Explore the vast range of titles available.

ABSTRACT Symbiotic interactions between humans and our communities of resident gut microbes (microbiota) play many roles in health and disease. Some gut bacteria utilize mucus as a nutrient source and can under certain conditions damage the protective barrier it forms, increasing disease susceptibility. We investigated how Ruminococcus torques— a known mucin degrader that has been implicated in inflammatory bowel diseases (IBDs)—degrades mucin glycoproteins or their component O -linked glycans to understand its effects on the availability of mucin-derived nutrients for other bacteria. We found that R. torques utilizes both mucin glycoproteins and released oligosaccharides from gastric and colonic mucins, degrading these substrates with a panoply of mostly constitutively expressed, secreted enzymes. Investigation of mucin oligosaccharide degradation by R. torques revealed strong α-L-fucosidase, sialidase and β1,4-galactosidase activities. There was a lack of detectable sulfatase and weak β1,3-galactosidase degradation, resulting in accumulation of glycans containing these structures on mucin polypeptides. While the Gram-negative symbiont, Bacteroides thetaiotaomicron grows poorly on mucin glycoproteins, we demonstrate a clear ability of R. torques to liberate products from mucins, making them accessible to B. thetaiotaomicron . This work underscores the diversity of mucin-degrading mechanisms in different bacterial species and the probability that some species are contingent on others for the ability to more fully access mucin-derived nutrients. The ability of R. torques to directly degrade a variety of mucin and mucin glycan structures and unlock released glycans for other species suggests that it is a keystone mucin degrader, which might contribute to its association with IBD. IMPORTANCE An important facet of maintaining healthy symbiosis between host and intestinal microbes is the mucus layer, the first defense protecting the epithelium from lumenal bacteria. Some gut bacteria degrade the various components of intestinal mucins, but detailed mechanisms used by different species are still emerging. It is imperative to understand these mechanisms as they likely dictate interspecies interactions and may illuminate species associated with bacterial mucus damage and subsequent disease susceptibility. Ruminococcus torques is positively associated with IBD in multiple studies. We identified mucin glycan-degrading enzymes in R. torques and found that it shares mucin degradation products with another species of gut bacteria, Bacteroides thetaiotaomicron . Our findings underscore the importance of understanding mucin degradation mechanisms in different gut bacteria and their consequences on interspecies interactions, which may identify keystone bacteria that disproportionately affect mucus damage and could therefore be key players in effects that result from reductions in mucus integrity.

Bioimaging plays an important role in cancer diagnosis and treatment. However, imaging sensitivity and specificity still constitute key challenges. Nanotechnology-based imaging is particularly promising for overcoming these limitations because nanosized imaging agents can specifically home in on tumors via the \"enhanced permeation and retention\" (EPR) effect, thus resulting in enhanced imaging sensitivity and specificity. Here, we report an original nano-system for positron emission tomography (PET) imaging based on an amphiphilic dendrimer, which bears multiple PET reporting units at the terminals. This dendrimer is able to self-assemble into small and uniform nanomicelles, which accumulate in tumors for effective PET imaging. Benefiting from the combined dendrimeric multivalence and EPR-mediated passive tumor targeting, this nanosystem demonstrates superior imaging sensitivity and specificity, with up to 14-fold increased PET signal ratios compared with the clinical gold reference 2-fluorodeoxyglucose ([ 18 F]FDG). Most importantly , this dendrimer system can detect imaging-refractory low-glucose-uptake tumors that are otherwise undetectable using [ 18 F]FDG. In addition, it is endowed with an excellent safety profile and favorable pharmacokinetics for PET imaging. Consequently , this dendrimer nanosystem constitutes an effective and promising approach for cancer imaging. Our study also demonstrates that nanotechnology based on self-assembling den-drimers provides a fresh perspective for biomedical imaging and cancer diagnosis.

The role of silicon (Si) in alleviating biotic and abiotic stresses in crops is well evidenced by empirical studies; however, the mechanisms by which it works are still poorly known. The aim of this study is to determine whether or not phytolith composition and distribution in wheat are affected by drought and, if so, why. Durum wheat was grown using hydroponics in the presence of polyethylene glycol (PEG)-6000 to perform a water-stress simulation. We developed an original method for in situ analysis of phytoliths in leaves via X-ray imaging. PEG was efficient in inhibiting water uptake by roots and creating stress, and prevented a small fraction of Si from being accumulated in the shoots. The application of Si with PEG maintained shoot and root fresh weights (FW) and relative water content at higher values than for plants without Si, especially at PEG 12%. Our data show that, under water stress in the presence of Si, accumulation of phytoliths over the veins provides better support to the leaf, thus allowing for a better development of the whole plant than in the absence of Si. The development of silicified trichomes in durum wheat depends primarily on the availability of Si in soil and is not an adaptation to water stress.

