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This study focuses on morpho-sedimentary changes in the bay of Safi (Atlantic coast of Morocco), due to a progressive extension of the port. For this purpose, several bathymetric and sedimentary surveys carried out by the Hydrographic and Oceanographic Service of the Navy (SHOM) in 1892, 1906 and 1940 respectively, coupled with a bathymetric and sedimentary measurement mission in 2009, were analyzed to understand the impact of the port developments on the bottom of Safi Bay. This analysis consists of making maps of the evolution of (i) sedimentary facies (of different dates 1892, 1906, 1940 and 2009) and (ii) the shallow seabed of the three periods 1892–1906, 1906–1940 and 1940–2009. The sedimentary facies maps show that the facies appear unstable and evolve intermittently in response to environmental changes in the bay (port construction and expansion). In addition, the overlay of the bathymetric maps indicates that the bay has undergone changes (lowering, stability, and raising) controlled by hydrodynamic conditions before, during, and even after harbor construction. Analysis of the data showed that the expansion of the port often reshaped the morphology of the bay's seabed. The consequences of these evolutions are the appearance of the fattening or the erosion of the bank and the filling of small depressions of sediments. This evolution is reflected in the modification of the funds near the port and the beach of Safi.

In basin modeling the thermodynamics of a multicomponent multiphase fluid flux are computationally too expensive when derived from a cubic equation of state and the Gibbs equality constraints. In this article we present an alternative implicit molar mass formulation technique using binary mixture thermodynamics. The two proposed solution methods are based on a hybrid smoother, Gauss–Seidel–Galerkin at each time-step with analytical computation of the derivatives. The new algorithm overcomes the difficulty of choosing an optimal relaxation parameter and reduce significantly the numerical effort for the computation of the molar masses. Numerical results are presented which show significant improvements with respect to previous methods. [ABSTRACT FROM AUTHOR]

A new technique is presented to determine the complex permittivity of each layer for a bi-layer dielectric material. The bilayer material sample is loaded in a Ku-band rectangular waveguide WR62 and its two port S-parameters are measured as a function of frequency using the E8634A Network Analyzer. Also, by applying transmission (ABCD) matrix, expressions for the S-parameters of the bi-layer dielectric material as a function of complex permittivity of each layer are developed. To estimate the complex permittivity of each layer’s dielectric material, the square sums of errors between the measured and calculated S-parameters are minimised using a nonlinear optimization algorithm. The complex permittivity of each layer for a bi-layer dielectric material such as FR4-Teflon, FR4-Delrin and Delrin-Teflon are determined at the Ku-band frequencies, and the average relative errors between the individual dielectric materials and those of each individual layer of the bi-layer dielectric materials are calculated.

Livestock breeding and particularly milk production play a major role in poverty alleviation and economic growth. The present study aimed at characterizing the production systems and opening avenues for milk production in a (sub)urban [urban community of Niamey (UCN)] and in a rural environment [rural district of Filingue (RDF)] in Niger. In UCN, surveys were carried out in 35 dairy sites randomly selected among the 150 already indexed within a radius of 50 km from the capital. Out of these, 12 sites were selected allowing the questionnaire to be administered to 169 heads of household. In RDF, 49 heads of household, located in five villages within 75 km of Filingue, were surveyed. Results showed that in UCN, breeders owned few dairy cows (five on average, i.e. 28% of the bovine herd), which produced in all seasons 7 to 10 L/household/day; they marketed fresh milk more often than in RDF because they had access to dairy transformation units. In RDF, they owned more cows (ten on average, i.e. 52% of the bovine herd), which produced only during the rainy season and the cold dry season (between 0 to 10 and 10 to 20 L/household/ day according to 66 and 20% of the persons surveyed, respectively); dairy products were transformed more often before sale (melted butter, curdled milk, cheese). The innovations observed in the surveyed breeders were related to changes in herd management. The constraints to dairy production development in the urban area concerned in particular production and preservation of good-quality fresh milk all the way to transforming units or consumers, while in the rural area, it concerned the lack of avenues. In urban areas, it is essential to organize the supply of food inputs, evening collection of milk and to popularize technical topics and innovating practices.

Camel livestock relies on natural forage resources, which are subjected to irregular rainfalls, poorly distributed in time and space. Mobility is one of the strategies used by herders to utilize these resources. However, it has been a while since socioeconomic and climatic changes, and demographic growth and urbanization have changed the rules of herd management. Know-how of dairy farm management is essential for the development of a dairy processing unit in Agadez, whose main activity focuses on camel milk transformation. To help know the various herd management types in Agadez suburban area, 100 camel herders were surveyed. Analysis of the data obtained on herd management practices and on global management of camel herds helped distinguish three main herd types, differentiated on the bases of animal feed practices, herders’ mobility, and a marked preference of some herders for this particular area, for socio-historical and ecological reasons. The first group of herders were sedentary; they owned an average size herd, used feed supplementation and sold camel milk. The second group mostly used transhumance during the rainy season; some herders supplemented their animals, but almost none of the herders sold camel milk. Herders in the third group owned large herds and therefore practiced nomadism regularly. Milk sale became a more common practice through the special contacts established by some of the producers of this group with the dairy processing unit. Herd size and composition, and forage and water resources were the main factors that determined herd movements.

