How the credit channel works: differentiating the bank lending channel and the balance sheet channel

The credit channel of monetary policy transmission operates through changes in lending. To examine this channel, we explore how movements in the real federal funds rate affect bank lending. Using data on individual loans from the Survey of Terms of Bank Lending, we are able to differentiate two ways the credit channel can work: by affecting overall bank lending (the bank lending channel) and by affecting the allocation of loans (the balance sheet channel). We find evidence consistent with the operation of both internal credit channels. During periods of tight monetary policy, banks adjust their stock of loans by reducing the maturity of loan originations and they reallocate their short-term loan supply from small firms to large firms. These results are stronger for large banks than for small banks.Monetary policy ; Bank loans

The Enduring Importance of Animal Models in Understanding Periodontal Disease

Whereas no single animal model can reproduce the complexity of periodontitis, different aspects of the disease can be addressed by distinct models. Despite their limitations, animal models are essential for testing the biological significance of in vitro findings and for establishing cause-and-effect relationships relevant to clinical observations, which are typically correlative. We provide evidence that animal-based studies have generated a durable framework for dissecting the mechanistic basis of periodontitis. These studies have solidified the etiologic role of bacteria in initiating the inflammatory response that leads to periodontal bone loss and have identified key mediators (IL-1, TNF, prostaglandins, complement, RANKL) that induce inflammatory breakdown. Moreover, animal studies suggest that dysbiosis, rather than individual bacterial species, are important in initiating periodontal bone loss and have introduced the concept that organisms previously considered commensals can play important roles as accessory pathogens or pathobionts. These studies have also provided insight as to how systemic conditions, such as diabetes or leukocyte adhesion deficiency, contribute to tissue destruction. In addition, animal studies have identified and been useful in testing therapeutic targets

The emerging oral pathogen, Filifactor alocis, modulates antimicrobial responses of primed human neutrophils.

Almost 50% of the adult population older than 30 years of age suffers from some form of periodontitis, a chronic inflammatory disease of the periodontal tissue caused by microbial subversion of the host immune response. Neutrophils are the most abundant leukocyte present in the oral mucosa. In periodontitis, periodontal pathogens have developed strategies to evade neutrophil antimicrobial responses and promote bacterial growth. Among these oral pathogens is Filifactor alocis which can modulate neutrophils’ antimicrobial responses by preventing phagosome maturation. During inflammation, neutrophils that reach the gingival tissue are primed by cytokines and chemokines. However, the response of primed human neutrophils to F. alocis is currently unknown. To address this gap in knowledge, human neutrophils were primed with TNF-α, an established priming agent, and the kinetics of phagocytosis and intracellular ROS production in response to serum opsonized F. alocis were tested. Our results showed a significant increase in phagocytosis of F. alocisby TNF-α-primed neutrophils compared to unprimed cells. However, the significant increase in bacteria uptake was not accompanied by increased ROS production. F. alocis significantly downregulated the respiratory burst response in human neutrophils independently of priming with TNF-α. Interestingly, priming of neutrophils with IL-8 did not result in a significant increase in phagocytosis of F. alocis, but IL-8-primed neutrophils did have a similar ROS phenotype to TNF-α-primed neutrophils. This suggests dome ability of F. alcois to modulate the phagocytic ability of IL-8-primed neutrophils. Future studies will aim to characterize F. alocis’ virulence factors that modulate neutrophil responses

Pathway analysis for intracellular Porphyromonas gingivalis using a strain ATCC 33277 specific database