Summary The ectomycorrhizal (ECM) symbiosis has independently evolved from diverse types of saprotrophic ancestors. In this study, we seek to identify genomic signatures of the transition to the ECM habit within the hyper-diverse Russulaceae. We present comparative analyses of the genomic architecture and the total and secreted gene repertoires of 18 species across the order Russulales of which 13 are newly sequenced, including a representative of a saprotrophic member of Russulaceae, Gloeopeniophorella convolvens. The genomes of ECM Russulaceae are characterized by a loss of genes for plant cell-wall degrading enzymes (PCWDEs), an expansion of genome size through increased transposable element (TE) content, a reduction in secondary metabolism clusters, and an association of small secreted proteins (SSPs) with TE “nests”, or dense aggregations of TEs. Some PCWDEs have been retained or even expanded, mostly in a species-specific manner. The genome of Gloeopeniophorella convolvens possesses some characteristics of ECM genomes (e.g., loss of some PCWDEs, TE expansion, reduction in secondary metabolism clusters). Functional specialization in ectomycorrhizal decomposition may drive diversification. Accelerated gene evolution predates the evolution of the ECM habit, indicating that changes in genome architecture and gene content may be necessary to prime the evolutionary switch.

Sickle cell disease (SCD) is among the most prevalent genetic disorders worldwide. It is characterized by unpredictable and potentially fatal vaso-occlusive crises, directly linked to the stiffening of red blood cells (RBCs) due to the formation of hemoglobin fibers in their cytoplasm. Here, we propose a new mechanical marker: the proportion of RBCs in a blood sample deformable enough to exhibit a specific tank-treading motion, in shear flow at a given shear rate. This marker is significantly lower in SCD patients than in controls and is sensitive to RBC density and dehydration, two factors that influence hemoglobin polymerization in SCD. The marker was tested in a cohort of 21 SCD patients, with weekly monitoring conducted over a period of 6 months. It correlates with key biological parameters of SCD including fetal hemoglobin levels, reticulocyte count, serum LDH levels, and the use of antihypertensive treatments. The marker significantly decreases before vaso-occlusive crises requiring hospitalization. These findings indicate that this marker may act as a comprehensive indicator of RBC deformability, offering valuable insights for the continuous clinical monitoring of SCD patients. It could play a role in managing or preventing vaso-occlusive crises and holds potential for the development of new diagnostic tests such as point-of-care or companion diagnostic devices for personalized medicine.

How regulatory information is encoded in the genome is poorly understood and poses a challenge when studying biological processes. We demonstrate here that genomic redistribution of Oct4 by alternative partnering with Sox2 and Sox17 is a fundamental regulatory event of endodermal specification. We show that Sox17 partners with Oct4 and binds to a unique ‘compressed’ Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at ‘canonical’ binding sites. The distinct selection of binding sites by alternative Sox/Oct partnering is underscored by our demonstration that rationally point‐mutated Sox17 partners with Oct4 on pluripotency genes earmarked by the canonical Sox/Oct motif. In an endodermal differentiation assay, we demonstrate that the compressed motif is required for proper expression of endodermal genes. Evidently, Oct4 drives alternative developmental programs by switching Sox partners that affects enhancer selection, leading to either an endodermal or pluripotent cell fate. This work provides insights in understanding cell fate transcriptional regulation by highlighting the direct link between the DNA sequence of an enhancer and a developmental outcome. Precise, cell type‐specific signal integration is crucial for developmental fate determination. The current paper elucidates enhancer‐dependent Oct4 switching between Sox2 and Sox17 to govern self‐renewal versus endodermal differentiation.

Mucociliary clearance is a biomechanical mechanism of airway protection. It consists of the active transport along the bronchial tree of the mucus, a fluid propelled by the coordinated beating of a myriad of cilia on the epithelial surface of the respiratory tract. The physics of mucus transport is poorly understood because it involves complex phenomena such as long-range hydrodynamic interactions, active collective ciliary motion, and the complex rheology of mucus. We propose a quantitative physical analysis of the ciliary activity and mucus transport on a large panel of human bronchial cultures from control subjects, patients with asthma and chronic obstructive pulmonary disease obtained from endobronchial biopsies. Here we report on the existence of multiple ciliary domains with sizes ranging from the tens of a micron to the centimeter, where ciliary beats present a circular orientational order. These domains are associated with circular mucus flow patterns, whose size scales with the average cilia density. In these domains, we find that the radial increase of the ciliated cell density coupled with the increase in the orientational order of ciliary beats result in a net local force proportional to the mucus velocity. We propose a phenomenological physical model that supports our results.

