Mfsd2b and Spns2 are essential for maintenance of blood vessels during development and protection of anaphylaxis

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is secreted by several cell types to induce signaling. We recently showed that Mfsd2b is an S1P transporter from hematopoietic cells, which contributes approximately 50% plasma S1P. To further determine the sources of plasma S1P, here, we report the characterizations of compound deletions of Mfsd2b and Spns2, another S1P transporter from endothelial cells. Global deletion of Mfsd2b and Spns2 (gDKO) resulted in embryonic lethality between E13.5 and E14.5 with severe hemorrhage that largely recapitulated the phenotypes from global S1P1 knockout mice, indicating that together with Mfsd2b, Spns2 also provides embryonic source of S1P for S1P1 stimulation. The hemorrhagic phenotypes in gDKO embryos were accompanied by increased angiogenesis and defects of tight junction proteins, indicating that S1P from Mfsd2b and Spns2 is essential for blood vessel integrity and maturation. The various sources of S1P in postnatal stages are yet to be fully understood. Postnatal ablation of S1P synthesis enzymes using Mx1Cre shows that Mx1Cre-sensitive cells provide most of plasma S1P. Interestingly, we showed that compound postnatal deletion of Mfsd2b and Spns2 using Mx1Cre (ctDKO-Mx1Cre) resulted in maximal reduction of 80% plasma S1P. Thus, a small amount of plasma S1P is supplied from other sources independent of Mfsd2b and Spns2. Nevertheless, the vasculature in the lung of ctDKO-Mx1Cre mice was compromised. Furthermore, ctDKO-Mx1Cre mice also exhibited severe susceptibility to anaphylaxis, indicating that S1P from Mfsd2b and Spns2 is indispensable during vascular stress. Together, our results show that Mfsd2b and Spns2 provide a critical source of S1P for embryonic development and they also provide a majority of plasma S1P for vascular homeostasis.

Optimal COVID-19 Vaccination Strategies with Limited Vaccine and Delivery Capabilities

We develop a model of infection spread that takes into account the existence of a vulnerable group as well as the variability of the social relations of individuals. We develop a compartmentalized power-law model, with power-law connections between the vulnerable and the general population, considering these connections as well as the connections among the vulnerable as parameters that we vary in our tests. We use the model to study a number of vaccination strategies under two hypotheses: first, we assume a limited availability of vaccine but an infinite vaccination capacity, so all the available doses can be administered in a short time (negligible with respect to the evolution of the epidemic). Then, we assume a limited vaccination capacity, so the doses are administered in a time non-negligible with respect to the evolution of the epidemic. We develop optimal strategies for the various social parameters, where a strategy consists of (1) the fraction of vaccine that is administered to the vulnerable population and (2) the criterion that is used to administer it to the general population. In the case of a limited vaccination capacity, the fraction (1) is a function of time, and we study how to optimize it to obtain a maximal reduction in the number of fatalities.

Amelioration of L-DOPA-induced dyskinesia with vitamin D3 in Parkinsonian mice model

L-DOPA Induced Dyskinesia (LID) is associated with prolonged L-DOPA therapy. Vitamin-D receptor modulation improves motor-cognitive deficit in experimental LID Parkinsonism. Therefore, in this study, we investigated the mechanism underlying the anti-dyskinetic potential of Vitamin D3 (VD3). Dyskinesia was induced by chronic L-DOPA administration in 6-OHDA lesioned male C57BL6 mice. The experimental groups (Dyskinesia, Dyskinesia/VD3, and Dyskinesia/Amantadine) and controls were challenged with L-DOPA to determine the abnormal involuntary movements (AIMs) score during 14 days of VD3 (30 mg/kg) or Amantadine (40 mg/kg) treatment. Global behavioral Axial, Limb & Orolingual (ALO) AIMs were scored for 1 min at every 20 mins interval, over a duration of 100 mins on days 1,3,7,11 and 14 of treatment. Thereafter, brain samples were collected and processed for immunoblotting to assess striatal expression of tyrosine hydroxylase (TH), monoamine oxidase (MAO), cathecol-o-methyl transferase (COMT), dopamine decarboxylase (DDC), CD11b, BAX, P47phox, and IL-1β. VD3 significantly attenuated ALO AIMs only on days 11 & 14, with maximal reduction of 32.7% compared with dyskinetic mice but had no effect on days 1, 3 & 7, while amantadine decreased AIMs all through days 1 to 14 with maximal reduction of 64.5%. TH and MAO-B expression were not significantly different across the groups. DDC was significantly suppressed in dyskinetic mice vs control (p<0.001) but remained unchanged in VD3 mice vs dyskinetic mice. COMT was upregulated in the dyskinetic group vs control (p<0.01) and attenuated in VD3 mice (p<0.05) compared to the dyskinetic group. Interestingly, VD3 inhibited significantly (p<0.01) oxidative stress (p47phox), apoptosis (BAX), inflammation (IL-1β), and microglial activation (CD11b) in dyskinetic mice. Overall, we find that the anti-dyskinetic effects of VD3 is associated with modulation of striatal oxidative stress, microglial responses, inflammation, and apoptotic signaling.

