bluuebunny/crossref_metadata_2025_split huggingface dataset:
An evolutionarily conserved olfactory receptor is required for sex differences in blood pressure
Authors: Xu Jiaojiao , Choi Rira , Gupta Kunal , Warren Helen R. , Santhanam Lakshmi , Pluznick Jennifer L. 
Published: November 2022

AbstractSex differences in blood pressure are well-established, with premenopausal women having lower blood pressure than men by ∼10mmHg; however, the underlying mechanisms are not fully understood. We report here that olfactory receptor 558 (Olfr558), which has not previously been studied in non-olfactory tissues, localizes to vascular smooth muscle cells in numerous tissues including the kidney and heart. In the kidney, Olfr558 colocalizes with renin (a hormone that plays a key role in blood pressure regulation) in the renal afferent arteriole. Based on the localization of Olfr558, we hypothesized that Olfr558 plays a role in blood pressure regulation. We find that sex differences in blood pressure are intact in Olfr558 wildtype (WT) mice, but, are absent in Olfr558 knockout (KO) mice. We find that male KO mice have lowered diastolic blood pressure, decreased renin expression and activity, and altered vascular reactivity. Female KO mice exhibit increased blood pressure and increased pulse wave velocity, indicating increased vascular stiffness. The human ortholog of Olfr558, OR51E1, was previously identified as a locus associated with diastolic blood pressure. We report here that a rare OR51E1 missense variant has a statistically significant sex interaction effect with diastolic blood pressure, increasing diastolic blood pressure in women but decreasing it in men. In addition, we characterize how two different clinically relevant OR51E1 variants influence OR51E1 signalingin vitro. In sum, our findings demonstrate an evolutionarily conserved role for Olfr558/OR51E1 to mediate sex differences in blood pressure by altering renin, vascular reactivity, and arterial stiffness.
Cold-induced loss of interaction with HSC70 triggers inflammasome activity of familial cold autoinflammatory syndrome-causing mutants of NLRP3
Authors: Raghawan Akhouri Kishore , Ramaswamy Rajashree , Swarup Ghanshyam 
Published: November 2022

AbstractNLRP3 is a cytoplasmic receptor protein, which initiates caspase-1 mediated inflammatory immune response upon detection of invading pathogen or a wide array of internal distress signals. Several gain-of function mutations of NLRP3 cause hereditary disorder of cold-induced hyper-inflammation known as familial cold autoinflammatory syndrome-1 (FCAS1). Although, caspase-1 activation and downstream interleukin-1β / interleukin-18 maturation are common effectors in pathophysiology of this disorder, molecular mechanisms of how exposure to subnormal temperature triggers mutant NLRP3-inflammsome activity is not understood. Here, we show that endogenous NLRP3 is in complex with HSC70 (HSPA8), and this interaction is reduced upon exposure to cold. FCAS-causing NLRP3-L353P and NLRP3-R260W mutants show enhanced interaction with HSC70. Upon exposure to subnormal temperature, NLRP3-L353P and NLRP3-R260W show enhanced inflammasome formation, increased caspase-1 activation and reduced interaction with HSC70. Knockdown of HSC70 results in increased inflammasome formation by L353P and R260W mutants of NLRP3. Our results suggest that interaction with HSC70 suppresses inflammasome formation by FCAS-causing NLRP3 mutants at physiological temperature, and loss of this inhibitory association at subnormal temperature causes aggravated inflammasome formation and caspase-1 activation leading to interleukin-1β maturation. These results provide evidence for HSC70 being a cold-sensor and a temperature-dependent regulator of inflammatory signaling by FCAS-causing NLRP3 mutants.
GAS2 encodes a 2-oxoglutarate dependent dioxygenase involved in ABA catabolism
Authors: Lange Theo , Atiq Nadiem , Lange Maria João Pimenta 
Published: November 2022

