Min-oscillations in Escherichia coli induced by interactions of membrane-bound proteins

During division it is of primary importance for a cell to correctly determine the site of cleavage. The bacterium Escherichia coli divides in the center, producing two daughter cells of equal size. Selection of the center as the correct division site is in part achieved by the Min-proteins. They oscillate between the two cell poles and thereby prevent division at these locations. Here, a phenomenological description for these oscillations is presented, where lateral interactions between proteins on the cell membrane play a key role. Solutions to the dynamic equations are compared to experimental findings. In particular, the temporal period of the oscillations is measured as a function of the cell length and found to be compatible with the theoretical prediction.Comment: 17 pages, 5 figures. Submitted to Physical Biolog

Fracture precursors in disordered systems

A two-dimensional lattice model with bond disorder is used to investigate the fracture behaviour under stress-controlled conditions. Although the cumulative energy of precursors does not diverge at the critical point, its derivative with respect to the control parameter (reduced stress) exhibits a singular behaviour. Our results are nevertheless compatible with previous experimental findings, if one restricts the comparison to the (limited) range accessible in the experiment. A power-law avalanche distribution is also found with an exponent close to the experimental values.Comment: 4 pages, 5 figures. Submitted to Europhysics Letter

Characteristics of drug-resistant tuberculosis in Abkhazia (Georgia), a high-prevalence area in Eastern Europe

Although multidrug-resistant (MDR) tuberculosis (TB) is a major public health problem in Eastern Europe, the factors contributing to emergence, spread and containment of MDR-TB are not well defined. Here, we analysed the characteristics of drug-resistant TB in a cross-sectional study in Abkhazia (Georgia) between 2003 and 2005, where standard short-course chemotherapy is supplemented with individualized drug-resistance therapy. Drug susceptibility testing (DST) and molecular typing were carried out for Mycobacterium tuberculosis complex strains from consecutive smear-positive TB patients. Out of 366 patients, 60.4% were resistant to any first-line drugs and 21% had MDR-TB. Overall, 25% of all strains belong to the Beijing genotype, which was found to be strongly associated with the risk of MDR-TB (OR 25.9, 95% CI 10.2-66.0) and transmission (OR 2.8, 95% CI 1.6-5.0). One dominant MDR Beijing clone represents 23% of all MDR-TB cases. The level of MDR-TB did not decline during the study period, coinciding with increasing levels of MDR Beijing strains among previously treated cases. Standard chemotherapy plus individualized drug-resistance therapy, guided by conventional DST, might be not sufficient to control MDR-TB in Eastern Europe in light of the spread of "highly transmissible" MDR Beijing strains circulating in the community

SARS-CoV-2 infection: A role for S1P/S1P receptor signaling in the nervous system?

The recent coronavirus disease (COVID-19) is still spreading worldwide. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, binds to its receptor angiotensin-converting enzyme 2 (ACE2), and replicates within the cells of the nasal cavity, then spreads along the airway tracts, causing mild clinical manifestations, and, in a majority of patients, a persisting loss of smell. In some individuals, SARS-CoV-2 reaches and infects several organs, including the lung, leading to severe pulmonary disease. SARS-CoV-2 induces neurological symptoms, likely contributing to morbidity and mortality through unknown mechanisms. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with pleiotropic properties and functions in many tissues, including the nervous system. S1P regulates neurogenesis and inflammation and it is implicated in multiple sclerosis (MS). Notably, Fingolimod (FTY720), a modulator of S1P receptors, has been approved for the treatment of MS and is being tested for COVID-19. Here, we discuss the putative role of S1P on viral infection and in the modulation of inflammation and survival in the stem cell niche of the olfactory epithelium. This could help to design therapeutic strategies based on S1P-mediated signaling to limit or overcome the host–virus interaction, virus propagation and the pathogenesis and complications involving the nervous system

A degraded adhesion model for creep force calculation based on the CONTACT algorithm

Degraded adhesion is observed extensively during the braking or traction process. An accurate degraded adhesion law, on the other hand, is difficult to acquire since it is characterized by a complicated non-linear behaviour involving various surface phenomena. This work provides a new local degraded adhesion model, its implementation in a wheel-rail contact model, and its application in a multibody railway vehicle model. The present degraded adhesion model takes into account large sliding and adhesion recovery phenomena, which are strictly related to the power dissipated at the contact interface. Implementation of the current local degraded adhesion model enhances Kalker's CONTACT algorithm. The application into multibody dynamics simulation demonstrates the high accuracy of computations. The model is validated by comparing it to experimental findings obtained from on-field tests. Simulated results regarding the tangential pressures, the slip velocity, and the dissipated power under degraded adhesion and partial adherence conditions are reported

Dual HDAC/BRD4 Inhibitors Relieves Neuropathic Pain by Attenuating Inflammatory Response in Microglia After Spared Nerve Injury

Despite the effort on developing new treatments, therapy for neuropathic pain is still a clinical challenge and combination therapy regimes of two or more drugs are often needed to improve efficacy. Accumulating evidence shows an altered expression and activity of histone acetylation enzymes in chronic pain conditions and restoration of these aberrant epigenetic modifications promotes pain-relieving activity. Recent studies showed a synergistic activity in neuropathic pain models by combination of histone deacetylases (HDACs) and bromodomain and extra-terminal domain (BET) inhibitors. On these premises, the present study investigated the pharmacological profile of new dual HDAC/BRD4 inhibitors, named SUM52 and SUM35, in the spared nerve injury (SNI) model in mice as innovative strategy to simultaneously inhibit HDACs and BETs. Intranasal administration of SUM52 and SUM35 attenuated thermal and mechanical hypersensitivity in the absence of locomotor side effects. Both dual inhibitors showed a preferential interaction with BRD4-BD2 domain, and SUM52 resulted the most active compound. SUM52 reduced microglia-mediated spinal neuroinflammation in spinal cord sections of SNI mice as showed by reduction of IBA1 immunostaining, inducible nitric oxide synthase (iNOS) expression, p65 nuclear factor-κB (NF-κB) and p38 MAPK over-phosphorylation. A robust decrease of the spinal proinflammatory cytokines content (IL-6, IL-1ß) was also observed after SUM52 treatment. Present results, showing the pain-relieving activity of HDAC/BRD4 dual inhibitors, indicate that the simultaneous modulation of BET and HDAC activity by a single molecule acting as multi-target agent might represent a promise for neuropathic pain relief. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-022-01243-6

Control of skeletal muscle atrophy associated to cancer or corticosteroids by ceramide kinase

Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and degradation. Although the signaling pathways involved in SkM mass wasting are multiple, the regulatory role of simple sphingolipids is limited. Here, we report the impairment of ceramide kinase (CerK), the enzyme responsible for the phosphorylation of ceramide to C1P, associated with the accomplishment of atrophic phenotype in various experimental models of SkM atrophy: in vivo animal model bearing the C26 adenocarcinoma or Lewis lung carcinoma tumors, in human and murine SkM cells treated with the conditioned medium obtained from cancer cells or with the glucocorticoid dexamethasone. Notably, we demonstrate in all the three experimental approaches a drastic decrease of CerK expression. Gene silencing of CerK promotes the up-regulation of atrogin-1/MAFbx expression, which was also observed after cell treatment with C8-ceramide, a biologically active ceramide analogue. Conversely, C1P treatment significantly reduced the corticosteroid’s effects. Altogether, these findings provide evidence that CerK, acting as a molecular modulator, may be a new possible target for SkM mass regulation associated with cancer or corticosteroids