Intraperitoneal Chemotherapy for Peritoneal Metastases: Technical Innovations, Preclinical and Clinical Advances and Future Perspectives

(1) Background: Tumors of the peritoneal serosa are called peritoneal carcinosis. Their origin may be primary by primitive involvement of the peritoneum (peritoneal pseudomyxoma, peritoneal mesothelioma, etc.). This damage to the peritoneum can also be a consequence of the dissipation of cancers—in particular, digestive (stomach, pancreas, colorectal, appendix) and gynecological (ovaries) ones in the form of metastases. The aim of the treatment is a maximal reduction of the macroscopic disease called “cytoreduction” in combination with hyperthermic intra-abdominal chemotherapy to treat residual microscopic lesions. (2) Methods: In this narrative review, we fundamentally synthetize the evolution of this process over time and its impact on clinical applications. (3) Results: Over the last past decade, different evolutions concerning both delivery modes and conditions concerning hyperthermic intra-abdominal chemotherapy have been realized. (4) Conclusion: The final objective of these evolutions is the improvement of the global and recurrence-free survival of primary and secondary malignant peritoneal pathologies. However, more large randomized controlled trials are needed to demonstrate the efficacy of such treatments with the help of molecular biology and genetics.

Osteoblast role in the pathogenesis of rheumatoid arthritis

In the pathogenesis of several rheumatic diseases, such as rheumatoid arthritis, spondyloarthritis, osteoarthritis, osteoporosis, alterations in osteoblast growth, differentiation and activity play a role. In particular, in rheumatoid arthritis bone homeostasis is perturbed: in addition to stimulating the pathologic bone resorption process performed by osteoclasts in course of rheumatoid arthritis, proinflammatory cytokines (such as Tumor Necrosis factor-α, Interleukin-1) can also inhibit osteoblast differentiation and function, resulting in net bone loss. Mouse models of rheumatoid arthritis showed that complete resolution of inflammation (with maximal reduction in the expression of pro-inflammatory factors) is crucial for bone healing, performed by osteoblasts activity. In fact, abnormal activity of factors and systems involved in osteoblast function in these patients has been described. A better understanding of the pathogenic mechanisms involved in osteoblast dysregulation could contribute to explain the generalized and focal articular bone loss found in rheumatoid arthritis. Nevertheless, these aspects have not been frequently and directly evaluated in studies. This review article is focused on analysis of the current knowledge about the role of osteoblast dysregulation occurring in rheumatoid arthritis: a better knowledge of these mechanisms could contribute to the realization of new therapeutic strategies.

The immunomodulatory activity of secnidazole–nitazoxanide in a murine cryptosporidiosis model