AbstractLiu et al.1recently reported the characterization ofArabidopsis thalianaGAS2 (Gain of Function in ABA-modulated Seed Germination 2), which was described as an enzyme that catalyzes the stereospecific hydration of GA12to produce GA1216, 17-dihydro-16α-ol (DHGA12). However, as previously reported2, we did not find conversion of [17-14C]-labeled or [1-,7-,12-,18-14C4]-labeled GA12by GAS2. Furthermore, the authors1state the isolation of endogenous DHGA12from dry Arabidopsis seeds, which we cannot confirm by our attempts to isolate this compound from 0.5 g dry Arabidopsis Col-0 seeds (data not shown). Instead, we present here data showing that the recombinant GAS2 enzyme is able to catabolize abscisic acid (ABA) to phaseic acid (PA) and further to a second product, putative 8’-carboxy-ABA (Fig. 1a).
Modulation of the microhomology-mediated end joining pathway suppresses large deletions and enhances homology-directed repair following CRISPR-Cas9-induced DNA breaks
Authors: Yuan Baolei , Bi Chongwei , Wang Jinchen , Jin Yiqing , Alsayegh Khaled , Tehseen Muhammad , Yi Gang , Hamdan Samir , Huang Yanyi , Li Mo 
Published: November 2022

ABSTRACTCRISPR-Cas9, an efficient genome editing tool, has been widely used in research and holds great promise in the clinic. However, large unintended rearrangements of the genome occur frequently after CRISPR-Cas9 editing and their potential risk cannot be ignored. In this study, we detected large deletions (LDs) induced by CRISPR-Cas9 in human embryonic stem cells (hESCs) and found the microhomology end joining (MMEJ) DNA repair pathway plays a predominant role in LD. We genetically targeted PARP1, RPA, POLQ and LIG3, which play critical roles in MMEJ, during CRISPR-Cas9 editing. By analyzing LD events in two independent gene loci, CD9 and PIGA, using flow cytometry and long-read individual molecule sequencing (IDMseq), we showed that knocking down PARP1 and LIG3 does not alter the frequency of Cas9-induced LD, while knocking down or inhibiting POLQ dramatically reduces LD. Knocking down RPA increases LD frequency, and overexpression of RPAs consistently reduces LD frequency. Interestingly, small-molecule inhibition of POLQ and delivery of recombinant RPA proteins also dramatically increase the efficiency of homology-directed repair (HDR). In conclusion, RPA and POLQ play opposite roles in Cas9-induced LD, modulation of POLQ and RPA can reduce LD and improve HDR, thus holding promise for safe and precise genome editing.
Rapid and Signal Crowdedness-Robust In-Situ Sequencing through Hybrid Block Coding
Authors: Chang Tianyi , Han Wuji , Jiang Mengcheng , Li Jizhou , Liao Zhizhao , Tang Mingchuan , Zhang Jianyun , Shen Jie , Chen Zitian , Fei Peng , Ren Xianwen , Pang Yuhong , Wang Guanbo , Wang Jianbin , Huang Yanyi 
Published: November 2022

AbstractSpatial transcriptomics technology has revolutionized our understanding of cell types and tissue organization, opening new possibilities for researchers to explore transcript distributions at subcellular levels. However, existing methods have limitations in resolution, sensitivity, or speed. To overcome these challenges, we introduce SPRINTseq (Spatially Resolved and signal-diluted Next-generation Targeted sequencing), an innovative in situ sequencing strategy that combines hybrid block coding and molecular dilution strategies. Our method enables fast and sensitive high-resolution data acquisition, as demonstrated by recovering over 142 million transcripts using a 108 gene panel from 453,843 cells from four mouse brain coronal slices in less than two days. Using this advanced technology, we uncover the cellular and subcellular molecular architecture of Alzheimer’s disease, providing additional information into abnormal cellular behaviors and their subcellular mRNA distribution. This improved spatial transcriptomics technology holds great promise for exploring complex biological processes and disease mechanisms.
Tree growth enhancement drives a persistent biomass gain in unmanaged temperate forests
Authors: Marqués Laura , Weng Ensheng , Bugmann Harald , Forrester David I. , Rohner Brigitte , Hobi Martina L. , Trotsiuk Volodymyr , Stocker Benjamin D. 
Published: November 2022