Lichens are complex symbiotic systems where fungi interact with an extracellular arrangement of one or more photosynthetic partners and an indeterminate number of other microbes. Recently, specific lichen-microbial community associations have been proposed. In this study, we aimed to characterize the differences in bacteria associated with closely related lichens, under a defined set of environmental conditions in Colombian paramos. Our goal was to determine if there is a correlation between microbiota and host divergence in lichen species belonging to the genus Sticta. We found that specific microbiota are defined by their mycobiont at the genus level. Further, distinct bacterial families show differences among the three studied genera, and specific amplicon sequence variants further discriminate among lichen species within each genus. A geographic component also determines the composition of these microbial communities among lichen species. Our functional analysis revealed that fungal partners play a key role in synthesizing complex polysaccharides, while bacterial-derived antioxidants and photoprotective mechanisms contribute to desiccation tolerance in lichens. These insights highlight the complex interactions within lichen symbioses that could be relevant in environments such as the paramo ecosystem., (© The Author(s) 2025. Published by Oxford University Press on behalf of FEMS.)

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1 + TCF-1 + neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1 - neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS + Bhlhe40 + T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS + macrophages, neoAg vaccines maintain CX3CR1 + CD206 + macrophages expressing the TREM2 receptor, unlike ICT, which suppresses them. TREM2 blockade enhances neoAg vaccine efficacy and is associated with fewer CX3CR1 + CD206 + macrophages and induction of neoAg-specific CD8 T cells. Our findings highlight different mechanisms underlying neoAg vaccines and different forms of ICT and identify combinatorial therapies to enhance neoAg vaccine efficacy., Competing Interests: Declaration of interests A.M.H. is currently employed by Lifecycle Biotechnologies, and her employment does not pose any direct conflict of interest with the research presented in this article. M.M.G. reports a personal honorarium of US $1,000.00 per year from Springer Nature Ltd (as an associate editor for Nature Precision Oncology) and served as a paid consultant for Merck. M. Colonna reports that they are a member of the scientific advisory board of Vigil Neuro and Cell Signaling Technology, received research grants from Vigil Neuro during the conduct of the study, and has a patent related to TREM2 modulation pending (PCT/US2021/019914). K.E.P. reports an advising relationship with Guardant Health that will result in advising fees., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mononuclear phagocytes (MPs) play a crucial role in tissue homeostasis; however, MPs also contribute to tumor progression and resistance to immune checkpoint blockade (ICB). Targeting MPs could be an effective strategy to enhance ICB efficacy. We report that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors. PKCδ -/- mice displayed reduced tumor progression compared to wild types, with increased response to anti-PD-1. Tumors from PKCδ -/- mice demonstrated T H 1-skewed immune response including increased antigen presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in control but not PKCδ -/- mice. Coinjection of PKCδ -/- M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to PKCδ +/+ controls. PKCδ deficiency reprogrammed MPs by activating type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram MPs to augment ICB efficacy.

Myeloid cells are increasingly being recognized as central players orchestrating or suppressing antitumor immune responses. With the advent of high-resolution analytical methods such as single-cell technologies, we now appreciate the heterogeneity and complexity of the myeloid compartment in the context of cancer. Because of their highly plastic nature, targeting myeloid cells has shown promising results either as a monotherapy or in combination with immunotherapy in preclinical models and cancer patients. However, the complexity of myeloid cell cellular crosstalk and molecular networks contributes to our poor understanding of the different myeloid cell subsets in tumorigenesis, which makes targeting myeloid cells challenging. Here, we summarize varied myeloid cell subsets and their contribution to tumor progression with a main focus on mononuclear phagocytes. The top three unanswered questions challenging the field of myeloid cells and cancer in the era of cancer immunotherapy are addressed. Through these questions, we discuss how myeloid cell origin and identity influence their function and disease outcomes. Different therapeutic strategies used to target myeloid cells in cancer are also addressed. Finally, the durability of myeloid cell targeting is interrogated by examining the complexity of resultant compensatory cellular and molecular mechanisms., Competing Interests: Declaration of Competing Interest Mehdi Chaib, Ubaid A. Tanveer, and Liza Makowski state that they have no conflicts of interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

There is increasing evidence suggesting the role of microbiome alterations in relation to pancreatic adenocarcinoma and tumor immune functionality. However, molecular mechanisms of the interplay between microbiome signatures and/or their metabolites in pancreatic tumor immunosurveillance are not well understood. We have identified that a probiotic strain (Lactobacillus casei) derived siderophore (ferrichrome) efficiently reprograms tumor-associated macrophages (TAMs) and increases CD8 + T cell infiltration into tumors that paralleled a marked reduction in tumor burden in a syngeneic mouse model of pancreatic cancer. Interestingly, this altered immune response improved anti-PD-L1 therapy that suggests promise of a novel combination (ferrichrome and immune checkpoint inhibitors) therapy for pancreatic cancer treatment. Mechanistically, ferrichrome induced TAMs polarization via activation of the TLR4 pathway that represses the expression of iron export protein ferroportin (FPN1) in macrophages. This study describes a novel probiotic based molecular mechanism that can effectively induce anti-tumor immunosurveillance and improve immune checkpoint inhibitors therapy response in pancreatic cancer., (© 2022. The Author(s).)

Poly(hydroxyurethanes) (PHUs) have been suggested as isocyanate-free, low-toxicity alternatives to polyurethanes (PUs). However, PHUs present low mechanical properties due to the presence of side reactions that limit the production of high-molar mass polymers. Here, we present the synthesis under mild conditions and atmospheric pressure of bi-cyclic carbonate monomer for the production of PHU nanocomposites with good physical properties. The kinetics of the bi-cyclic carbonate synthesis and its complete conversion to urethane were followed by FTIR. The addition of functionalized boron nitrate (f-BN) with sucrose crystals improved the thermal degradation temperature as well as the glass transition by approximately 20 °C and 10 °C, respectively. The storage modulus of PHU films gradually increases with the concentration of f-BN in the composite.

