogate and visualise the diversity of clonal populations in malignant or non-malignant tissues are currently lacking. cloneMap is a tool to represent clonal heterogeneity in a sample or set of samples, accounting for the clone size and phylogenetic relationships between clones. We apply cloneMap to several publicly available cancer sequencing datasets to demonstrate its ability to provide biological inferences of clonal heterogeneity. cloneMap is an R package available on github (https://github.com/amf71/cloneMap).
PHYTOREMEDIATION OF REACTIVE TURQUOISE BLUE H5G USINGIN VITROCULTURES OFSOLANUM VIRGINIANUM(L.)
Authors: Patil Dhanashree S. , Patil Swaroopa A.
Published: July 2022

Solanum virginianum(L.) belonging to family Solanaceae selected for decolourisation of Reactive Turquoise Blue H5G dye.In vitrogrown cultures ofS. virginianumwere able to remove more than 50% dye concentration up to 110mg/l. comparative analysis of biochemical and antioxidant study showed more activity in treated plants as compared to untreated plants. The phytotoxicity study demonstrated the non-toxic nature of degraded metabolites. Use of such non-edible yet medicinal plant for phytoremediation is discussed.
Biophysical control of neural trajectories under disordered brain dynamics
Authors: Sarazin Matthieu , Medernach David , Naudé Jérémie , Delord Bruno
Published: July 2022

Neural trajectories constitute propagating sequences of activity that are essential to cognitive representations. Understanding how neural trajectories overcome the disorganizing influence of neural noise in the awake state remains challenging. Theoretical and artificial network models have focused on optimizing the synaptic pathways underlying trajectory propagation. However, in a biophysical network with synaptic plasticity, solely altering synaptic connectivity induces a tight tradeoff between spurious trajectory interruptions and inductions by noise. Formal analysis predicts that separating the inhibitory fluctuations-driven spontaneous activity from the excitatory-driven trajectory propagation is key to reliable triggering and propagation. Amongst biophysical solutions, calcium-activated suprathreshold intrinsic conductances provided the best trajectory reliability by mitigating the reliance of propagation on connectivity. These mechanisms display parametric robustness and generalize to a variety of static and dynamic attractors with uni- and bidirectional propagation. Thus, we provide a unified framework for cognitive-associated neural trajectories robust to neural noise in the awake state.
Revealing the Neurobiology Underlying Interpersonal Neural Synchronization with Multimodal Data Fusion
Authors: Lotter Leon D. , Kohl Simon H. , Gerloff Christian , Bell Laura , Niephaus Alexandra , Kruppa Jana A. , Dukart Juergen , Schulte-Rüther Martin , Reindl Vanessa , Konrad Kerstin
Published: July 2022

Humans synchronize with one another to foster successful interactions. Here, we use a multimodal data fusion approach with the aim of elucidating the neurobiological mechanisms by which interpersonal neural synchronization (INS) occurs. Our meta-analysis of 22 functional magnetic resonance imaging and 69 near-infrared spectroscopy hyperscanning experiments (740 and 3,721 subjects) revealed robust brain-regional correlates of INS in the right temporoparietal junction and left ventral prefrontal cortex. Integrating this meta-analytic information with public databases, biobehavioral and brain-functional association analyses suggested that INS involves sensory-integrative hubs with functional connections to mentalizing and attention networks. On the molecular and genetic levels, we found INS to be associated with GABAergic neurotransmission and layer IV/V neuronal circuits, protracted developmental gene expression patterns, and disorders of neurodevelopment. Although limited by the indirect nature of phenotypic-molecular association analyses, our findings generate new testable hypotheses on the neurobiological basis of INS.
The long-lasting legacy of reproduction: lifetime reproductive success shapes expected genetic contributions of humans after ten generations
Authors: Young Euan A. , Chesterton Ellie , Lummaa Virpi , Postma Erik , Dugdale Hannah L.
Published: July 2022

An individual’s lifetime reproductive success (LRS) measures its realised genetic contributions to the next generation, but how well does it predict these over longer periods? Here we use human genealogical data to estimate expected individual genetic contributions (IGC) and quantify the degree to which LRS, relative to other fitness proxies, predicts IGC over longer periods in natural populations. This allows an identification of the life-history stages that are most important in shaping variation in IGC. We use historical genealogical data from two non-isolated local populations in Switzerland to estimate the stabilised IGC for 2,230 individuals ~10 generations after they were born. We find that LRS explains 30% less variation in IGC than the best predictor of IGC, the number of grandoffspring. However, albeit less precise than the number of grandoffspring, we show that LRS does provide an unbiased prediction of IGC and overall predicts IGC better than lifespan and similarly when accounting for offspring survival to adulthood. Overall, our findings demonstrate the value of human genealogy data to evolutionary biology and showing that reproduction - more than lifespan or offspring survival - impacts the long-term genetic contributions of historic humans, even in a population with appreciable migration.
Immunological imprinting of humoral immunity to SARS-CoV-2 in children
Authors: Dowell Alexander C. , Lancaster Tara , Bruton Rachel , Ireland Georgina , Bentley Christopher , Sylla Panagiota , Zuo Jianmin , Scott Sam , Jadir Azar , Begum Jusnara , Roberts Thomas , Stephens Christine , Ditta Shabana , Shepherdson Rebecca , Powell Annabel A. , Brent Andrew J. , Brent Bernadette , Baawuah Frances , Okike Ifeanyichukwu , Beckmann Joanne , Ahmad Shazaad , Aiano Felicity , Garstang Joanna , Ramsay Mary E. , Azad Rafaq , Waiblinger Dagmar , Willett Brian , Wright John , Ladhani Shamez N. , Moss Paul
Published: July 2022

