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Microbiota-directed complementary food (MDCF) formulations have been designed to repair the gut communities of malnourished children. A randomized controlled trial demonstrated that one formulation, MDCF-2, improved weight gain in malnourished Bangladeshi children compared to a more calorically dense standard nutritional intervention. Metagenome-assembled genomes from study participants revealed a correlation between ponderal growth and expression of MDCF-2 glycan utilization pathways by Prevotella copri strains. To test this correlation, here we use gnotobiotic mice colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains, with or without P. copri isolates closely matching the metagenome-assembled genomes. Combining gut metagenomics and metatranscriptomics with host single-nucleus RNA sequencing and gut metabolomic analyses, we identify a key role of P. copri in metabolizing MDCF-2 glycans and uncover its interactions with other microbes including Bifidobacterium infantis. P. copri-containing consortia mediated weight gain and modulated energy metabolism within intestinal epithelial cells. Our results reveal structure-function relationships between MDCF-2 and members of the gut microbiota of malnourished children with potential implications for future therapies.

A right-hand-dominant female presented 5 weeks following a right middle finger intralesional cantharidin injection for a common wart by a dermatologist. The patient experienced progressive stiffness, blistering, swelling, pain, and ultimately, full-thickness skin necrosis surrounding the injection site. Careful debridement followed by a full-thickness skin graft was performed with no evidence of involvement of the germinal matrix or terminal extensor tendon. At the 7-month postoperative mark, the patient's graft exhibited favorable healing and improved functionality that did not require further follow-up. Intralesional injection of cantharidin solutions for digital warts leads to progressive skin necrosis. Our case required prompt debridement and defect coverage. Involvement of the underlying anatomical structures was also a concern. Dermatologists and hand surgeons should be familiar with this complication as intralesional cantharidin injections are contraindicated.

Evidence is accumulating that perturbed postnatal development of the gut microbiome contributes to childhood malnutrition1-4. Here we analyse biospecimens from a randomized, controlled trial of a microbiome-directed complementary food (MDCF-2) that produced superior rates of weight gain compared with a calorically more dense conventional ready-to-use supplementary food in 12-18-month-old Bangladeshi children with moderate acute malnutrition4. We reconstructed 1,000 bacterial genomes (metagenome-assembled genomes (MAGs)) from the faecal microbiomes of trial participants, identified 75 MAGs of which the abundances were positively associated with ponderal growth (change in weight-for-length Z score (WLZ)), characterized changes in MAG gene expression as a function of treatment type and WLZ response, and quantified carbohydrate structures in MDCF-2 and faeces. The results reveal that two Prevotella copri MAGs that are positively associated with WLZ are the principal contributors to MDCF-2-induced expression of metabolic pathways involved in utilizing the component glycans of MDCF-2. The predicted specificities of carbohydrate-active enzymes expressed by their polysaccharide-utilization loci are correlated with (1) the in vitro growth of Bangladeshi P. copri strains, possessing varying degrees of polysaccharide-utilization loci and genomic conservation with these MAGs, in defined medium containing different purified glycans representative of those in MDCF-2, and (2) the levels of faecal carbohydrate structures in the trial participants. These associations suggest that identifying bioactive glycan structures in MDCFs metabolized by growth-associated bacterial taxa will help to guide recommendations about their use in children with acute malnutrition and enable the development of additional formulations.

Abstract The antimicrobial resistance crisis along with challenges of antimicrobial discovery revealed the vital necessity to develop new antibiotics. Many of the animal proline-rich antimicrobial peptides (PrAMPs) inhibit the process of bacterial translation. Genome projects allowed to identify immune-related genes encoding animal host defense peptides. Here, using genome mining approach, we discovered a family of proline-rich cathelicidins, named rumicidins. The genes encoding these peptides are widespread among ruminant mammals. Biochemical studies indicated that rumicidins effectively inhibited the elongation stage of bacterial translation. The cryo-EM structure of the Escherichia coli 70S ribosome in complex with one of the representatives of the family revealed that the binding site of rumicidins span the ribosomal A-site cleft and the nascent peptide exit tunnel interacting with its constriction point by the conservative Trp23-Phe24 dyad. Bacterial resistance to rumicidins is mediated by knockout of the SbmA transporter or modification of the MacAB-TolC efflux pump. A wide spectrum of antibacterial activity, a high efficacy in the animal infection model, and lack of adverse effects towards human cells in vitro make rumicidins promising molecular scaffolds for development of ribosome-targeting antibiotics.