Marine sponges and their microbial symbiotic communities are rich sources of diverse natural products (NPs) that often display biological activity, yet little is known about the global distribution of NPs and the symbionts that produce them. Since the majority of sponge symbionts remain uncultured, it is a challenge to characterize their NP biosynthetic pathways, assess their prevalence within the holobiont, and measure the diversity of NP biosynthetic gene clusters (BGCs) across sponge taxa and environments. Here, we explore the microbial biosynthetic landscapes of three high-microbial-abundance (HMA) sponges from the Atlantic Ocean and the Mediterranean Sea. This data set reveals striking novelty, with <1% of the recovered gene cluster families (GCFs) showing similarity to any characterized BGC. When zooming in on the microbial communities of each sponge, we observed higher variability of specialized metabolic and taxonomic profiles between sponge species than within species. Nonetheless, we identified conservation of GCFs, with 20% of sponge GCFs being shared between at least two sponge species and a GCF core comprised of 6% of GCFs shared across all species. Within this functional core, we identified a set of widespread and diverse GCFs encoding nonribosomal peptide synthetases that are potentially involved in the production of diversified ether lipids, as well as GCFs putatively encoding the production of highly modified proteusins. The present work contributes to the small, yet growing body of data characterizing NP landscapes of marine sponge symbionts and to the cryptic biosynthetic potential contained in this environmental niche. IMPORTANCE Marine sponges and their microbial symbiotic communities are a rich source of diverse natural products (NPs). However, little is known about the sponge NP global distribution landscape and the symbionts that produce them. Here, we make use of recently developed tools to perform untargeted mining and comparative analysis of sponge microbiome metagenomes of three sponge species in the first study considering replicate metagenomes of multiple sponge species. We present an overview of the biosynthetic diversity across these sponge holobionts, which displays extreme biosynthetic novelty. We report not only the conservation of biosynthetic and taxonomic diversity but also a core of conserved specialized metabolic pathways. Finally, we highlight several novel GCFs with unknown ecological function, and observe particularly high biosynthetic potential in Acidobacteriota and Latescibacteria symbionts. This study paves the way toward a better understanding of the marine sponge holobionts' biosynthetic potential and the functional and ecological role of sponge microbiomes.

Bariatric surgery is a sustainable weight loss approach, including vertical sleeve gastrectomy (VSG). Obesity exacerbates tumor growth, while diet-induced weight loss impairs progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters response to therapy. Using a pre-clinical model of obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy were investigated. Weight loss by VSG or weight-matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as diet in reducing tumor burden despite achieving similar weight and adiposity loss. Leptin did not associate with changes in tumor burden; however, circulating IL-6 was elevated in VSG mice. Uniquely, VSG tumors displayed elevated inflammation and immune checkpoint ligand PD-L1+ myeloid and non-immune cells. VSG tumors also had reduced T lymphocytes and markers of cytolysis, suggesting an ineffective anti-tumor microenvironment which prompted investigation of immune checkpoint blockade. While obese mice were resistant to immune checkpoint blockade, anti-PD-L1 potently impaired tumor progression after VSG through improved anti-tumor immunity. Thus, in formerly obese mice, surgical weight loss followed by immunotherapy reduced breast cancer burden. Finally, we compared transcriptomic changes in adipose tissue after bariatric surgery from patients and mouse models. A conserved b ariatric s urgery- a ssociated weight loss s ignature (BSAS) was identified which significantly associated with decreased tumor volume. Findings demonstrate conserved impacts of obesity and bariatric surgery-induced weight loss pathways associated with breast cancer progression., Competing Interests: LS, MC, EK, HJ, ML, BC, UT, JH, JC, NJ, DD, TM, MB, RS, AP, BT, JC, DH, MD, KC, JP, LM No competing interests declared, (© 2022, Sipe et al.)

Intestinal epithelial tight junction disruption is a primary contributing factor in alcohol-associated endotoxemia, systemic inflammation, and multiple organ damage. Ethanol and acetaldehyde disrupt tight junctions by elevating intracellular Ca 2+ . Here we identify TRPV6, a Ca 2+ -permeable channel, as responsible for alcohol-induced elevation of intracellular Ca 2+ , intestinal barrier dysfunction, and systemic inflammation. Ethanol and acetaldehyde elicit TRPV6 ionic currents in Caco-2 cells. Studies in Caco-2 cell monolayers and mouse intestinal organoids show that TRPV6 deficiency or inhibition attenuates ethanol- and acetaldehyde-induced Ca 2+ influx, tight junction disruption, and barrier dysfunction. Moreover, Trpv6 -/- mice are resistant to alcohol-induced intestinal barrier dysfunction. Photoaffinity labeling of 3-azibutanol identifies a histidine as a potential alcohol-binding site in TRPV6. The substitution of this histidine, and a nearby arginine, reduces ethanol-activated currents. Our findings reveal that TRPV6 is required for alcohol-induced gut barrier dysfunction and inflammation. Molecules that decrease TRPV6 function have the potential to attenuate alcohol-associated tissue injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDA) tumors have a highly immunosuppressive desmoplastic tumor microenvironment (TME) where immune checkpoint inhibition (ICI) therapy has been exceptionally ineffective. Transforming growth factor-β (TGF-β) receptor activation leads to cancer and immune cell proliferation and phenotype, and cytokine production leading to tumor progression and worse overall survival in PDA patients. We hypothesized that TGF-β receptor inhibition may alter PDA progression and antitumor immunity in the TME. Here, we used a syngeneic preclinical murine model of PDA to explore the impact of TGF-β pathway inhibitor galunisertib (GAL), dual checkpoint immunotherapy (anti-PD-L1 and CTLA-4), the chemotherapy gemcitabine (GEM), and their combinations on antitumor immune responses. Blockade of TGF-β and ICI in immune-competent mice bearing orthotopically injected murine PDA cells significantly inhibited tumor growth and was accompanied by antitumor M1 macrophage infiltration. In contrast, GEM treatment resulted in increased PDA tumor growth, decreased antitumor M1 macrophages, and decreased cytotoxic CD8+ T cell subpopulation compared to control mice. Together, these findings demonstrate the ability of TGF-β inhibition with GAL to prime antitumor immunity in the TME and the curative potential of combining GAL with dual ICI. These preclinical results indicate that targeted inhibition of TGF-β may enhance the efficacy of dual immunotherapy in PDA. Optimal manipulation of the immune TME with non-ICI therapy may enhance therapeutic efficacy., (© 2022 Wiley Periodicals LLC.)