Hepatic steatosis may be caused by type 2 diabetes or obesity and is one of the origins of chronic liver disease. A non-invasive technique based on microwave propagation can be a good solution to monitor hepatic tissue pathologies. The present work is devoted to the dielectric permittivity measurements in healthy and fatty liver in the microwave range. A mouse model following normal and high sugar/glucose (HFS) diets was used. We demonstrated the change in the triglyceride and glucose concentration in the hepatic tissue of HFS diet mice. The difference in the dielectric permittivity of healthy and fatty liver was observed in the range from 100 MHz to 2 GHz. The dielectric permittivity was found to be 42 in the healthy tissue and 31 in the fatty liver tissue at 1 GHz. The obtained results demonstrate that dielectric permittivity can be a sensitive tool to distinguish between healthy and fatty hepatic tissue.

APJ has been extensively described in the pathophysiology of angiogenesis and cell proliferation. The prognostic value of APJ overexpression in many diseases is now established. This study aimed to design a PET radiotracer that specifically binds to APJ. Apelin-F13A-NODAGA (AP747) was synthesized and radiolabeled with gallium-68 ([ 68 Ga]Ga-AP747). Radiolabeling purity was excellent (> 95%) and stable up to 2 h. Affinity constant of [ 67 Ga]Ga-AP747 was measured on APJ-overexpressing colon adenocarcinoma cells and was in nanomolar range. Specificity of [ 68 Ga]Ga-AP747 for APJ was evaluated in vitro by autoradiography and in vivo by small animal PET/CT in both colon adenocarcinoma mouse model and Matrigel plug mouse model. Dynamic of [ 68 Ga]Ga-AP747 PET/CT biodistributions was realized on healthy mice and pigs for two hours, and quantification of signal in organs showed a suitable pharmacokinetic profile for PET imaging, largely excreted by urinary route. Matrigel mice and hindlimb ischemic mice were submitted to a 21-day longitudinal follow-up with [ 68 Ga]Ga-AP747 and [ 68 Ga]Ga-RGD 2 small animal PET/CT. [ 68 Ga]Ga-AP747 PET signal in Matrigel was significantly more intense than that of [ 68 Ga]Ga-RGD 2 . Revascularization of the ischemic hind limb was followed by LASER Doppler. In the hindlimb, [ 68 Ga]Ga-AP747 PET signal was more than twice higher than that of [ 68 Ga]Ga-RGD 2 on day 7, and significantly superior over the 21-day follow-up. A significant, positive correlation was found between the [ 68 Ga]Ga-AP747 PET signal on day 7 and late hindlimb perfusion on day 21. We developed a new PET radiotracer that specifically binds to APJ, [ 68 Ga]Ga-AP747 that showed more efficient imaging properties than the most clinically advanced tracer of angiogenesis, [ 68 Ga]Ga-RGD 2 .

Krüppel-like factors (Klf) 4 and 5 are two closely related members of the Klf family, known to play key roles in cell cycle regulation, somatic cell reprogramming and pluripotency. Here we focus on the functional divergence between Klf4 and Klf5 in the inhibition of mouse embryonic stem (ES) cell differentiation. Using microarrays and chromatin immunoprecipitation coupled to ultra-high-throughput DNA sequencing, we show that Klf4 negatively regulates the expression of endodermal markers in the undifferentiated ES cells, including transcription factors involved in the commitment of pluripotent stem cells to endoderm differentiation. Knockdown of Klf4 enhances differentiation towards visceral and definitive endoderm. In contrast, Klf5 negatively regulates the expression of mesodermal markers, some of which control commitment to the mesoderm lineage, and knockdown of Klf5 specifically enhances differentiation towards mesoderm. We conclude that Klf4 and Klf5 differentially inhibit mesoderm and endoderm differentiation in murine ES cells. The Krüppel-like factors Klf4 and Klf5 have wide roles in cell biology including the regulation of pluripotency. In this study, Aksoy et al . demonstrate that Klf4 preferentially blocks the expression of endodermal markers in embryonic stem cells, whereas Klf5 negatively regulates mesodermal factors.