This paper deals with the solution of Maxwell's equations to model the electromagnetic fields in the case of a layered earth. The integrals involved in the solution are approximated by means of a ...novel approach based on the splitting of the reflection term. The inverse problem, consisting in the computation of the unknown underground conductivity distribution from a set of modeled magnetic field components, is also considered. Two optimization algorithms are applied, based on line- and global-search methods, and a new minimization approach is presented. Several EM surveys from the ground surface are simulated, considering the horizontal coplanar (HCP) and perpendicular (PRP) magnetic dipolar configurations. The numerical experiments, carried out for the study of river-levees integrity, allowed to estimate the errors associated to these kind of investigations, and confirm the reliability of the technique.
•Solution of Maxwell's equations by means of a Gaussian rule.•Two optimization algorithms for the resolution of the inverse problem.•Useful integral approximations for the optimization process.
Influenza A virus (IAV) uses the low pH in late endocytic vacuoles as a cue for penetration by membrane fusion. Here, we analyzed the prefusion reactions that prepare the core for uncoating after it ...has been delivered to the cytosol. We found that this priming process occurs in two steps that are mediated by the envelope-embedded M2 ion channel. The first weakens the interactions between the matrix protein, M1, and the viral ribonucleoprotein bundle. It involves a conformational change in a linker sequence and the C-terminal domain of M1 after exposure to a pH below 6.5. The second step is triggered by a pH of <6.0 and by the influx of K(+) ions. It causes additional changes in M1 as well as a loss of stability in the viral ribonucleoprotein bundle. Our results indicate that both the switch from Na(+) to K(+) in maturing endosomes and the decreasing pH are needed to prime IAV cores for efficient uncoating and infection of the host cell.
The entry of IAV involves several steps, including endocytosis and fusion at late endosomes. Entry also includes disassembly of the viral core, which is composed of the viral ribonucleoproteins and the RNA genome. We have found that the uncoating process of IAV is initiated long before the core is delivered into the cytosol. M2, an ion channel in the viral membrane, is activated when the virus passes through early endosomes. Here, we show that protons entering the virus through M2 cause a conformational change in the matrix protein, M1. This weakens interactions between M1 and the viral ribonucleoproteins. A second change was found to occur when the virus enters late endosomes. The preacidified core is then exposed to a high concentration of K(+), which affects the interactions between the ribonucleoproteins. Thus, when cores are finally delivered to the cytosol, they are already partially destabilized and, therefore, uncoating competent and infectious.
In yeast, the glucose-induced degradation-deficient (GID) E3 ligase selectively degrades superfluous gluconeogenic enzymes. Here, we identified all subunits of the mammalian GID/CTLH complex and ...provide a comprehensive map of its hierarchical organization and step-wise assembly. Biochemical reconstitution demonstrates that the mammalian complex possesses inherent E3 ubiquitin ligase activity, using Ube2H as its cognate E2. Deletions of multiple GID subunits compromise cell proliferation, and this defect is accompanied by deregulation of critical cell cycle markers such as the retinoblastoma (Rb) tumor suppressor, phospho-Histone H3 and Cyclin A. We identify the negative regulator of pro-proliferative genes Hbp1 as a
GID/CTLH proteolytic substrate. Indeed, Hbp1 accumulates in cells lacking GID/CTLH activity, and Hbp1 physically interacts and is ubiquitinated in vitro by reconstituted GID/CTLH complexes. Our biochemical and cellular analysis thus demonstrates that the GID/CTLH complex prevents cell cycle exit in G1, at least in part by degrading Hbp1.
Changes in protein conformation can affect protein function, but methods to probe these structural changes on a global scale in cells have been lacking. To enable large-scale analyses of protein ...conformational changes directly in their biological matrices, we present a method that couples limited proteolysis with a targeted proteomics workflow. Using our method, we assessed the structural features of more than 1,000 yeast proteins simultaneously and detected altered conformations for ~300 proteins upon a change of nutrients. We find that some branches of carbon metabolism are transcriptionally regulated whereas others are regulated by enzyme conformational changes. We detect structural changes in aggregation-prone proteins and show the functional relevance of one of these proteins to the metabolic switch. This approach enables probing of both subtle and pronounced structural changes of proteins on a large scale.