Myeloid-derived suppressor cells (MDSCs) are an immature innate cell population that expands in pathological conditions such as cancer and suppresses T cells via production of immunosuppressive factors. Conversely, efficient cytotoxic T cell priming is dependent on the ability of antigen-presenting cells (APCs) to cross-present tumor antigens to CD8 + T cells, a process that requires a specific subtype of dendritic cells (DCs) called conventional DC1 (cDC1) which are often dysfunctional in cancer. One way to activate cDC1 is ligation of CD40 which is abundantly expressed by myeloid cells and its agonism leads to myeloid cell activation. Thus, targeting MDSCs while simultaneously expanding cross-presenting DCs represents a promising strategy that, when combined with agonistic CD40, may result in long-lasting protective immunity. In this study, we investigated the effect of PKC agonists PEP005 and prostratin on MDSC expansion, differentiation, and recruitment to the tumor microenvironment. Our findings demonstrate that PKC agonists decreased MDSC expansion from hematopoietic progenitors and induced M-MDSC differentiation to an APC-like phenotype that expresses cDC1-related markers via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Simultaneously, PKC agonists favored cDC1 expansion at the expense of cDC2 and plasmacytoid DCs (pDC). Functionally, PKC agonists blunted MDSC suppressive activity and enhanced MDSC cross-priming capacity both in vitro and in vivo. Finally, combination of PKC agonism with agonistic CD40 mAb resulted in a marked reduction in tumor growth with a significant increase in intratumoral activated CD8 + T cells and tissue-resident memory CD8 + T cells in a syngeneic breast cancer mouse model. In sum, this work proposes a novel promising strategy to simultaneously target MDSCs and promote APC function that may have highly impactful clinical relevance in cancer patients., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Cattle productivity depends on our ability to fully understand and manipulate the fermentation process of plant material that occurs in the bovine rumen, which ultimately leads to the improvement of animal health and increased productivity with a reduction in environmental impact. An essential step in this direction is the phylogenetic and functional characterization of the microbial species composing the ruminal microbiota. To address this challenge, we separated a ruminal fluid sample by size and density using a sucrose density gradient. We used the full sample and the smallest fraction (5%), allowing the enrichment of bacteria, to assemble metagenome-assembled genomes (MAGs). We obtained a total of 16 bacterial genomes, 15 of these enriched in the smallest fraction of the gradient. According to the recently proposed Genome Taxonomy Database (GTDB) taxonomy, these MAGs belong to Bacteroidota, Firmicutes&#95;A, Firmicutes, Proteobacteria, and Spirochaetota phyla. Fifteen MAGs were novel at the species level and four at the genus level. The functional characterization of these MAGs suggests differences from what is currently known from the genomic potential of well-characterized members from this complex environment. Species of the phyla Bacteroidota and Spirochaetota show the potential for hydrolysis of complex polysaccharides in the plant cell wall and toward the production of B-complex vitamins and protein degradation in the rumen. Conversely, the MAGs belonging to Firmicutes and Alphaproteobacteria showed a reduction in several metabolic pathways; however, they have genes for lactate fermentation and the presence of hydrolases and esterases related to chitin degradation. Our results demonstrate that the separation of the rumen microbial community by size and density reduced the complexity of the ruminal fluid sample and enriched some poorly characterized ruminal bacteria allowing exploration of their genomic potential and their functional role in the rumen ecosystem., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hernández, Chaib De Mares, Jimenez, Reyes and Caro-Quintero.)

Purpose: Immunotherapy, such as checkpoint inhibitors against anti-programmed death-ligand 1 (PD-L1), has not been successful in treating patients with pancreatic ductal adenocarcinoma (PDAC). Tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), dendritic cells (DCs), and the TGF-β cytokine are critical in anti-cancer immunity. We hypothesized that TGF-β enhances the immunosuppressive effects of TAM, MDSC, and DC presence in tumors., Methods: Using a murine PDAC cell line derived from a genetically engineered mouse model, we orthotopically implanted treated cells plus drug embedded in Matrigel into immunocompetent mice. Treatments included saline control, TGF-β1, or a TGF-β receptor 1 small molecule inhibitor, galunisertib. We investigated TAM, MDSC, DC, and TAM PD-L1 expression with flow cytometry in tumors. Separately, we used the TIMER2.0 database to analyze TAM and PD-L1 gene expression in human PDAC tumors in TCGA database., Results: TGF-β did not alter MDSC or DC frequencies in the primary tumors. However, in PDAC metastases to the liver, TGF-β decreased the proportion of MDSCs (P=0.022) and DCs (P=0.005). TGF-β significantly increased the percent of high PD-L1 expressing TAMs (32 ± 6 % vs. 12 ± 5%, P=0.013) but not the proportion of TAMs in primary and metastatic tumors. TAM PD-L1 gene expression in TCGA PDAC database was significantly correlated with tgb1 and tgfbr1 gene expression (P<0.01)., Conclusions: TGF-β is important in PDAC anti-tumor immunity, demonstrating context-dependent impact on immune cells. TGF-β has an overall immunosuppressive effect mediated by TAM PD-L1 expression and decreased presence of DCs. Future investigations will focus on enhancing anti-cancer immune effects of TGF-β receptor inhibition., (© 2021. The Society for Surgery of the Alimentary Tract.)

Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity. VIDEO ABSTRACT., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vitamin C (ascorbic acid, AscH2) has been shown to enhance immunity. Here, we studied its immunomodulatory effect on human endothelial cells (ECs) during S. aureus infection., Materials and Methods: The ex vivo effects of AscH2 were performed on primary human umbilical vein endothelial cells (HUVECs) infected or not with S. aureus., Results: AscH2 treatment induced a marked downregulation of nitric oxide (NO) production and a moderate upregulation of arginase activity in S. aureus-infected HUVECs (respectively, p < 0.05 and p > 0.05). Although the upregulated release levels of soluble intercellular adhesion molecular 1 (sICAM-1/sCD54) and sE-selectin (sCD62E) molecules were not significantly different between treated and untreated S. aureus-infected HUVECs, AscH2 treatment induced reversing effect on sICAM-1 release when comparing to uninfected control HUVECs. Moreover, AscH2 treatment appears to have a significant effect on preventing HUVEC necrosis induced by S. aureus infection (p < 0.05). Furthermore, AscH2 treatment induced a significant upregulation of cell protective redox biomarker in S. aureus-infected, as shown by superoxide dismutase (SOD) activity (p < 0.05), but not by catalase activity (p > 0.05). Additionally, S. aureus infection markedly downregulated total bound calcium ions ( b Ca 2+ ) levels as compared to control HUVECs, whereas, AscH2 treatment induced a slight upregulation of b Ca 2+ levels in infected HUVECs as compared to infected and untreated HUVECs (p > 0.05). On the other hand, AscH2 treatment downregulated increased total cellular cholesterol content ( tcc CHOL) levels in HUVECs induced by S. aureus infection (p < 0.05). In addition, AscH2 treatment markedly reversed S. aureus effect on upregulation of intracellular glucose ( i GLU) levels within infected HUVECs (p < 0.05). Moreover, AscH2 treatment significantly downregulated S. aureus growth (p < 0.05), and significantly upregulated bacterial internalization and intracellular killing by HUVECs (p < 0.05), as well as their cell cycle activation (p < 0.01). Finally, AscH2 treatment has a slight effect on the production of interleukin 6 (IL-6), but induced a marked downregulation of that of IL-1β in S. aureus-infected HUVECs (respectively, p > 0.05, and p < 0.05)., Conclusions: Our outcomes demonstrated that, during S. aureus infection, AscH2 treatment promotes human ECs survival and function, as well as prevents inflammatory response exacerbation, while inducing bactericidal activity., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The tumor microenvironment (TME) is a complex network of epithelial and stromal cells, wherein stromal components provide support to tumor cells during all stages of tumorigenesis. Among these stromal cell populations are myeloid cells, which are comprised mainly of tumor-associated macrophages (TAM), dendritic cells (DC), myeloid-derived suppressor cells (MDSC), and tumor-associated neutrophils (TAN). Myeloid cells play a major role in tumor growth through nurturing cancer stem cells by providing growth factors and metabolites, increasing angiogenesis, as well as promoting immune evasion through the creation of an immune-suppressive microenvironment. Immunosuppression in the TME is achieved by preventing critical anti-tumor immune responses by natural killer and T cells within the primary tumor and in metastatic niches. Therapeutic success in targeting myeloid cells in malignancies may prove to be an effective strategy to overcome chemotherapy and immunotherapy limitations. Current therapeutic approaches to target myeloid cells in various cancers include inhibition of their recruitment, alteration of function, or functional re-education to an antitumor phenotype to overcome immunosuppression. In this review, we describe strategies to target TAMs and MDSCs, consisting of single agent therapies, nanoparticle-targeted approaches and combination therapies including chemotherapy and immunotherapy. We also summarize recent molecular targets that are specific to myeloid cell populations in the TME, while providing a critical review of the limitations of current strategies aimed at targeting a single subtype of the myeloid cell compartment. The goal of this review is to provide the reader with an understanding of the critical role of myeloid cells in the TME and current therapeutic approaches including ongoing or recently completed clinical trials., (Copyright © 2020 Chaib, Chauhan and Makowski.)