Introduction. Cryptosporidium parvum causes intestinal parasitic infections affecting both immunosuppressed and immunocompetent individuals. Gap statement. Given the absence of effective treatments for cryptosporidiosis, especially in immunodeficient patients, the present study was designed to assess the therapeutic efficacy of secnidazole (SEC) and its combination with nitazoxanide (NTZ) in comparison to single NTZ treatment in relation to the immune status of a murine model of C. parvum infection. Methodology. The infected groups were administered NTZ, SEC or NTZ–SEC for three or five successive doses. At days 10 and 12 post-infection (p.i.), the mice were sacrificed, and the efficacy of the applied drugs was evaluated by comparing the histopathological alterations in ileum and measuring the T helper Th1 (interferon gamma; IFN-γ), Th2 [interleukin (IL)-4 and IL-10] and Th17 (IL-17) cytokine profiles in serum. Results. The NTZ–SEC combination recorded the maximal reduction of C. parvum oocyst shedding, endogenous stages count and intestinal histopathology, regardless of the immune status of the infected mice. The efficacy of NTZ–SEC was dependent on the period of administration, as the 5 day-based treatment protocol was also more effective than the 3 day-based one in terms of immunocompetence and immunosuppression. The present treatment schedule induced an immunomodulatory effect from SEC that developed a protective immune response against C. parvum infection with reduced production of serum IL-17, IFN-γ, IL-4 and IL-10. Conclusions. Application of NTZ–SEC combined therapy may be useful in treatment of C. parvum, especially in cases involving immunosuppression.

CLUE: Exact maximal reduction of kinetic models by constrained lumping of differential equations

Motivation Detailed mechanistic models of biological processes can pose significant challenges for analysis and parameter estimations due to the large number of equations used to track the dynamics of all distinct configurations in which each involved biochemical species can be found. Model reduction can help tame such complexity by providing a lower-dimensional model in which each macro-variable can be directly related to the original variables. Results We present CLUE, an algorithm for exact model reduction of systems of polynomial differential equations by constrained linear lumping. It computes the smallest dimensional reduction as a linear mapping of the state space such that the reduced model preserves the dynamics of user-specified linear combinations of the original variables. Even though CLUE works with nonlinear differential equations, it is based on linear algebra tools, which makes it applicable to high-dimensional models. Using case studies from the literature, we show how CLUE can substantially lower model dimensionality and help extract biologically intelligible insights from the reduction. Availability An implementation of the algorithm and relevant resources to replicate the experiments herein reported are freely available for download at https://github.com/pogudingleb/CLUE. Supplementary information Supplementary data are available at Bioinformatics online.

WHO vaccination protocol can be improved to save more lives

Coronavirus disease 2019 (COVID-19) pandemic, a virus infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, has impacted all countries of the world, and the main 2021’s challenge is clearly vaccinating the greater number of persons, in the shortest time span, for a maximal reduction in the number of deaths and in the significant economic impacts. Large-scale vaccination aimed to achieve herd immunity poses many logistic and social difficulties [1], with different vaccine candidates and designs [2,3], and vaccination priorities will determine the evolution of the current COVID-19 pandemic. In this paper we explicitly propose an alternative vaccination protocol that can be more effective than those already being deployed, as the ones in the European Union [4] and in the United States [5]. We report strong evidence based on an epidemiological model for the importance of contact hubs (or superspreaders), having a much larger average number of contacts than in the rest of the population [6-11], on the effectiveness of the vaccination strategy. We show that carefully choosing who will be in the first group to be vaccinated can significantly impact on both health services demand and total death toll, by increasing the overall numbers of lives saved and of hospitalizations. We argue that the approach here considered, which does not coincide with current proposals, and given the current conditions with a lack of basic resources for proper vaccination in several countries, and with a significant reduction in mobility and social isolation restrictions, should be considered by all authorities participating in the design of COVID-19 vaccination with the intent of maximising the number of human lives saved.

Effects of oleuropein on rat’s atria and thoracic aorta: a study of antihypertensive mechanisms

Oleuropein (OLE) is the main bioactive ingredient in the leaves of the olive plant Olea europaea L. (Oleaceae), which has proven beneficial due to the antiinflammatory, antiatherogenic, anticancer, antimicrobial, and antiviral effects. This study aimed to investigate the antihypertensive and vasodilator potential of OLE by analyzing its acute effects on spontaneous atrial contractions and vasomotor responses of the isolated thoracic aorta in rats. We showed that the application of OLE induces negative chronotropic and inotropic effects on the heart. OLE also causes mild aortic vasodilation given that the maximal reduction in tension of intact aortic rings precontracted with phenylephrine was approximately 30%. This vasodilation is likely dependent on the nitric oxide released from the endothelium based on the effect obtained on denuded and phenylephrine precontracted aortic rings and responses reordered following vasoconstriction induced by high concentrations of K+ and heparin. Our findings provide a basis for further testing of OLE cardiovascular effects, which may lead to subsequent clinical research for its application in the treatment of hypertension and heart disease.