AbstractWhile enhanced tree growth over the last decades has been reported in forests across the globe, it remains unclear whether it drives persistent biomass increases of the stands, particularly in mature forests. Enhanced tree growth and stand-level biomass are often linked with a simultaneous increase in density-driven mortality and a reduction in tree longevity. Identifying empirical evidence regarding the balance between these processes is challenging due to the confounding effects of stand history, management, and environmental changes. Here, we investigate the link between growth and biomass via the shift in the negative relationship between average tree size and stand density (tree number). We find increasing stand density for a given tree size in unmanaged closed-canopy forests in Switzerland over the past six decades and a positive relationship between growth and stand density - qualitatively consistent with simulations by a mechanistic, cohort-resolving ecosystem model (LM3-PPA). Model simulations show that, in the absence of other disturbances, enhanced growth persistently increases biomass stocks despite simultaneous decreases in carbon residence time and tree longevity, independent of assumptions about the drivers of tree mortality. However, the magnitude of simulated changes critically depends on the shape of the mortality parameterizations. Our analyses reconcile reports of growth-induced reductions of tree longevity with model predictions of persistent biomass increases, and with our finding of a trend towards denser forests in response to growth - also in mature stands.
Comparative analysis ofGlycine BBXgene family reveals lineage-specific evolution and expansion
Authors: Deshmukh Reena , Datta Sourav 
Published: November 2022

AbstractBBXgenes are associated with photomorphogenesis, hormone response and seed gemination. Although,BBXgene family is reported inG. max, little is known about its classification and expansion. Similarly, no information is available for theBBXgene family in its closest relativeGlycine soja(Siebold & Zucc.). With extensive genome diversity,G. sojacan be used as an effective genetic reservoir for introgressing important agronomic traits inG. max. In the present study, we carried out a comprehensive comparative genome-wide analysis ofBBXgene family inG. maxandG. soja, to identify their evolutionary relationship and origin in plant lineage. Our results show an ancientBBXgene family expansion through segmental duplication, further suggesting, that theGmBBXmembers are the out-paralogs. These genes show lineage-specific evolution and expansion in the ancestralGlycinegenome supported by the incidences of microsynteny betweenG. maxandG. soja. The two genomes also showed interesting evidence of conserved linkages which might be due to their common ancestor descendance, with minimum horizontal expansion inG. maxafter its split fromG. soja. Our study suggests that theBBXgene family diverged before the split ofG. maxandG. soja. As the two genomes share several regions of synteny, the paralogous members inG. maxcould have been a result of segmental duplications.
Trabecular bone remodeling in the ageing mouse: a micro-multiphysics agent-basedin silicomodel using single-cell mechanomics
Authors: Boaretti Daniele , Marques Francisco C. , Ledoux Charles , Singh Amit , Kendall Jack J. , Wehrle Esther , Kuhn Gisela A. , Bansod Yogesh D. , Schulte Friederike A. , Müller Ralph 
Published: November 2022

AbstractBone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. Notably,in silicomodels are regarded as powerful tools to further understand the signaling pathways that regulate this intricate spatial cellular interplay. To this end, we have established a 3D multiscale micro-multiphysics agent-based (micro-MPA)in silicomodel of trabecular bone remodeling using longitudinalin vivodata from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A)mice, a mouse model of premature aging. Our model includes a variety of cells as single agents and receptor-ligand kinetics, mechanomics, diffusion and decay of cytokines which regulate the cells’ behavior. We highlighted its capabilities by simulating trabecular bone remodeling in the CV6 of 5 mice over 4 weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. Based on the progression of the average trabecular bone volume fraction (BV/TV), we identified a configuration of the model parameters to simulate homeostatic trabecular bone remodeling, here named basal. Crucially, we also produced anabolic, anti-anabolic, catabolic and anti-catabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. Our results showed that changes in the levels of OPG and RANKL were positively and negatively correlated with the BV/TV values after 4 weeks in comparison to basal levels, respectively. Conversely, changes in Scl levels produced small fluctuations in BV/TV in comparison to the basal state. From these results, Scl was deemed to be the main driver of equilibrium while RANKL and OPG were shown to be involved in changes in bone volume fraction with potential relevance for age-related bone features. Ultimately, this micro-MPA model provides valuable insights into how cells respond to their local mechanical environment and can help to identify critical pathways affected by degenerative conditions and ageing.
Analysis of cancer genomic amplifications identifies druggable collateral dependencies within the amplicon
Authors: Pons G , Gallo-Oller G , Navarro N , Zarzosa P , Sansa-Girona J , García-Gilabert L , Magdaleno A , Segura MF , Sánchez de Toledo J , Gallego S , Moreno L , Roma J 
Published: November 2022

