Toll-like receptor 2 (TLR2) belongs to the TLR protein family that plays an important role in the immune and inflammation response system. While TLR2 is predominantly expressed in immune cells, its... Show moreToll-like receptor 2 (TLR2) belongs to the TLR protein family that plays an important role in the immune and inflammation response system. While TLR2 is predominantly expressed in immune cells, its expression has also been detected in the brain, specifically in microglia and astrocytes. Recent studies indicate that genomic deletion of TLR2 can result in impaired neurobehavioural function. It is currently not clear if the genomic deletion of TLR2 leads to any alterations in the microstructural features of the brain. In the current study, we noninvasively assess microstructural changes in the brain of TLR2-deficient (tlr2-/-) zebrafish using state-of-the art magnetic resonance imaging (MRI) methods at ultrahigh magnetic field strength (17.6 T). A significant increase in cortical thickness and an overall trend towards increased brain volumes were observed in young tlr2-/- zebrafish. An elevated T2 relaxation time and significantly reduced apparent diffusion coefficient (ADC) unveil brain-wide microstructural alterations, potentially indicative of cytotoxic oedema and astrogliosis in the tlr2-/- zebrafish. Multicomponent analysis of the ADC diffusivity signal by the phasor approach shows an increase in the slow ADC component associated with restricted diffusion. Diffusion tensor imaging and diffusion kurtosis imaging analysis revealed diminished diffusivity and enhanced kurtosis in various white matter tracks in tlr2-/- compared with control zebrafish, identifying the microstructural underpinnings associated with compromised white matter integrity and axonal degeneration. Taken together, our findings demonstrate that the genomic deletion of TLR2 results in severe alterations to the microstructural features of the zebrafish brain. This study also highlights the potential of ultrahigh field diffusion MRI techniques in discerning exceptionally fine microstructural details within the small zebrafish brain, offering potential for investigating microstructural changes in zebrafish models of various brain diseases. Show less
Remme, R.P.; Meacham, M.; Pellowe, K.E.; Andersson, E.; Guerry, A.D.; Janke, B.; ... ; Oudenhoven, A.P.E. van 2024
In an increasingly urbanized world, the concepts of ecosystem services and nature-based solutions can help tackle grand challenges. However, ambiguity in their definitions and in the relationship... Show moreIn an increasingly urbanized world, the concepts of ecosystem services and nature-based solutions can help tackle grand challenges. However, ambiguity in their definitions and in the relationship between the two concepts complicates comprehensive research efforts as well as their effective application in policy and planning in urban systems. This paper presents a framework to clarify and explicitly relate the two concepts, enhancing their applicability in the management of urban challenges. Within the framework, addressing urban challenges serves as the starting point for the development and implementation of nature-based solutions. Nature-based solutions alter the flows of ecosystem services that are produced by an ecosystem by altering the performance of the ecosystem or by changing how people engage with the ecosystem. This results both in changes in the target ecosystem services, as well as non-targeted ecosystem services, leading to benefits. Using two illustrative case studies, we show how the framework can be applied to two urban challenges that are expected to increase in intensity in cities across the world: stormwater management and urban heat stress. Moreover, we highlight key research topics that will benefit from more integrated use of nature-based solutions and ecosystem services. The framework helps emphasize co-benefits, and can be used to help make co-benefits and multifunctionality explicit in urban decision-making and planning processes. Show less
Valero, C.; Golkaram, M.; Vos, J.L.; Xu, B.; Fitzgerald, C.; Lee, M.; ... ; Morris, L.G.T. 2023
BACKGROUND. Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and... Show moreBACKGROUND. Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in approximately 20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have a modest predictive value in HNSCC.METHODS. We analyzed clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated patients with R/M HNSCC, of whom 69 had virus-associated and 64 had non-virus-associated tumors.RESULTS. Hierarchical clustering of genomic data revealed 6 molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than did a model based on TMB alone. Recursive partitioning analysis identified 3 features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS.CONCLUSION. These findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential responses to ICB and identify a clinical-genomic classifier that outperformed the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered. Show less
Park, S; Liu, L.; Demirkır, Ç.; Heijden, O. van der; Lohse, D.; Krug, D.; Koper, M.T.M. 2023
