bluuebunny/crossref_metadata_2025_split 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

AbstractTemporal 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.HighlightsTemporal Diffusion Ratio (TDR) 2-seq approach maps areas with restricted diffusionOptimised gradient waveform pair is: long δ + low G and short δ + high GIf data is noisy calculating TDR using HARDI acquisition subsets increases accuracyWe demonstrate TDR for the first time pre-clinically in rat spinal cordPre-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

AbstractRecessive 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

ABSTRACTMany 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

AbstractThere 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

AbstractBackgroundPreparation 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.MethodsWe 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).ResultsDRL 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.DiscussionThe 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

AbstractFoliar 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.HighlightModification 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

AbstractClimate 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

AbstractSerine 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

AbstractBackgroundMycobacterium 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.MethodsThe 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.ResultsThe 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.ConclusionA 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

BackgroundSocioeconomic 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.MethodsThis 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.ResultsChildren 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.ConclusionsOur 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

AbstractPrevious 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.