AbstractThe identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations or fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy number genomic amplifications generate multiple collateral dependencies within the amplified region in 94% of cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency leads to the identification of genes, the expression of which may constitute predictive biomarkers of dependency.
Ventral Tegmental Area dopamine projections to the hippocampus trigger long-term potentiation and contextual learning
Authors: Sayegh Fares , Macri Catherine , Macedo Juliana Pi , Lejards Camille , Rampon Claire , Verret Laure , Dahan Lionel 
Published: November 2022

AbstractIn most models, dopamine is not involved in the initiation but only in the long-term maintenance of LTP and memory. Conversely, we discovered that repeatedly stimulating Schaffer collaterals in concomitance with midbrain dopamine afferents to CA1 triggers hippocampal LTP. Moreover, we show that this dopamine pathway is involved in contextual learning. Thus, midbrain dopamine can play the role of a teaching signal triggering non-Hebbian LTP and allowing supervised learning.
Cassava Detection from UAV Images Using YOLOv5 Object Detection Model: Towards Weed Control in a Cassava Farm
Authors: Nnadozie Emmanuel C. , Iloanusi Ogechukwu , Ani Ozoemena , Yu Kang 
Published: November 2022

AbstractMost deep learning-based weed detection methods either yield high accuracy, but are slow for real-time applications or too computationally intensive for implementation on smaller devices usable on resource-constrained platforms like UAVs; on the other hand, most of the faster methods lack good accuracy. In this work, two versions of the deep learning-based YOLOv5 object detection model – YOLOv5n and YOLOv5s - were evaluated for cassava detection as a step towards real-time weed detection. The performance of the models were compared when trained with different image resolutions. The robustness of the models were also evaluated under varying field conditions like illumination, weed density, and crop growth stages. YOLOv5s showed the best accuracy whereas YOLOv5n had the best inference speed. For similar image resolutions, YOLOv5s performed better, however, training YOLOv5n with higher image resolutions could yield better performance than training YOLOv5s with lower image resolutions. Both models were robust to variations in field conditions. The speed vs accuracy plot highlighted a range of possible speed/accuracy trade-offs to guide real-time deployment of the object detection models for cassava detection.
Fish Aggregating Devices could enhance the effectiveness of blue water MPAs
Authors: Bode Michael , Game Edward T , Wegmann Alex , Pollock Kydd 
Published: November 2022

ABSTRACTIn the past two decades, drifting fish aggregation devices (FADs) have revolutionised pelagic fisheries, and are now responsible for the majority of tuna purse seine catches. Here, we argue that by taking advantage of the same proven aggregative properties, FADs could be used to enhance the benefits provided by blue water Marine Protected Areas (MPAs). Using models of commercially-targeted fish populations, we explore the potential benefits that could be achieved if unfished conservation FADs were positioned within blue water MPAs. Our results suggest that conservation FADs could deliver benefits, both to target species and the broader ecosystem. By increasing the residence time of exploited species, conservation FADs will reduce average mortality rates inside MPAs. By increasing the local density of species whose populations are depressed by exploitation, FADs can also improve the function of ecosystems in blue water MPAs. Conservation FADs could therefore amplify the benefits of blue water MPAs. We find this amplification is largest in those contexts where blue water MPAs have attracted the most criticism - when their area is small compared to both the open ocean and the distribution of fish stocks that move through them.
Auditory prediction hierarchy in the human hippocampus and amygdala
Authors: Tzovara Athina , Fedele Tommaso , Sarnthein Johannes , Ledergerber Debora , Lin Jack J. , Knight Robert T. 
Published: November 2022

