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In this paper we show that the geodesic flow of a Finsler metric is Anosov if and only if there exists a C^2 open neighborhood of Finsler metrics all of whose closed geodesics are hyperbolic. For surfaces this result holds also for Riemannian metrics. This follows from a recent result of Contreras and Mazzucchelli [Duke Math. J. 173 (2024), pp. 347–390]. Furthermore, geodesic flows of Riemannian or Finsler metrics on surfaces are C^2 stably ergodic if and only if they are Anosov. [ABSTRACT FROM AUTHOR]

Acute respiratory infections (ARIs) are amongst the leading causes of death and disability, and the greatest burden of disease impacts children, pregnant women, and the elderly. Respiratory viruses account for the majority of ARIs. The unfolded protein response (UPR) is a host homeostatic defence mechanism primarily activated in response to aberrant endoplasmic reticulum (ER) resident protein accumulation in cell stresses including viral infection. The UPR has been implicated in the pathogenesis of several respiratory diseases, as the respiratory system is particularly vulnerable to chronic and acute activation of the ER stress response pathway. Many respiratory viruses therefore employ strategies to modulate the UPR during infection, with varying effects on the host and the pathogens. Here, we review the specific means by which respiratory viruses affect the host UPR, particularly in association with the high production of viral glycoproteins, and the impact of UPR activation and subversion on viral replication and disease pathogenesis. We further review the activation of UPR in common co-morbidities of ARIs and discuss the therapeutic potential of modulating the UPR in virally induced respiratory diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma continues to be one of the deadliest cancers worldwide. Preclinical studies involving animals rarely include sex as a major biological variable in testing the efficacy of new drugs. In an animal model of pancreatic cancer, we analyzed the impact of sex on the pathological features of the disease and on an experimental small molecule-based therapy tested in vivo for the first time. While the therapy shows potential, the obtained results are confounded by sex-specific effects. This study, therefore, highlights the importance of sex-inclusive research while simultaneously providing a basis for further studies of the therapy tested. Preclinical studies rarely test the efficacy of therapies in both sexes. The field of oncology is no exception in this regard. In a model of syngeneic, orthotopic, metastasized pancreatic ductal adenocarcinoma we evaluated the impact of sex on pathological features of this disease as well as on the efficacy and possible adverse side effects of a novel, small molecule-based therapy inhibiting KRAS:SOS1, MEK1/2 and PI3K signaling in male and female C57BL/6J mice. Male mice had less tumor infiltration of CD8-positive cells, developed bigger tumors, had more lung metastasis and a lower probability of survival compared to female mice. These more severe pathological features in male animals were accompanied by higher distress at the end of the experiment. The evaluated inhibitors BI-3406, trametinib and BKM120 showed synergistic effects in vitro. This combinatorial therapy reduced tumor weight more efficiently in male animals, although the drug concentrations were similar in the tumors of both sexes. These results underline the importance of sex-specific preclinical research and at the same time provide a solid basis for future studies with the tested compounds. [ABSTRACT FROM AUTHOR]

Two singularity theorems can be proven if one attempts to let a Lorentzian cobordism interpolate between two topologically distinct manifolds. On the other hand, Cartier and DeWitt-Morette have given a rigorous definition for quantum field theories (QFTs) by means of path integrals. This paper uses their results to study whether QFTs can be made compatible with topology changes. We show that path integrals over metrics need a finite norm for the latter and for degenerate metrics, this problem can sometimes be resolved with tetrads. We prove that already in the neighborhood of some cuspidal singularities, difficulties can arise to define certain QFTs. On the other hand, we show that simple QFTs can be defined around conical singularities that result from a topology change in a simple setup. We argue that the ground state of many theories of quantum gravity will imply a small cosmological constant and, during the expansion of the universe, will cause frequent topology changes. Unfortunately, it is difficult to describe the transition amplitudes consistently due to the aforementioned problems. We argue that one needs to describe QFTs by stochastic differential equations, and in the case of gravity, by Regge calculus in order to resolve this problem. [ABSTRACT FROM AUTHOR]