We present a detailed study of the nuclear star clusters (NSCs) and massive black holes (BHs) of four of the nearest low-mass early-type galaxies: M32, NGC 205, NGC 5102, and NGC 5206. We measure the ...dynamical masses of both the BHs and NSCs in these galaxies using Gemini/NIFS or VLT/SINFONI stellar kinematics, Hubble Space Telescope (HST) imaging, and Jeans anisotropic models. We detect massive BHs in M32, NGC 5102, and NGC 5206, while in NGC 205, we find only an upper limit. These BH mass estimates are consistent with previous measurements in M32 and NGC 205, while those in NGC 5102 and NGC 5206 are estimated for the first time and both found to be <106 M . This adds to just a handful of galaxies with dynamically measured sub-million M central BHs. Combining these BH detections with our recent work on NGC 404's BH, we find that 80% (4/5) of nearby, low-mass ( M ; km s−1) early-type galaxies host BHs. Such a high occupation fraction suggests that the BH seeds formed in the early epoch of cosmic assembly likely resulted in abundant seeds, favoring a low-mass seed mechanism of the remnants, most likely from the first generation of massive stars. We find dynamical masses of the NSCs ranging from 2 to 73 × 106 M and compare these masses to scaling relations for NSCs based primarily on photometric mass estimates. Color gradients suggest that younger stellar populations lie at the centers of the NSCs in three of the four galaxies (NGC 205, NGC 5102, and NGC 5206), while the morphology of two are complex and best fit with multiple morphological components (NGC 5102 and NGC 5206). The NSC kinematics show they are rotating, especially in M32 and NGC 5102 ( ).
Abstract
Background
Muscle pain and stiffness are strictly interconnected. Injuries frequently occur during sport activities, causing muscle pain, with or without stiffness, and require effective as ...well as fast-acting treatments. Topical products can be ideal for the treatment of such physical alterations as they are convenient and simple to use. In this study, it was investigated the application of a novel topical formulation, EGYFIL™, for the treatment of pain and stiffness due to muscle contracture, trauma, and/or overtraining. The lotion is composed of hyaluronic acid, a well-known ingredient for the pain alleviation, mixed with skin conditioning SH-Polypeptide-6 and SH-Oligopeptide-1, embedded in it.
Methods
Twenty-six patients with pain and/or stiffness were enrolled. After a screening visit (Time 0, t0), patients were treated for the first time with the IP. The treatment consisted of topical application of the pain lotion. Level of pain and stiffness were measured with Numerical Rating Scale (NRS). Patients’ pain and/or stiffness were evaluated at t0 (prior to using the product), after three hours (t1), and after three days (t2) of treatment. Participants were free to apply and re-apply the product ad libitum over the course of the study period (3 days). Potential adverse events (AE) and tolerance were evaluated during each visit.
Results
There was a 22% decrease in pain in the first three hours (
p
< 0.001), followed by an additional 20% decrease after three days (
p
=0.0873). Overall, there was a 42% decrease in pain over the three days of the study (
p
=0.001). Furthermore, a 24% reduction in stiffness in the first three hours (
p
=0.025) and a 38% decrease in stiffness over three days (
p
< 0.001) were observed. Reduction in pain and stiffness were neither age, nor sex dependent. No adverse effects were reported during the study.
Conclusion
EGYFIL™ is safe and seems to reduce pain and stiffness in patients during the 3 days of treatment, already after 3 h from the first application.
Trial registration
ClinicalTrials.gov ID: NCT05711953. This trial was registered on 03/02/2023.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although chromosome partitioning during mitosis is well studied, the molecular mechanisms that allow proper segregation of cytoplasmic organelles in human cells are poorly understood. Here we show ...that mitochondria interact with growing microtubule tips and are transported towards the daughter cell periphery at the end of mitosis. This phenomenon is promoted by the direct and cell cycle-dependent interaction of the mitochondrial protein Miro and the cytoskeletal-associated protein Cenp-F. Cenp-F is recruited to mitochondria by Miro at the time of cytokinesis and associates with microtubule growing tips. Cells devoid of Cenp-F or Miro show decreased spreading of the mitochondrial network as well as cytokinesis-specific defects in mitochondrial transport towards the cell periphery. Thus, Miro and Cenp-F promote anterograde mitochondrial movement and proper mitochondrial distribution in daughter cells.
Biological processes are regulated by intermolecular interactions and chemical modifications that do not affect protein levels, thus escaping detection in classical proteomic screens. We demonstrate ...here that a global protein structural readout based on limited proteolysis-mass spectrometry (LiP-MS) detects many such functional alterations, simultaneously and in situ, in bacteria undergoing nutrient adaptation and in yeast responding to acute stress. The structural readout, visualized as structural barcodes, captured enzyme activity changes, phosphorylation, protein aggregation, and complex formation, with the resolution of individual regulated functional sites such as binding and active sites. Comparison with prior knowledge, including other ‘omics data, showed that LiP-MS detects many known functional alterations within well-studied pathways. It suggested distinct metabolite-protein interactions and enabled identification of a fructose-1,6-bisphosphate-based regulatory mechanism of glucose uptake in E. coli. The structural readout dramatically increases classical proteomics coverage, generates mechanistic hypotheses, and paves the way for in situ structural systems biology.
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•Dynamic structural proteomic screens detect functional changes at high resolution•Detect enzyme activity, phosphorylation, and molecular interactions in situ•Generate new molecular hypotheses and increase functional proteomics coverage•Enabled discovery of a regulatory mechanism of glucose uptake in E. coli
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