<p>Abstract</p> <p>Background</p> <p><it>Porphyromonas gingivalis </it>is a Gram-negative intracellular pathogen associated with periodontal disease. We have previously reported on whole-cell quantitative proteomic analyses to investigate the differential expression of virulence factors as the organism transitions from an extracellular to intracellular lifestyle. The original results with the invasive strain <it>P. gingivalis </it>ATCC 33277 were obtained using the genome sequence available at the time, strain W83 [GenBank: <ext-link ext-link-id="AE015924" ext-link-type="gen">AE015924</ext-link>]. We present here a re-processed dataset using the recently published genome annotation specific for strain ATCC 33277 [GenBank: <ext-link ext-link-id="AP009380" ext-link-type="gen">AP009380</ext-link>] and an analysis of differential abundance based on metabolic pathways rather than individual proteins.</p> <p>Results</p> <p>Qualitative detection was observed for 1266 proteins using the strain ATCC 33277 annotation for 18 hour internalized <it>P. gingivalis </it>within human gingival epithelial cells and controls exposed to gingival cell culture medium, an improvement of 7% over the W83 annotation. Internalized cells showed increased abundance of proteins in the energy pathway from asparagine/aspartate amino acids to ATP. The pathway producing one short chain fatty acid, propionate, showed increased abundance, while that of another, butyrate, trended towards decreased abundance. The translational machinery, including ribosomal proteins and tRNA synthetases, showed a significant increase in protein relative abundance, as did proteins responsible for transcription.</p> <p>Conclusion</p> <p>Use of the ATCC 33277 specific genome annotation resulted in improved proteome coverage with respect to the number of proteins observed both qualitatively in terms of protein identifications and quantitatively in terms of the number of calculated abundance ratios. Pathway analysis showed a significant increase in overall protein synthetic and transcriptional machinery in the absence of significant growth. These results suggest that the interior of host cells provides a more energy rich environment compared to the extracellular milieu. Shifts in the production of cytotoxic fatty acids by intracellular <it>P. gingivalis </it>may play a role in virulence. Moreover, despite extensive genomic re-arrangements between strains W83 and 33277, there is sufficient sequence similarity at the peptide level for proteomic abundance trends to be largely accurate when using the heterologous strain annotated genome as the reference for database searching.</p

O-mannosylation in Candida albicans enables development of interkingdom biofilm communities

Peer reviewedPublisher PD

Organotypic model of the gingiva for studying bacterial and viral pathogens implicated in periodontitis

Background: Three-dimensional (3D) tissue models bridge the gap between conventional two-dimensional cell cultures and animal models. The aim of this study was to develop an organotypic 3D gingival (OTG) model to provide a tool to investigate bacterial and viral pathogens in periodontitis. Methods: The OTG model composed of gingival fibroblasts (GFs) and telomerase- immortalized gingival keratinocytes (TIGKs) was constructed and applied to study infections by Porphyromonas gingivalis and herpes simplex virus 1 (HSV-1). Immunohistochemical stain-ing, confocal microscopy, qPCR, titration techniques, and colony-forming unit counts were applied to interrogate epithelial markers expression, monitor P. gingivalis and HSV-1 presence, and evaluate the immune response along with the efficiency of antimicrobial drugs. Results: The OTG model resembled the morphology of the human gingiva. During infection, both pathogens penetrated deep into the tissue and persisted for a few days with P. gingivalis also forming a biofilm on the cell surface. The infection triggered the expression of inflammatory mediators in cells and both pathogens were efficiently eliminated by specific antimicrobials. Conclusions: Presented OTG model constitutes a simple and convenient tool to study the interaction between bacterial and viral pathogens within the gingival tissue, including penetration, persistence and biofilm formation. It is also suitable to examine the efficiency of antimicrobial drugs

Interspecies metabolite transfer fuels the methionine metabolism of Fusobacterium nucleatum to stimulate volatile methyl mercaptan production

Hara Takeshi, Sakanaka Akito, Lamont Richard J., et al. Interspecies metabolite transfer fuels the methionine metabolism of Fusobacterium nucleatum to stimulate volatile methyl mercaptan production. mSystems 2, 118 (2024); https://doi.org/10.1128/msystems.00764-23.The major oral odor compound methyl mercaptan (CH3SH) is strongly associated with halitosis and periodontitis. CH3SH production stems from the metabolism of polymicrobial communities in periodontal pockets and on the tongue dorsum. However, understanding of CH3SH-producing oral bacteria and their interactions is limited. This study aimed to investigate CH3SH production by major oral bacteria and the impact of interspecies interactions on its generation. Using a newly constructed large-volume anaerobic noncontact coculture system, Fusobacterium nucleatum was found to be a potent producer of CH3SH, with that production stimulated by metabolic interactions with Streptococcus gordonii, an early dental plaque colonizer. Furthermore, analysis of extracellular amino acids using an S. gordonii arginine-ornithine antiporter (ArcD) mutant demonstrated that ornithine excreted from S. gordonii is a key contributor to increased CH3SH production by F. nucleatum. Further study with 13C, 15N-methionine, as well as gene expression analysis, revealed that ornithine secreted by S. gordonii increased the demand for methionine through accelerated polyamine synthesis by F. nucleatum, leading to elevated methionine pathway activity and CH3SH production. Collectively, these findings suggest that interaction between S. gordonii and F. nucleatum plays a key role in CH3SH production, providing a new insight into the mechanism of CH3SH generation in oral microbial communities. A better understanding of the underlying interactions among oral bacteria involved in CH3SH generation can lead to the development of more appropriate prophylactic approaches to treat halitosis and periodontitis. An intervention approach like selectively disrupting this interspecies network could also offer a powerful therapeutic strategy