The emergence of SARS-CoV-2 variants alters the efficacy of existing immunity towards the viral spike protein, whether acquired from infection or vaccination. Mutations that impact N -glycosylation of spike may be particularly important in influencing antigenicity, but their consequences are difficult to predict. Here, we compare the glycosylation profiles and antigenicity of recombinant viral spike of ancestral Wu-1 and the Gamma strain, which has two additional N -glycosylation sites due to amino acid substitutions in the N-terminal domain (NTD). We found that a mutation at residue 20 from threonine to asparagine within the NTD caused the loss of NTD-specific antibody COVA2-17 binding. Glycan site-occupancy analyses revealed that the mutation resulted in N -glycosylation switching to the new sequon at N20 from the native N17 site. Site-specific glycosylation profiles demonstrated distinct glycoform differences between Wu-1, Gamma, and selected NTD variant spike proteins, but these did not affect antibody binding. Finally, we evaluated the specificity of spike proteins against convalescent COVID-19 sera and found reduced cross-reactivity against some mutants, but not Gamma spike compared to Wuhan spike. Our results illustrate the impact of viral divergence on spike glycosylation and SARS-CoV-2 antibody binding profiles. [ABSTRACT FROM AUTHOR]

Sustainable beer production requires a comprehensive assessment of potential hazards such as pesticides in both the finished product and waste streams, as these streams can be used to create high-value by-products. This study presents the tracking of 13 fungicides (azoxystrobin, boscalid, epoxiconazole, fenpropidin, fenpropimorph, fluquiconazole, flutriafol, fluxapyroxad, kresoxym-methyl, spiroxamine, propiconazole, prothioconazole-desthio, and tebuconazole), two insecticides (chlorpyrifos-methyl and deltamethrin), one herbicide (glyphosate), and one growth regulator (mepiquat) through the beer brewing process. Field-treated rye, wheat, and barley samples containing pesticide residues were used as adjunct during brewing. Samples of the beer as well as the by-products (spent grain, spent hops, trub and spent yeast) were collected and extracted with a modified QuEChERS method for pesticide residues analysis using GC-MS/MS and LC-MS/MS. Results show that an average of 58% of pesticide residues are retrieved in the by-products with the highest fraction (53%) recovered in the spent grain, 4% in trub, 1% in spent hops, no residues detected in spent yeast and 9% in the beer. This is consistent with these nonpolar pesticides tending to remain adsorbed to the spent grain during brewing. Glyphosate and mepiquat, the most polar pesticides included in this study, showed a different behavior, with the largest fraction (>80%) being retrieved in sweet wort and transferred to the beer. Processing factors were generated for each pesticide from the adjunct to the beer and to the four by-products. [ABSTRACT FROM AUTHOR]

Zinc (Zn) is gaining increased recognition as a biodegradable metal in biomedical applications but clinical translation is limited due to its poor biocompatibility. This study addresses these issues through an innovative biomimetic strategy, introducing an efficient surface nanoengineering approach that creates nano‐geometric features and chemical compositions by modulating the exposure time to a biological medium – Dulbecco's Modified Eagle Medium(DMEM). These nanoengineered Zn implants exhibited tunable degradation rates. The nanostructures enhanced human osteoblast attachment, proliferation, and differentiation following direct contact, and improved macrophage function by promoting pseudopod formation and transitioning from a pro‐inflammatory M1 to a pro‐reparative M2 phenotype. In vivo studies show that the surface‐engineered implants effectively promoted tissue integration via M2 macrophage polarization, resulting in a favorable immunomodulatory environment, and increased collagen deposition. Proteomic analyses show that the tissues in the vicinity of the surface‐engineered Zn implants are enriched with proteins related to key wound healing biological mechanisms such as cell adhesion, cytoskeletal structural arrangement, and immune response. This study highlights the improved biocompatibility and anti‐inflammatory effects of surface‐engineered Zn, with important implications for the clinical translation of biodegradable Zn‐based orthopedic implants. [ABSTRACT FROM AUTHOR]

Bacterial ABC toxin complexes (Tcs) comprise three core proteins: TcA, TcB and TcC. The TcA protein forms a pentameric assembly that attaches to the surface of target cells and penetrates the cell membrane. The TcB and TcC proteins assemble as a heterodimeric TcB-TcC subcomplex that makes a hollow shell. This TcB-TcC subcomplex self-cleaves and encapsulates within the shell a cytotoxic `cargo' encoded by the C-terminal region of the TcC protein. Here, we describe the structure of a previously uncharacterized TcC protein from Yersinia entomophaga, encoded by a gene at a distant genomic location from the genes encoding the rest of the toxin complex, in complex with the TcB protein. When encapsulated within the TcB-TcC shell, the C-terminal toxin adopts an unfolded and disordered state, with limited areas of local order stabilized by the chaperone-like inner surface of the shell. We also determined the structure of the toxin cargo alone and show that when not encapsulated within the shell, it adopts an ADP-ribosyltransferase fold most similar to the catalytic domain of the SpvB toxin from Salmonella typhimurium. Our structural analysis points to a likely mechanism whereby the toxin acts directly on actin, modifying it in a way that prevents normal polymerization., (open access.)