The vertical distribution of ozone plays an important role in atmospheric chemistry, climate change, air pollution, and human health. Over the 21st century, spaceborne remote-sensing methods and instrumentation have evolved to better determine this distribution. We quantify the ability of ozone retrievals to characterize this distribution through a sequential combination of thermal infrared (TIR) and ultraviolet (UV) spectral radiances, harnessing co-located TIR measurements from the Cross-track Infrared Sounder (CrIS) on board the Suomi National Polar-orbiting Partnership (NPP) and UV measurements from the TROPOspheric Monitoring Instrument (TROPOMI), which is on the Sentinel 5-Precursor (S5P) satellite. Using the MUlti-SpEctra, MUlti-SpEcies, MUlti-SEnsors (MUSES) algorithm, the sequential combination of TIR and UV measurements, which follows retrievals from each instrument separately, moderately improves the ability of satellites to characterize global ozone profiles over the use of each instrument/band individually. The CrIS retrievals enhanced by TROPOMI radiances in the Huggins band (325–335 nm) show good agreement with independent datasets both in the troposphere and in the stratosphere in spite of calibration issues in the TROPOMI UV. Improved performance is characterized in the stratosphere from CrIS-TROPOMI, firstly through a modest increase in the degrees of freedom for signal (DFS; often between 0.1–0.2) and secondly through comparisons with the Microwave Limb Sounder (MLS), where a global multi-month-long comparison shows a mean difference ∼×10 lower than either CrIS or TROPOMI individually and R2 values 3 % higher. In the troposphere, CrIS-TROPOMI and CrIS show similar degrees of freedom for signal, with about 2 globally, but these are higher in the tropics partitioned equally between the lower and upper troposphere. CrIS-TROPOMI validation with ozonesondes shows improved performance over CrIS-only validation, with a difference in the tropospheric-column bias of between 30 % and 200 % depending on the season. Cross-comparisons with satellite instruments and reanalysis datasets show similar performances in terms of correlations and biases. These results demonstrate that CrIS and CrIS-TROPOMI retrievals have the potential to improve global satellite ozone retrievals, especially with future developments. If spectral accuracy is improved in future TROPOMI calibration, the degrees of freedom for signal in the stratosphere could double when using bands 1 and 2 of TROPOMI (270–330 nm), while tropospheric degrees of freedom for signal could increase by 25 %.

Abstract Spontaneous symmetry breaking and emergent polar order are each of fundamental importance to a range of scientific disciplines, as well as generating rich phase behaviour in liquid crystals (LCs). Here, we show the union of these phenomena to lead to two previously undiscovered polar liquid states of matter. Both phases have a lamellar structure with an inherent polar ordering of their constituent molecules. The first of these phases is characterised by polar order and a local tilted structure; the tilt direction processes about a helix orthogonal to the layer normal, the period of which is such that we observe selective reflection of light. The second new phase type is anti-ferroelectric, with the constituent molecules aligning orthogonally to the layer normal. This has led us to term the phases the $${{{{{\rm{Sm}}}}}}{{{{{{\rm{C}}}}}}}_{{{{{{\rm{P}}}}}}}^{{{{{{\rm{H}}}}}}}$$ Sm C P H and SmAAF phases, respectively. Further to this, we obtain room temperature ferroelectric nematic (NF) and $${{{{{\rm{Sm}}}}}}{{{{{{\rm{C}}}}}}}_{{{{{{\rm{P}}}}}}}^{{{{{{\rm{H}}}}}}}$$ Sm C P H phases via binary mixture formulation of the novel materials described here with a standard NF compound (DIO), with the resultant materials having melting points (and/or glass transitions) which are significantly below ambient temperature. The new soft matter phase types discovered herein can be considered as electrical analogues of topological structures of magnetic spins in hard matter.