Although the phylum Chloroflexota is ubiquitous, its biology and evolution are poorly understood due to limited cultivability. Here, we isolated two motile, thermophilic bacteria from hot spring... Show moreAlthough the phylum Chloroflexota is ubiquitous, its biology and evolution are poorly understood due to limited cultivability. Here, we isolated two motile, thermophilic bacteria from hot spring sediments belonging to the genus Tepidiforma and class Dehalococcoidia within the phylum Chloroflexota. A combination of cryo-electron tomography, exometabolomics, and cultivation experiments using stable isotopes of carbon revealed three unusual traits: flagellar motility, a peptidoglycan-containing cell envelope, and heterotrophic activity on aromatics and plant-associated compounds. Outside of this genus, flagellar motility has not been observed in Chloroflexota, and peptidoglycan-containing cell envelopes have not been described in Dehalococcoidia. Although these traits are unusual among cultivated Chloroflexota and Dehalococcoidia, ancestral character state reconstructions showed flagellar motility and peptidoglycan-containing cell envelopes were ancestral within the Dehalococcoidia, and subsequently lost prior to a major adaptive radiation of Dehalococcoidia into marine environments. However, despite the predominantly vertical evolutionary histories of flagellar motility and peptidoglycan biosynthesis, the evolution of enzymes for degradation of aromatics and plant-associated compounds was predominantly horizontal and complex. Together, the presence of these unusual traits in Dehalococcoidia and their evolutionary histories raise new questions about the timing and selective forces driving their successful niche expansion into global oceans. Show less
Severe allergic reactions to certain types of meat following tick bites have been reported in geographic regions which are endemic with ticks. This immune response is directed to a carbohydrate... Show moreSevere allergic reactions to certain types of meat following tick bites have been reported in geographic regions which are endemic with ticks. This immune response is directed to a carbohydrate antigen (galactose-alpha-1,3-galactose or alpha-Gal), which is present in glycoproteins of mammalian meats. At the moment, asparagine-linked complex carbohydrates (N-glycans) with alpha-Gal motifs in meat glycoproteins and in which cell types or tissue morphologies these alpha-Gal moieties are present in mammalian meats are still unclear. In this study, we analyzed alpha-Gal-containing N-glycans in beef, mutton, and pork tenderloin and provided for the first time the spatial distribution of these types of N-glycans in various meat samples. Terminal alpha-Gal-modified N-glycans were found to be highly abundant in all analyzed samples (55, 45, and 36% of N-glycome in beef, mutton, and pork, respectively). Visualizations of the N-glycans with alpha-Gal modification revealed that this motif was mainly present in the fibroconnective tissue. To conclude, this study contributes to a better understanding of the glycosylation biology of meat samples and provides guidance for processed meat products, in which only meat fibers are required as an ingredient (i.e., sausages or canned meat). Show less
Moderation analysis is an integral part of precision medicine research. Concerning moderation analysis with categorical outcomes, we start with an interesting observation, which shows that... Show moreModeration analysis is an integral part of precision medicine research. Concerning moderation analysis with categorical outcomes, we start with an interesting observation, which shows that heterogeneous treatment effects could be equivalently estimated via a role exchange between the outcome and the treatment variable in logistic regression models. Hence two estimators of moderating effects can be obtained. We then established the joint asymptotic normality for the two estimators, on which basis refined inference can be made for moderation analysis. The improved precision is helpful in addressing the lack-of-power problem that is common in search of moderators. The above-mentioned results hold for both experimental and observational data. We investigate the proposed method by simulation and provide an illustration with data from a randomized trial on wart treatment. Show less
Jiang, M.; Behrens, P.A.; Yang, Y.H.; Tang, Z.P.; Chen, D.J.; Yu, Y.D.; ... ; Tukker, A. 2022
Economic prosperity is vital to human development but relies heavily on material extraction, which causes environmental degradation. To successfully decouple growth from degradation, it is... Show moreEconomic prosperity is vital to human development but relies heavily on material extraction, which causes environmental degradation. To successfully decouple growth from degradation, it is essential to identify the primary drivers of countries' material footprints (MFs). However, such understanding remains limited due to the complexities of investment-versus consumption-driven growth. Here, we focus on the MF of China between 2007 and 2012, which was responsible for 24%-30% of global material use. We adopt input-output models that consider trade and classify investment/consumption to estimate, at the province level, the relationship between MFs and the Human Development Index (HDI). Results show that during 2007-2012, China's per capita MF mirrored its HDI and increased by nearly 20%. This is especially prominent in poorer provinces. We further find that it was investments, particularly capital investments associated with construction and manufacturing, that dominated China's MF rather than a consumption-driven demand. Given vast infrastructure gaps in emerging economies and post-pandemic investment plans, these findings emphasize the need for a better understanding of the drivers of growth. Show less
Emerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models... Show moreEmerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals. Show less
Sun, Z.; Qiao, D.; Shi, Y.; Barz, M.; Liu, L.; Chen, Y. 2021
It remains unclear how the precise length of one-dimensional nanovehicles influences the characters of vaccination. Here, a unimolecular nanovehicle with tailored size and aspect ratio (AR) is... Show moreIt remains unclear how the precise length of one-dimensional nanovehicles influences the characters of vaccination. Here, a unimolecular nanovehicle with tailored size and aspect ratio (AR) is applied to deliver CpG oligodeoxynucleotide, a Toll-like receptor (TLR) 9 agonist, as an adjuvant of recombinant hepatitis B virus surface antigen (rHBsAg), for treating chronic hepatitis B (CHB). Cationic nanovehicles with fixed width (ca. 45 nm) but varied length (46 nm-180 nm), AR from 1 to 4, are prepared through controlled polymerization and are loaded with CpG by electrostatic interaction. We reveal that the nanoadjuvant with AR = 2 shows the highest retention in proximal lymph nodes. Importantly, it is more easily internalized into antigen-presenting cells and accumulates in the late endosome, where TLR9 is located. Such a nanoadjuvant exhibits the strongest immune response with rHBsAg to clear the hepatitis B virus in the CHB mouse model, showing that the AR of nanovehicles governs the efficiency of vaccination. Show less