AbstractOur brains can extract structure from the environment and form predictions given past sensory experience. Predictive circuits have been identified in wide-spread cortical regions. However, the contribution of subcortical areas, such as the hippocampus and amygdala in the formation of predictions remains under-explored. Here, we hypothesized that the hippocampus would be sensitive to predictability in sound sequences, while the amygdala would be sensitive to unexpected violations of auditory rules. We presented epileptic patients undergoing presurgical monitoring with standard and deviant sounds, in a predictable or unpredictable context. Onsets of auditory responses and unpredictable deviance effects were detected at earlier latencies in the temporal cortex compared to the amygdala and hippocampus. Deviance effects in 1-20 Hz local field potentials were detected in the lateral temporal cortex, irrespective of predictability. The amygdala showed stronger deviance responses in the unpredictable context. Additionally, low frequency deviance responses in the hippocampus (1-8 Hz) were observed in the predictable but not in the unpredictable context. Our results reveal a distributed cortical-subcortical network underlying the generation of auditory predictions, comprising temporal cortex and the hippocampus and amygdala, and suggest that the neural basis of sensory predictions and prediction error signals needs to be extended to subcortical regions.
Rapid adaptation of recombining populations on tunable fitness landscapes
Authors: Li Juan , Amado André , Bank Claudia 
Published: November 2022

AbstractHow does standing genetic variation affect polygenic adaptation in recombining populations? Despite a large body of work in quantitative genetics, epistatic and weak additive fitness effects among simultaneously segregating genetic variants are difficult to capture experimentally or to predict theoretically. In this study, we simulated adaptation on fitness landscapes with tunable ruggedness driven by standing genetic variation in recombining populations. We confirmed that recombination hinders the movement of a population through a rugged fitness landscape. When surveying the effect of epistasis on the fixation of alleles, we found that the combined effects of high ruggedness and high recombination probabilities lead to preferential fixation of alleles that had a high initial frequency. This indicates that positively epistatic alleles escape from being broken down by recombination when they start at high frequency. We further extract direct selection coefficients and pairwise epistasis along the adaptive path. When taking the final fixed genotype as the reference genetic background, we observe that, along the adaptive path, beneficial direct selection appears stronger and pairwise epistasis weaker than in the underlying fitness landscape. Quantitatively, the ratio of epistasis and direct selection is smaller along the adaptive path (≈1) than expected. Thus, adaptation on a rugged fitness landscape may lead to spurious signals of direct selection generated through epistasis. Our study highlights how the interplay of epistasis and recombination constrains the adaptation of a diverse population to a new environment.
Allele-specific gene editing approach for vision loss restoration inRHO-associated Retinitis Pigmentosa
Authors: Liu Xiaozhen , Qiao Jing , Jia Ruixuan , Zhang Fan , Meng Xiang , Li Yang , Yang Liping 
Published: November 2022

AbstractMutantRHOis the most frequent genetic cause of autosomal dominant retinitis pigmentosa. Here, we developed an allele-specific gene editing therapeutic drug to selectively target the human T17MRHOmutant allele while leaving the wild-typeRHOallele intact for the first time. We identified aStaphylococcus aureusCas9 (SaCas9) guide RNA that was highly active and specific to the human T17MRHOallele.In vitroexperiments using HEK293T cells and patient-specific induced pluripotent stem cells (iPSCs) demonstrated active nuclease activity and high specificity. Subretinal delivery of a single adeno-associated virus serotype 2/8 packaging SaCas9 and sgRNA to the retinas of theRHOhumanized mice showed that this therapeutic drug targeted the mutant allele selectively, thereby downregulating the mutantRHOmRNA expression. Administration of this therapeutic drug resulted in a long-term (up to 11 months after treatment) improvement of retinal function and preservation of photoreceptors in the mutant humanized heterozygous mice. Our study demonstrated a dose-dependent therapeutic effectin vivo.Unwanted off-target effects were not observed at the whole-genome sequencing level. Our study provides strong support for the further development of this effective therapeutic drug to treatRHO-T17M associated autosomal dominant retinitis pigmentosa (adRP), also offers a generalizable framework for developing gene editing medicine. Furthermore, our success in retoring the vision loss in the sufferingRHOhumanized mice verifies the feasibility of allele-specific CRISPR/Cas9-based medicines for other autosomal dominant inherited retinal dystrophies.