Understanding how members of the human gut microbiota prioritize nutrient resources is one component of a larger effort to decipher the mechanisms defining microbial community robustness and resiliency in health and disease. This knowledge is foundational for development of microbiota-directed therapeutics. To model how bacteria prioritize glycans in the gut, germfree mice were colonized with 13 human gut bacterial strains, including seven saccharolytic Bacteroidaceae species. Animals were fed a Western diet supplemented with pea fiber. After community assembly, an inducible CRISPR-based system was used to selectively and temporarily reduce the absolute abundance of Bacteroides thetaiotaomicron or B. cellulosilyticus by 10- to 60-fold. Each knockdown resulted in specific, reproducible increases in the abundances of other Bacteroidaceae and dynamic alterations in their expression of genes involved in glycan utilization. Emergence of these alternate consumers was associated with preservation of community saccharolytic activity. Using an inducible system for CRISPR base editing in vitro, we disrupted translation of transporters critical for utilizing dietary polysaccharides in Phocaeicola vulgatus, a B. cellulosilyticus knockdown-responsive taxon. In vitro and in vivo tests of the resulting P. vulgatus mutants allowed us to further characterize mechanisms associated with its increased fitness after knockdown. In principle, the approach described can be applied to study utilization of a range of nutrients and to preclinical efforts designed to develop therapeutic strategies for precision manipulation of microbial communities.

Abstract Background Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL. Results We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β

Abstract Periodically, the European Space Agency (ESA) updates scientific roadmaps in consultation with the scientific community. The ESA SciSpacE Science Community White Paper (SSCWP) 9, “Biology in Space and Analogue Environments”, focusses in 5 main topic areas, aiming to address key community-identified knowledge gaps in Space Biology. Here we present one of the identified topic areas, which is also an unanswered question of life science research in Space: “How to Obtain an Integrated Picture of the Molecular Networks Involved in Adaptation to Microgravity in Different Biological Systems?” The manuscript reports the main gaps of knowledge which have been identified by the community in the above topic area as well as the approach the community indicates to address the gaps not yet bridged. Moreover, the relevance that these research activities might have for the space exploration programs and also for application in industrial and technological fields on Earth is briefly discussed.

BackgroundAntimicrobial resistance (AMR) poses a critical threat to public health and disproportionately affects the health and well-being of persons in low-income and middle-income countries. Our aim was to identify synthetic antimicrobials termed conjugated oligoelectrolytes (COEs) that effectively treated AMR infections and whose structures could be readily modified to address current and anticipated patient needs.MethodsFifteen chemical variants were synthesized that contain specific alterations to the COE modular structure, and each variant was evaluated for broad-spectrum antibacterial activity and for in vitro cytotoxicity in cultured mammalian cells. Antibiotic efficacy was analyzed in murine models of sepsis; in vivo toxicity was evaluated via a blinded study of mouse clinical signs as an outcome of drug treatment.FindingsWe identified a compound, COE2-2hexyl, that displayed broad-spectrum antibacterial activity. This compound cured mice infected with clinical bacterial isolates derived from patients with refractory bacteremia and did not evoke bacterial resistance. COE2-2hexyl has specific effects on multiple membrane-associated functions (e.g., septation, motility, ATP synthesis, respiration, membrane permeability to small molecules) that may act together to negate bacterial cell viability and the evolution of drug-resistance. Disruption of these bacterial properties may occur through alteration of critical protein-protein or protein-lipid membrane interfaces-a mechanism of action distinct from many membrane disrupting antimicrobials or detergents that destabilize membranes to induce bacterial cell lysis.InterpretationThe ease of molecular design, synthesis and modular nature of COEs offer many advantages over conventional antimicrobials, making synthesis simple, scalable and affordable. These COE features enable the construction of a spectrum of compounds with the potential for development as a new versatile therapy for an imminent global health crisis.FundingU.S. Army Research Office, National Institute of Allergy and Infectious Diseases, and National Heart, Lung, and Blood Institute.

Ferroelectric nematic liquid crystals exhibit unique non-linear optical properties, with the potential to become transformative materials for photonic applications. A promising direction relies on the fabrication of tailored polar orientational patterns via photoalignment, thus shaping the non-linear optical susceptibility through thin slabs of the ferroelectric fluid. Here, we explore the fabrication of 2D periodic SHG active arrays in ferroelectric nematic fluids, for different materials, cell thicknesses and motifs. Based on polarizing optical microscopy observations in combination with optical simulations, second harmonic generation microscopy and interferometry, the 3D structure of the motifs is revealed. Two different 2D periodic patterns are explored, showing that the balance between flexoelectric and electrostatic energy can lead to different domain structures, an effect which is rooted in the difference between the flexoelectric properties of the materials. It is shown that by combining the surface-inscribed alignment with different spontaneous degrees of twist, 2D SHG active arrays can be obtained in the micrometre scale, in which adjacent areas exhibit maximum SHG signals at opposite angles.