Focal adhesions are foci for tyrosine-based signal transduction via GIV/Girdin and G proteins.

GIV/Girdin is a multimodular signal transducer and a bona fide metastasis-related protein. As a guanidine exchange factor (GEF), GIV modulates signals initiated by growth factors (chemical signals) by activating the G protein Gαi. Here we report that mechanical signals triggered by the extracellular matrix (ECM) also converge on GIV-GEF via β1 integrins and that focal adhesions (FAs) serve as the major hubs for mechanochemical signaling via GIV. GIV interacts with focal adhesion kinase (FAK) and ligand-activated β1 integrins. Phosphorylation of GIV by FAK enhances PI3K-Akt signaling, the integrity of FAs, increases cell-ECM adhesion, and triggers ECM-induced cell motility. Activation of Gαi by GIV-GEF further potentiates FAK-GIV-PI3K-Akt signaling at the FAs. Spatially restricted signaling via tyrosine phosphorylated GIV at the FAs is enhanced during cancer metastasis. Thus GIV-GEF serves as a unifying platform for integration and amplification of adhesion (mechanical) and growth factor (chemical) signals during cancer progression

Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling

Peer reviewedPublisher PD

Plasminogen Activator Inhibitor-1 in Cigarette Smoke Exposure and Influenza A Virus Infection-Induced Lung Injury

Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE), which contributes to chronic obstructive pulmonary disease (COPD). Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV) infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT) mice with passive CSE (PCSE), p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC apoptosis and lung inflammation. Further, inhibition of p53-mediated induction of PAI-1 by treatment of WT mice with caveolin-1 scaffolding domain peptide (CSP) reduced PCSE-induced lung inflammation and reversed PCSE-induced suppression of eosinophil-associated RNase1 (EAR1). Competitive inhibition of the p53-PAI-1 mRNA interaction by expressing p53-binding 3\u27UTR sequences of PAI-1 mRNA likewise suppressed CS-induced PAI-1 and AEC apoptosis and restored EAR1 expression. Consistent with PCSE-induced lung injury, IAV infection increased p53, PAI-1 and apoptosis in AECs in association with pulmonary inflammation. Lung inflammation induced by PCSE was worsened by subsequent exposure to IAV. Mice lacking PAI-1 that were exposed to IAV showed minimal viral burden based on M2 antigen and hemagglutination analyses, whereas transgenic mice that overexpress PAI-1 without PCSE showed increased M2 antigen and inflammation after IAV infection. These observations indicate that increased PAI-1 expression promotes AEC apoptosis and exacerbates lung inflammation induced by IAV following PCSE

Microfluidic analysis techniques for safety assessment of pharmaceutical nano- and microsystems

This chapter reviews the evolution of microfabrication methods and materials, applicable to manufacturing of micro total analysis systems (or lab‐on‐a‐chip), from a general perspective. It discusses the possibilities and limitations associated with microfluidic cell culturing, or so called organ‐on‐a‐chip technology, together with selected examples of their exploitation to characterization of pharmaceutical nano‐ and microsystems. Materials selection plays a pivotal role in terms of ensuring the cell adhesion and viability as well as defining the prevailing culture conditions inside the microfluidic channels. The chapter focuses on the hepatic safety assessment of nanoparticles and gives an overview of the development of microfluidic immobilized enzyme reactors that could facilitate examination of the hepatic effects of nanomedicines under physiologically relevant conditions. It also provides an overview of the future prospects regarding system‐level integration possibilities facilitated by microfabrication of miniaturized separation and sample preparation systems as integral parts of microfluidic in vitro models.Non peer reviewe

Magnetic Field Properties inside the Jet of Mrk 421: Multiwavelength Polarimetry Including the Imaging X-ray Polarimetry Explorer

We conducted a polarimetry campaign from radio to X-ray wavelengths of the high-synchrotron-peak (HSP) blazar Mrk 421, including Imaging X-ray Polarimetry Explorer (IXPE) measurements on 2022 December 6-8. We detected X-ray polarization of Mrk 421 with a degree of $\Pi_{\rm X}$=14$\pm$1$\%$ and an electric-vector position angle $\psi_{\rm X}$=107$\pm$3$^{\circ}$ in the 2-8 keV band. From the time variability analysis, we find a significant episodic variation in $\psi_{\rm X}$. During 7 months from the first IXPE pointing of Mrk 421 in 2022 May, $\psi_{\rm X}$ varied across the range of 0$^{\circ}$ to 180$^{\circ}$, while $\Pi_{\rm X}$ maintained similar values within $\sim$10-15$\%$. Furthermore, a swing in $\psi_{\rm X}$ in 2022 June was accompanied by simultaneous spectral variations. The results of the multiwavelength polarimetry show that the X-ray polarization degree was generally $\sim$2-3 times greater than that at longer wavelengths, while the polarization angle fluctuated. Additionally, based on radio, infrared, and optical polarimetry, we find that rotation of $\psi$ occurred in the opposite direction with respect to the rotation of $\psi_{\rm X}$ over longer timescales at similar epochs. The polarization behavior observed across multiple wavelengths is consistent with previous IXPE findings for HSP blazars. This result favors the energy-stratified shock model developed to explain variable emission in relativistic jets. The accompanying spectral variation during the $\psi_{\rm X}$ rotation can be explained by a fluctuation in the physical conditions, e.g., in the energy distribution of relativistic electrons. The opposite rotation direction of $\psi$ between the X-ray and longer-wavelength polarization accentuates the conclusion that the X-ray emitting region is spatially separated from that at longer wavelengths.Comment: 17 pages, 13 figures, 4 tables; Accepted for publication in A&