Immunometabolism has emerged as a major mechanism central to adaptive and innate immune regulation. From early observations that inflammatory cytokines were induced in obese adipose tissue and that these cytokines contributed to metabolic disease, it was clear that metabolism and the immunological state are inextricably linked. With a second research wave arising from studies in cancer metabolism to also study the intrinsic metabolic pathways of immune cells themselves and how those pathways influence cell fate and function, immunometabolism is a rapidly maturing area of research. Several key themes and goals drive the field. There is abundant evidence that metabolic pathways are closely tied to cell signaling and differentiation which leads different subsets of immune cells to adopt unique metabolic programs specific to their state and environment. In this way, metabolic signaling drives cell fate. It is also apparent that microenvironment greatly influences cell metabolism. Immune cells adopt programs specific for the tissues where they infiltrate and reside. Ultimately, a central goal of the field is to apply immunometabolism findings to the discovery of novel therapeutic strategies in a wide range of diseases, including cancer, autoimmunity, and metabolic syndrome. This review summarizes these facets of immunometabolism and highlights opportunities for clinical translation., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Bile acids (BAs) are known facilitators of nutrient absorption but recent paradigm shifts now recognize BAs as signaling molecules regulating both innate and adaptive immunity. Bile acids are synthesized from cholesterol in the liver with subsequent microbial modification and fermentation adding complexity to pool composition. Bile acids act on several receptors such as Farnesoid X Receptor and the G protein-coupled BA receptor 1 (TGR5). Interestingly, BA receptors (BARs) are expressed on immune cells and activation either by BAs or BAR agonists modulates innate and adaptive immune cell populations skewing their polarization toward a more tolerogenic anti-inflammatory phenotype. Intriguingly, recent evidence also suggests that BAs promote anti-tumor immune response through activation and recruitment of tumoricidal immune cells such as natural killer T cells. These exciting findings have redefined BA signaling in health and disease wherein they may suppress inflammation on the one hand, yet promote anti-tumor immunity on the other hand. In this review, we provide our readers with the most recent understanding of the interaction of BAs with the host microbiome, their effect on innate and adaptive immunity in health and disease with a special focus on obesity, bariatric surgery-induced weight loss, and immune checkpoint blockade in cancer., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Coniochaeta species are versatile ascomycetes that have great capacity to deconstruct lignocellulose. Here, we explore the transcriptome of Coniochaeta sp. strain 2T2.1 from wheat straw-driven cultures with the fungus growing alone or as a member of a synthetic microbial consortium with Sphingobacterium multivorum w15 and Citrobacter freundii so4. The differential expression profiles of carbohydrate-active enzymes indicated an onset of (hemi)cellulose degradation by 2T2.1 during the initial 24 hours of incubation. Within the tripartite consortium, 63 transcripts of strain 2T2.1 were differentially expressed at this time point. The presence of the two bacteria significantly upregulated the expression of one galactose oxidase, one GH79-like enzyme, one multidrug transporter, one laccase-like protein (AA1 family) and two bilirubin oxidases, suggesting that inter-kingdom interactions (e.g. amensalism) take place within this microbial consortium. Overexpression of multicopper oxidases indicated that strain 2T2.1 may be involved in lignin depolymerization (a trait of enzymatic synergism), while S. multivorum and C. freundii have the metabolic potential to deconstruct arabinoxylan. Under the conditions applied, 2T2.1 appears to be a better degrader of wheat straw when the two bacteria are absent. This conclusion is supported by the observed suppression of its (hemi)cellulolytic arsenal and lower degradation percentages within the microbial consortium., (© FEMS 2019.)

Fungi are evolutionary shape shifters and adapt quickly to new environments. Ectomycorrhizal (EM) symbioses are mutualistic associations between fungi and plants and have evolved repeatedly and independently across the fungal tree of life, suggesting lineages frequently reconfigure genome content to take advantage of open ecological niches. To date analyses of genomic mechanisms facilitating EM symbioses have involved comparisons of distantly related species, but here, we use the genomes of three EM and two asymbiotic (AS) fungi from the genus Amanita as well as an AS outgroup to study genome evolution following a single origin of symbiosis. Our aim was to identify the defining features of EM genomes, but our analyses suggest no clear differentiation of genome size, gene repertoire size, or transposable element content between EM and AS species. Phylogenetic inference of gene gains and losses suggests the transition to symbiosis was dominated by the loss of plant cell wall decomposition genes, a confirmation of previous findings. However, the same dynamic defines the AS species A. inopinata, suggesting loss is not strictly associated with origin of symbiosis. Gene expansions in the common ancestor of EM Amanita were modest, but lineage specific and large gene family expansions are found in two of the three EM extant species. Even closely related EM genomes appear to share few common features. The genetic toolkit required for symbiosis appears already encoded in the genomes of saprotrophic species, and this dynamic may explain the pervasive, recurrent evolution of ectomycorrhizal associations.

Aplysina aerophoba is an emerging model marine sponge, with a well-characterized microbial community in terms of diversity and structure. However, little is known about the expressed functional capabilities of its associated microbes. Here, we present the first metaproteomics-based study of the microbiome of A. aerophoba. We found that transport and degradation of halogenated and chloroaromatic compounds are common active processes in the sponge microbiomes. Our data further reveal that the highest number of proteins were affiliated to a sponge-associated Tectomicrobium, presumably from the family Entotheonellaceae, as well as to the well-known symbiont "Candidatus Synechococcus spongiarium", suggesting a high metabolic activity of these two microorganisms in situ. Evidence for nitric oxide (NO) conversion to nitrous oxide was consistently observed for Tectomicrobia across replicates, by production of the NorQ protein. Moreover, we found a potential energy-yielding pathway through CO oxidation by putative Chloroflexi bacteria. Finally, we observed expression of enzymes that may be involved in the transformation of chitin, glycoproteins, glycolipids and glucans into smaller molecules, consistent with glycosyl hydrolases predicted from analyses of the genomes of Poribacteria sponge symbionts. Thus, this study provides crucial links between expressed proteins and specific members of the A. aerophoba microbiome.

The genus Paraburkholderia encompasses mostly environmental isolates with diverse predicted lifestyles. Genome analyses have shown that bacteriophages form a considerable portion of some Paraburkholderia genomes. Here, we analyzed the evolutionary history of prophages across all Paraburkholderia spp. Specifically, we investigated to what extent the presence of prophages and their distribution affect the diversity/diversification of Paraburkholderia spp., as well as to what extent phages coevolved with their respective hosts. Particular attention was given to the presence of CRISPR-Cas arrays as a reflection of past interactions with phages. We thus analyzed 36 genomes of Paraburkholderia spp., including those of 11 new strains, next to those of three Burkholderia species. Most genomes were found to contain at least one full prophage sequence. The highest number was found in Paraburkholderia sp. strain MF2-27; the nine prophages found amount to up to 4% of its genome. Among all prophages, potential moron genes (e.g., DNA adenine methylase) were found that might be advantageous for host cell fitness. Co-phylogenetic analyses indicated the existence of complex evolutionary scenarios between the different Paraburkholderia hosts and their prophages, including short-term co-speciation, duplication, host-switching and phage loss events. Analysis of the CRISPR-Cas systems showed a record of diverse, potentially recent, phage infections. We conclude that, overall, different phages have interacted in diverse ways with their Paraburkholderia hosts over evolutionary time.