Deep learning for fine-grained image retrieval in an incremental context is less investigated. In this paper, we explore this task to realize the model's continuous retrieval ability. That means,... Show moreDeep learning for fine-grained image retrieval in an incremental context is less investigated. In this paper, we explore this task to realize the model's continuous retrieval ability. That means, the model enables to perform well on new incoming data and reduce forgetting of the knowledge learned on preceding old tasks. For this purpose, we distill semantic correlations knowledge among the representations extracted from the new data only so as to regularize the parameters updates using the teacher-student framework. In particular, for the case of learning multiple tasks sequentially, aside from the correlations distilled from the penultimate model, we estimate the representations for all prior models and further their semantic correlations by using the representations extracted from the new data. To this end, the estimated correlations are used as an additional regularization and further prevent catastrophic forgetting over all previous tasks, and it is unnecessary to save the stream of models trained on these tasks. Extensive experiments demonstrate that the proposed method performs favorably for retaining performance on the already-trained old tasks and achieving good accuracy on the current task when new data are added at once or sequentially. Show less
In recent years a vast amount of visual content has been generated and shared from various fields, such as social media platforms, medical images, and robotics. This abundance of content creation... Show moreIn recent years a vast amount of visual content has been generated and shared from various fields, such as social media platforms, medical images, and robotics. This abundance of content creation and sharing has introduced new challenges. In particular, searching databases for similar content, i.e.content based image retrieval (CBIR), is a long-established research area, and more efficient and accurate methods are needed for real time retrieval. Artificial intelligence has made progress in CBIR and has significantly facilitated the process of intelligent search. In this survey we organize and review recent CBIR works that are developed based on deep learning algorithms and techniques, including insights and techniques from recent papers. We identify and present the commonly-used benchmarks and evaluation methods used in the field. We collect common challenges and propose promising future directions. More specifically, we focus on image retrieval with deep learning and organize the state of the art methods according to the types of deep network structure, deep features, feature enhancement methods, and network fine-tuning strategies. Our survey considers a wide variety of recent methods, aiming to promote a global view of the field of instance-based CBIR. Show less
Liu, L.; Bosse, M.; Megens, H.-J.; Visser, M.C. de; Groenen, M.A.M.; Madsen, O. 2020
Increasing human disturbance and climate change have a major impact on habitat integrity and size, with far‐reaching consequences for wild fauna and flora. Specifically, population decline and... Show moreIncreasing human disturbance and climate change have a major impact on habitat integrity and size, with far‐reaching consequences for wild fauna and flora. Specifically, population decline and habitat fragmentation result in small, isolated populations. To what extend different endangered species can cope with small population size is still largely unknown. Studies on the genomic landscape of these species can shed light on past demographic dynamics and current genetic load, thereby also providing guidance for conservation programs. The pygmy hog (Porcula salvania) is the smallest and rarest wild pig in the world, with current estimation of only a few hundred living in the wild. Here, we analyzed whole‐genome sequencing data of six pygmy hogs, three from the wild and three from a captive population, along with 30 pigs representing six other Suidae. First, we show that the pygmy hog had a very small population size with low genetic diversity over the course of the past ~1 million years. One indication of historical small effective population size is the absence of mitochondrial variation in the six sequenced individuals. Second, we evaluated the impact of historical demography. Runs of homozygosity (ROH) analysis suggests that the pygmy hog population has gone through past but not recent inbreeding. Also, the long‐term, extremely small population size may have led to the accumulation of harmful mutations suggesting that the accumulation of deleterious mutations is exceeding purifying selection in this species. Thus, care has to be taken in the conservation program to avoid or minimize the potential for further inbreeding depression, and guard against environmental changes in the future. Show less
Jiang, M.; Liu, L.; Behrens, P.A.; Wang, T.; Tang, Z.; Chen, D.; ... ; Zhu, B. 2020
A broad-based interlaboratory study of glycosylation profiles of a reference and modified IgG antibody involving 103 reports from 76 laboratories.Glycosylation is a topic of intense current... Show moreA broad-based interlaboratory study of glycosylation profiles of a reference and modified IgG antibody involving 103 reports from 76 laboratories.Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submitted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide community-derived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods. Show less