The Streptococcus gordonii adhesin CshA protein binds host fibronectin via a catch-clamp mechanism

Adherence of bacteria to biotic or abiotic surfaces is a prerequisite for host colonization and represents an important step in microbial pathogenicity. This attachment is facilitated by bacterial adhesins at the cell surface. Because of their size and often elaborate multidomain architectures, these polypeptides represent challenging targets for detailed structural and functional characterization. The multifunctional fibrillar adhesin CshA, which mediates binding to both host molecules and other microorganisms, is an important determinant of colonization by Streptococcus gordonii, an oral commensal and opportunistic pathogen of animals and humans. CshA binds the high-molecular-weight glycoprotein fibronectin (Fn) via an N-terminal non-repetitive region, and this protein-protein interaction has been proposed to promote S. gordonii colonization at multiple sites within the host. However, the molecular details of how these two proteins interact have yet to be established. Here we present a structural description of the Fn binding N-terminal region of CshA, derived from a combination of X-ray crystallography, small angle X-ray scattering, and complementary biophysical methods. In vitro binding studies support a previously unreported two-state “catch-clamp” mechanism of Fn binding by CshA, in which the disordered N-terminal domain of CshA acts to “catch” Fn, via formation of a rapidly assembled but also readily dissociable pre-complex, enabling its neighboring ligand binding domain to tightly clamp the two polypeptides together. This study presents a new paradigm for target binding by a bacterial adhesin, the identification of which will inform future efforts toward the development of anti-adhesive agents that target S. gordonii and related streptococci

Constraints on the thermal evolution of metamorphic core complexes from the timing of high-pressure metamorphism on Naxos, Greece

Metamorphic core complexes are classically interpreted to have formed during crustal extension, although many also occur in compressional environments. New U–(Th)–Pb allanite and xenotime geochronologic data from the structurally highest Zas Unit (Cycladic Blueschist Unit) of the Naxos metamorphic core complex, Greece, integrated with pressure–temperature–time (P–T–t) histories, are incorporated into a thermal model to test the role of crustal thickening and extension in forming metamorphic core complexes. Metamorphism on Naxos is diachronous, with peak metamorphic conditions propagating down structural section over a ~30–35 m.y. period, from ca. 50 Ma to 15 Ma. At the highest structural level, the Zas Unit records blueschist-facies metamorphism (~14.5–19 kbar, 470–570 °C) at ca. 50 Ma, during northeast-directed subduction of the Adriatic continental margin. The Zas Unit was subsequently extruded toward the SW and thrust over more proximal continental margin and basement rocks (Koronos and Core units). This contractional episode resulted in crustal thickening and Barrovian metamorphism from ca. 40 Ma and reached peak kyanite-sillimanite–grade conditions of ~10–5 kbar and 600–730 °C at 20–15 Ma. Model P–T–t paths, assuming conductive relaxation of isotherms following overthrusting, are consistent with the clockwise P–T–t evolution. In contrast, extension results in exhumation and cooling of the crust, which is inconsistent with key components of the thermal evolution. Barrovian metamorphism on Naxos is therefore interpreted to have resulted from crustal thickening over a ~30–35 m.y. time period prior to extension, normal faulting, and rapid exhumation after a thermal climax at ca. 15 Ma