The numbers and diversity of microbes in ecosystems within and around us is unmatched, yet most of these microorganisms remain recalcitrant to in vitro cultivation. Various high-throughput molecular techniques, collectively termed multi-omics, provide insights into the genomic structure and metabolic potential as well as activity of complex microbial communities. Nonetheless, pure or defined cultures are needed to (1) decipher microbial physiology and thus test multi-omics-based ecological hypotheses, (2) curate and improve database annotations and (3) realize novel applications in biotechnology. Cultivation thus provides context. In turn, we here argue that multi-omics information awaits integration into the development of novel cultivation strategies. This can build the foundation for a new era of omics information-guided microbial cultivation technology and reduce the inherent trial-and-error search space. This review discusses how information that can be extracted from multi-omics data can be applied for the cultivation of hitherto uncultured microorganisms. Furthermore, we summarize groundbreaking studies that successfully translated information derived from multi-omics into specific media formulations, screening techniques and selective enrichments in order to obtain novel targeted microbial isolates. By integrating these examples, we conclude with a proposed workflow to facilitate future omics-aided cultivation strategies that are inspired by the microbial complexity of the environment.

Plant biomass (PB) is an important source of sugars useful for biofuel production, whose degradation efficiency depends on synergistic and dynamic interactions of different enzymes. Here, using a metatranscriptomics-based approach, we explored the expression of PB-degrading enzymes in a five-species synthetic bacterial consortium during cultivation on sugarcane bagasse as a unique carbon source. By analyzing the temporal expression dynamics of a selection of enzymes we revealed the functional role of each consortium member and disentangled the potential interactions between them. Based on normalized expression values and the taxonomic affiliation of all the transcripts within thirty carbohydrate-active enzyme (CAZy) families, we observed a successional profile. For instance, endo-glucanases/-xylanases (e.g., GH8, GH10, and GH16) were significantly expressed at 12 h, whereas exo-glucanases (e.g., GH6 and GH48) and α-arabinosidases/β-xylosidases (e.g., GH43) were highly expressed at 48 h. Indeed, a significant peak of extracellular β-xylosidase activity was observed at this stage. Moreover, we observed a higher expression of several CAZy families at 12-48 h, suggesting easy access to the main plant polysaccharides. Based on this evidence, we predicted that the highest level of collaboration between strains takes place at the initial stages of growth. Here, Paenibacillus , Brevundimonas , and Chryseobacterium were the most important contributors, whereas Stenotrophomonas was highly active at the end of the culture (96-192 h) without contributing to a large extent to the expression of lignocellulolytic enzymes. Our results contribute to the understanding of enzymatic and ecological mechanisms within PB-degrading microbial consortia, yielding new perspectives to improve the PB saccharification processes.

Global increases in coral disease prevalence have been linked to ocean warming through changes in coral-associated bacterial communities, pathogen virulence and immune system function. However, the interactive effects of temperature and pathogens on the coral holobiont are poorly understood. Here, we assessed three compartments of the holobiont (host, Symbiodinium and bacterial community) of the coral Montipora aequituberculata challenged with the pathogen Vibrio coralliilyticus and the commensal bacterium Oceanospirillales sp. under ambient (27°C) and elevated (29.5 and 32°C) seawater temperatures. Few visual signs of bleaching and disease development were apparent in any of the treatments, but responses were detected in the holobiont compartments. V. coralliilyticus acted synergistically and negatively impacted the photochemical efficiency of Symbiodinium at 32°C, while Oceanospirillales had no significant effect on photosynthetic efficiency. The coral, however, exhibited a minor response to the bacterial challenges, with the response towards V. coralliilyticus being significantly more pronounced, and involving the prophenoloxidase-activating system and multiple immune system-related genes. Elevated seawater temperatures did not induce shifts in the coral-associated bacterial community, but caused significant gene expression modulation in both Symbiodinium and the coral host. While Symbiodinium exhibited an antiviral response and upregulated stress response genes, M. aequituberculata showed regulation of genes involved in stress and innate immune response processes, including immune and cytokine receptor signalling, the complement system, immune cell activation and phagocytosis, as well as molecular chaperones. These observations show that M. aequituberculata is capable of maintaining a stable bacterial community under elevated seawater temperatures and thereby contributes to preventing disease development., (© 2018 John Wiley & Sons Ltd.)

Sponges are engaged in intimate symbioses with a diversity of microorganisms from all three domains of life, namely Bacteria, Archaea and Eukarya. Sponges have been well studied and categorized for their bacterial communities, some displaying a high microbial abundance (HMA), while others show low microbial abundance (LMA). However, the associated Archaea and Eukarya have remained relatively understudied. We assessed the bacterial, archaeal and eukaryotic diversities in the LMA sponge species Dysidea avara and Dysidea etheria by deep amplicon sequencing, and compared the results to those in the HMA sponges Aplysina aerophoba and Aplysina cauliformis . D. avara and A. aerophoba are sympatric in the Mediterranean Sea, while D. etheria and A. cauliformis are sympatric in the Caribbean Sea. The bacterial communities followed a host-specific pattern, with host species identity explaining most of the variation among samples. We identified OTUs shared by the Aplysina species that support a more ancient association of these microbes, before the split of the two species studied here. These shared OTUs are suitable targets for future studies of the microbial traits that mediate interactions with their hosts. Even though the archaeal communities were not as rich as the bacterial ones, we found a remarkable diversification and specificity of OTUs of the family Cenarchaeaceae and the genus Nitrosopumilus in all four sponge species studied. Similarly, the differences in fungal communities were driven by sponge identity. The structures of the communities of small eukaryotes such as dinophytes and ciliophores (alveolates), and stramenopiles, could not be explained by either sponge host, sponge genus or geographic location. Our analyses suggest that the host specificity that was previously described for sponge bacterial communities also extends to the archaeal and fungal communities, but not to other microbial eukaryotes.