Socio-demographic risk factors associated with HIV infection in patients seeking medical advice in a rural hospital of India

Despite the fact that two thirds of HIV infected people in India are rural residents, risk factors associated with HIV infection in rural areas are not well known. In this study we have collected socio-demographic data of 6406 patients who were tested for HIV infection in a rural hospital of India and we have investigated risk factors associated with HIV. In women the most important risk factor was being a widow and the risk was higher in younger than in older widows. Other variables found to be associated with HIV infection were age between 25 and 45 years in men, low education level (especially those who only completed primary education) and working in a field not related to agriculture in scheduled castes and men from scheduled tribes. The results of this study express the need for HIV screening of widows who live in rural areas of Indian States with high HIV prevalence

Mortality in HIV-infected patients with tuberculosis treated with streptomycin and a two-week intensified regimen: data from an HIV cohort study using inverse probability of treatment weighting

Background. Despite the dramatic scale-up of antiretroviral therapy in low- and middle-income countries, tuberculosis (TB) is still the main cause of death among HIV-infected patients in resource-limited settings. Previous studies in patients with TB meningitis suggest that the use of higher doses of common anti-TB drugs could reduce mortality. Methods. Using clinical data from an HIV cohort study in India, we compared the mortality among HIV-infected patients diagnosed with TB according to the regimen received during the first two weeks of treatment: standard anti-tuberculosis therapy (ATT) (N = 847), intensified ATT (N = 322), and intensified ATT with streptomycin (N = 446). The intensified ATT comprised double dose of rifampicin and substitution of ethambutol with levofloxacin. Multivariate analysis was performed using Cox proportional hazard models and inverse probability of treatment weighting (IPTW) based on propensity scores. Patients with TB meningitis were excluded. Results. The use of intensified ATT alone did not improve survival. However, when streptomycin was added, the use intensified ATT was associated with reduced mortality in Cox models (adjusted hazard ratio 0.72, 95% CI [0.57–0.91]) and after IPTW (hazard ratio 0.77, 95% CI [0.67–0.96]). Other factors associated with improved survival were high serum albumin concentration, high CD4 lymphocyte cell-counts, and high glomerular filtration rates. Factors associated with increased mortality were high urea concentrations, being on antiretroviral therapy at the time of ATT initiation and high BUN/creatinine ratio. In an effect modification analysis, the survival benefits of the intensified ATT with streptomycin disappeared in patients with severe hypoalbuminemia. Conclusion. The results of this study are in accordance with a previous study from our cohort involving patients with TB meningitis, and suggest that an intensified 2-week ATT with streptomycin could reduce mortality in HIV infected patients with TB. As this is an observational study, we should be cautious about our conclusions, but given the high mortality of HIV-related TB, our findings deserve further research

Gender Differences, Routes of Transmission, Socio-Demographic Characteristics and Prevalence of HIV Related Infections of Adults and Children in an HIV Cohort from a Rural District of India

Despite 67% of HIV infected people in India are rural residents, the epidemiology of HIV in rural areas is not well known. This is an observational cohort study of 11,040 HIV infected people living in a rural district of India. The prevalence of hepatitis B, hepatitis C and syphilis of HIV infected patients were compared to the seroprevalence in 16,641 blood donors from the same area. The age of diagnosis in adults was below 35 years in 70% of cases and 56% were illiterate. One third of women were widows and only 3.6% of adults had a permanent job. Women were diagnosed at earlier age, had lower level of education, had poorer employment conditions and depended more on their relatives than men. In a survey performed to a subgroup of patients, 81% of women referred to have acquired HIV from their spouse, whereas 51% of men acquired HIV from commercial sex. Patients with HIV had significantly higher prevalence of hepatitis B, hepatitis C and syphilis than blood donors. Seroprevalence of HIV-2, hepatitis C and toxoplasmosis were low compared to other sites. Six percent were children (<15 years) and almost half of them had lost one or both of their parents. The study shows the poor socio-economical situation and the high level of illiteracy of people living with HIV in rural India, especially women. Future health programmes of HIV in India should take into account the particularities of the HIV epidemic in rural areas