Omicron variants of SARS-CoV-2 are globally dominant and infection rates are very high in children. We determined immune responses following Omicron BA.1/2 infection in children aged 6-14 years and related this to prior and subsequent SARS-CoV-2 infection or vaccination. Primary Omicron infection elicited a weak antibody response with poor functional neutralizing antibodies. Subsequent Omicron reinfection or COVID-19 vaccination elicited increased antibody titres with broad neutralisation of Omicron subvariants. Prior pre-Omicron SARS-CoV-2 virus infection or vaccination primed for robust antibody responses following Omicron infection but these remained primarily focussed against ancestral variants. Primary Omicron infection thus elicits a weak antibody response in children which is boosted after reinfection or vaccination. Cellular responses were robust and broadly equivalent in all groups, providing protection against severe disease irrespective of SARS-CoV-2 variant. Immunological imprinting is likely to act as an important determinant of long-term humoral immunity, the future clinical importance of which is unknown.
Deep Insertion, Deletion, and Missense Mutation Libraries for Exploring Protein Variation in Evolution, Disease, and Biology
Authors: Macdonald Christian B. , Nedrud David , Grimes Patrick Rockefeller , Trinidad Donovan , Fraser James S. , Coyote-Maestas Willow
Published: July 2022

Insertions and deletions (indels) are a major source of genetic variation in evolution and the cause of nearly 30% of Mendelian disease. Despite their importance, indels are left out of nearly every systematic mutational scan to date due to technical challenges associated with making indel-containing libraries, limiting our understanding of indels in disease, biology, and evolution. Here we present a library generation method, DIMPLE, that generates deletions, insertions, and missense at similar frequencies within any gene. To benchmark DIMPLE, we generated libraries within four genes (Kir2.1, VatD, TRPV1, and OPRM1) of varying length and evolutionary origin. DIMPLE produces libraries that are near complete, low cost, and low bias. We measured how missense mutations and indels of varying length impact the potassium channel Kir2.1 surface expression. Across all Kir2.1’s secondary structure, deletions are more disruptive than insertions, beta sheets are extremely sensitive to large deletions, and flexible loops allow insertions far more frequently than deletions. DIMPLE’s low bias, ease of use, and low cost will enable high throughput probing of the importance of indels in disease and evolution.
Durable alveolar engraftment of PSC-derived lung epithelial cells into immunocompetent mice
Authors: Herriges Michael J , Yampolskaya Maria , Thapa Bibek R , Lindstrom-Vautrin Jonathan , Wang Feiya , Na Cheng-Lun , Ma Liang , Montminy McKenna M , Huang Jessie , Villacorta-Martin Carlos , Mehta Pankaj , Kotton Darrell N
Published: July 2022

Durable reconstitution of the injured distal lung epithelium with pluripotent stem cell (PSC) derivatives, if realized, would represent a promising potential therapy for diseases that result from alveolar damage. Here we differentiate murine PSCs in vitro into self-renewing lung epithelial progenitors able to engraft into the injured distal lung epithelium of immunocompetent, syngeneic mouse recipients. Emulating the roadmap of the developing embryo, we generate transplantable PSC-derived Nkx2-1+/Sox9+ lung epithelial progenitors that are highly similar to cultured primary embryonic distal lung bud tip progenitors. These cells display a stable phenotype after frozen archiving or extensive expansion in culture, providing a nearly inexhaustible source of cells that can be engrafted into syngeneic injured mouse lungs without the need for immunosuppression. After transplantation PSC-derived tip-like progenitors downregulate Sox9 and mature in the distal lung, upregulating alveolar type 2 cell markers or assuming the flat morphology and molecular phenotype of terminally differentiated alveolar type 1 cells. After months in vivo, donor-derived cells retain their alveolar epithelial type 2-like and type 1-like phenotypes, as characterized by single cell RNA sequencing, ultrastructural analyses, in vivo histologic profiling, and ex vivo organoid assays that demonstrate continued capacity of the engrafted cells to proliferate and differentiate. These results indicate durable reconstitution of the distal lung’s facultative progenitor and differentiated epithelial cell compartments in vivo with PSC-derived cells, thus establishing a novel model for pulmonary cell therapy which can be utilized to better understand the mechanisms and utility of engraftment prior to future clinical studies.