Here, we report the draft genome sequences of three fungal-interactive 10.1601/nm.27008 strains, denoted BS110, BS007 and BS437. Phylogenetic analyses showed that the three strains belong to clade II of the genus 10.1601/nm.1619, which was recently renamed 10.1601/nm.26956. This novel genus primarily contains environmental species, encompassing non-pathogenic plant- as well as fungal-interactive species. The genome of strain BS007 consists of 11,025,273 bp, whereas those of strains BS110 and BS437 have 11,178,081 and 11,303,071 bp, respectively. Analyses of the three annotated genomes revealed the presence of (1) a large suite of substrate capture systems, and (2) a suite of genetic systems required for adaptation to microenvironments in soil and the mycosphere. Thus, genes encoding traits that potentially  confer fungal interactivity were found, such as type 4 pili, type 1, 2, 3, 4 and 6 secretion systems, and biofilm formation (PGA, alginate and pel ) and glycerol uptake systems. Furthermore, the three genomes also revealed the presence of a highly conserved five-gene cluster that had previously been shown to be upregulated upon contact with fungal hyphae. Moreover, a considerable number of prophage-like and CRISPR spacer sequences was found, next to genetic systems responsible for secondary metabolite production. Overall, the three 10.1601/nm.27008 strains possess the genetic repertoire necessary for adaptation to diverse soil niches, including those influenced by soil fungi., Competing Interests: The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The genus Amanita encompasses both symbiotic, ectomycorrhizal fungi and asymbiotic litter decomposers; all species are derived from asymbiotic ancestors. Symbiotic species are no longer able to degrade plant cell walls. The carbohydrate esterases family 1 (CE1s) is a diverse group of enzymes involved in carbon metabolism, including decomposition and carbon storage. CE1 genes of the ectomycorrhizal A. muscaria appear diverged from all other fungal homologues, and more similar to CE1s of bacteria, suggesting a horizontal gene transfer (HGT) event. In order to test whether AmanitaCE1s were acquired horizontally, we built a phylogeny of CE1s collected from across the tree of life, and describe the evolution of CE1 genes among Amanita and relevant lineages of bacteria. CE1s of symbiotic Amanita were very different from CE1s of asymbiotic Amanita, and are more similar to bacterial CE1s. The protein structure of one CE1 gene of A. muscaria matched a depolymerase that degrades the carbon storage molecule poly((R)-3-hydroxybutyrate) (PHB). Asymbiotic Amanita do not carry sequence or structural homologues of these genes. The CE1s acquired through HGT may enable novel metabolisms, or play roles in signaling or defense. This is the first evidence for the horizontal transfer of carbohydrate metabolism genes into ectomycorrhizal fungi., (© 2014 The Authors New Phytologist © 2014 New Phytologist Trust.)

In the microhabitat that surrounds fungal hyphae in soil, coined the mycosphere, carbonaceous compounds that are released from the hyphae stimulate the growth of heterotrophic bacteria, and thus activate organism-to-organism contacts through genetic interactions. Therefore, the mycosphere is postulated to constitute a gene transfer arena, in which a plethora of genes, including locally adaptive ones, are swapped across the resident microbial communities. Such genetic transfers may have plasmids, in particular ones with broad host ranges, as the basis. Indeed, evidence is increasing for the contention that plasmids play crucial roles as accelerators of evolution in the mycosphere, serving as a horizontal gene pool and, therefore, providing competence factors to local bacteria as well as fungi. The evidence so far points at mycosphere roles for two major plasmid classes, the IncP-1 and PromA groups. Moreover, recent data indicate that bacterium-to-fungus gene transfers are detectable and have been evolutionarily important. The large gene pool present in the mycosphere, coupled with the chances for cell-to-cell contact between mycosphere dwellers allows enhanced recombination frequencies, and as such, organisms are selected locally for enhanced fitness., (© 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)

Tenascin C (TNC) is a component of the provisional extracellular matrix (ECM) that characterizes solid tumours. Cell surface annexin II is a high-affinity receptor for large TNC splice variants. The aim of this study was to analyse whether TNC and annexin II play a role in the development of pancreatic ductal adenocarcinoma (PDAC). PDAC is characterized by a rich ECM populated by pancreatic stellate cells, which play a crucial role in pancreatic desmoplasia. The mRNA and protein levels of TNC and of annexin II were analysed in pancreatic tissues by DNA array, quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemistry. TNC large splice variants were detected by RT-PCR. Enzyme linked immunosorbent assay (ELISA) was used to measure TNC levels in serum and culture supernatants. TNC and annexin II mRNA levels were significantly higher in pancreatic cancer tissues than in the normal pancreas. TNC expression was detected with increased frequency in the progression from PanIN-1 lesions to PDAC, and a parallel switch from cytoplasmic to cell surface expression of annexin II was observed. Large TNC transcripts were found in pancreatic cancer and in chronic pancreatitis, but not in the normal pancreas. TNC expression was demonstrated in pancreatic stellate cells, where it could be induced by tumour necrosis factor alpha (TNFalpha), transforming growth factor beta1 (TGF-beta1) and by cancer cell supernatants supplemented with TGF-beta1. In conclusion, the expression of TNC and cell surface annexin II increases in the progression from low-grade PanIN lesions to pancreatic cancer. Pancreatic stellate cells are identified as a source of TNC in pancreatic tissues, possibly under the influence of soluble factors released by the tumour cells.

Campylobacter enteritis appears to be a frequent cause of bacterial diarrhoea, especially among children. The species isolated in our study are C. jejuni and C. coli. The clinical characteristics are acute diarrhoea (sometimes with blood) and abdominal pain. The evolution is usually favorable without treatment. In serious and prolonged cases, the treatment is based on Erythromycin which was active against all the strains.