Parametric testing of a linearly driven Stirling cryogenic refrigerator

The parametric testing of a novel Stirling cycle cryogenic refrigerator which incorporates electromagnetic bearings, clearance seals and electronically controlled linear motion was studied. The last feature, which involves the use of two linear motors, position transducers and a highly accurate electronic feedback network, produces the system capability which forms the basis for the tests. The test results provide designers with an understanding of the basic operation of the Stirling cycle and give potential users some indication of the capabilities of this refrigerator under off design conditions

Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases

The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells constantly cope with several protective and harmful agents to maintain the multiple physiological functions of the barrier as well as its integrity. However, both genetic defects and environmental factors can break such equilibrium, thus promoting gut dysbiosis, dysregulated immune-inflammatory responses, and even the development of chronic pathological conditions. Here, we review and discuss the molecular and cellular pathways underlying intestinal barrier structural and functional homeostasis, focusing on potential alterations that may undermine this fine balance

A magnetically suspended linearly driven cryogenic refrigerator

This paper described a novel Stirling cycle cryogenic refrigerator which was designed, fabricated and successfully tested at Philips Laboratories. The prominent features of the machine are an electro-magnetic bearing system, a pair of moving magnet linear motors, and clearance seals with a 25 mu m radial gap. The all-metal and ceramic construction eliminates long-term organic contamination of the helium working fluid. The axial positions of the piston and displacer are electronically controlled, permitting independent adjustment of the amplitude of each and their relative phase relationship during operation. A simple passive counterbalance reduces axial vibrations. The design of the refrigerator system components is discussed and a comparison is made between performance estimates and measured results

Robustness Verification of Support Vector Machines

We study the problem of formally verifying the robustness to adversarial examples of support vector machines (SVMs), a major machine learning model for classification and regression tasks. Following a recent stream of works on formal robustness verification of (deep) neural networks, our approach relies on a sound abstract version of a given SVM classifier to be used for checking its robustness. This methodology is parametric on a given numerical abstraction of real values and, analogously to the case of neural networks, needs neither abstract least upper bounds nor widening operators on this abstraction. The standard interval domain provides a simple instantiation of our abstraction technique, which is enhanced with the domain of reduced affine forms, which is an efficient abstraction of the zonotope abstract domain. This robustness verification technique has been fully implemented and experimentally evaluated on SVMs based on linear and nonlinear (polynomial and radial basis function) kernels, which have been trained on the popular MNIST dataset of images and on the recent and more challenging Fashion-MNIST dataset. The experimental results of our prototype SVM robustness verifier appear to be encouraging: this automated verification is fast, scalable and shows significantly high percentages of provable robustness on the test set of MNIST, in particular compared to the analogous provable robustness of neural networks

Tbet Expression in Regulatory T Cells Is Required to Initiate Th1-Mediated Colitis

In normal conditions gut homeostasis is maintained by the suppressive activity of regulatory T cells (Tregs), characterized by the expression of the transcription factor FoxP3. In human inflammatory bowel disease, which is believed to be the consequence of the loss of tolerance toward antigens normally contained in the gut lumen, Tregs have been found to be increased and functionally active, thus pointing against their possible role in the pathogenesis of this immune-mediated disease. Though, in inflammatory conditions, Tregs have been shown to upregulate the T helper (Th) type 1-related transcription factor Tbet and to express the pro-inflammatory cytokine IFN\u3b3, thus suggesting that at a certain point of the inflammatory process, Tregs might contribute to inflammation rather than suppress it. Starting from the observation that Tregs isolated from the lamina propria of active but not inactive IBD patients or uninflamed controls express Tbet and IFN\u3b3, we investigated the functional role of Th1-like Tregs in the dextran sulfate model of colitis. As observed in human IBD, Th1-like Tregs were upregulated in the inflamed lamina propria of treated mice and the expression of Tbet and IFN\u3b3 in Tregs preceded the accumulation of conventional Th1 cells. By using a Treg-specific Tbet conditional knockout, we demonstrated that Tbet expression in Tregs is required for the development of colitis. Indeed, Tbet knockout mice developed milder colitis and showed an impaired Th1 immune response. In these mice not only the Tbet deficient Tregs but also the Tbet proficient conventional T cells showed reduced IFN\u3b3 expression. However, Tbet deficiency did not affect the Tregs suppressive capacity in vitro and in vivo in the adoptive transfer model of colitis. In conclusion here we show that Tbet expression by Tregs sustains the early phase of the Th1-mediated inflammatory response in the gut

Inhomogeneous Diastereomeric Composition of Mongersen Antisense Phosphorothioate Oligonucleotide Preparations and Related Pharmacological Activity Impairment

Mongersen is a 21-mer antisense oligonucleotide designed to downregulate Mothers against decapentaplegic homolog 7 (SMAD7) expression to treat Crohn's disease. Mongersen was manufactured in numerous batches at different scales during several years of clinical development, which all appeared identical, using common physicochemical analytical techniques, while only phosphorous-31 nuclear magnetic resonance (P-31-NMR) in solution showed marked differences. Close-up analysis of 27 mongersen batches revealed marked differences in SMAD7 downregulation in a cell-based assay. Principal component analysis of P-31-NMR profiles showed strong correlation with SMAD7 downregulation and, therefore, with pharmacological efficacy in vitro. Mongersen contains 20 phosphorothioate (PS) linkages, whose chirality (Rp/Sp) was not controlled during manufacturing. A different diastereomeric composition throughout batches would lead to superimposable analytical data, but to distinct P-31-NMR profiles, as indeed we found. We tentatively suggest that this may be the origin of different biological activity. As similar manifolds are expected for other PS-based oligonucleotides, the protocol described here provides a general method to identify PS chirality issues and a chemometric tool to score each preparation for this elusive feature

Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This work received support from the “Fondazione Umberto di Mario ONLUS”, Rome, and AIRC (MFAG-12108 to CS and IG-13049 to GM)

Interleukin-21 sustains inflammatory signals that contribute to sporadic colon tumorigenesis

Interleukin (IL)-21 triggers inflammatory signals that contribute to the growth of neoplastic cells in mouse models of colitis-associated colorectal cancer (CRC). Because most CRCs are sporadic and arise in the absence of overt inflammation we have investigated the role of IL-21 in these tumors in mouse and man. IL-21 was highly expressed in human sporadic CRC and produced mostly by IFN-γ-expressing T-bet/RORγt double-positive CD3+CD8- cells. Stimulation of human CRC cell lines with IL-21 did not directly activate the oncogenic transcription factors STAT3 and NF-kB and did not affect CRC cell proliferation and survival. In contrast, IL-21 modulated the production of protumorigenic factors by human tumor infiltrating T cells. IL-21 was upregulated in the neoplastic areas, as compared with non-tumor mucosa, of Apc(min/+) mice, and genetic ablation of IL-21 in such mice resulted in a marked decrease of both tumor incidence and size. IL-21 deficiency was associated with reduced STAT3/NF-kB activation in both immune cells and neoplastic cells, diminished synthesis of protumorigenic cytokines (that is, IL-17A, IL-22, TNF-α and IL-6), downregulation of COX-2/PGE2 pathway and decreased angiogenesis in the lesions of Apc(min/+) mice. Altogether, data suggest that IL-21 promotes a protumorigenic inflammatory circuit that ultimately sustains the development of sporadic CRC

Bovine Lactoferrin Prevents Invasive Fungal Infections in Very Low Birth Weight Infants: A Randomized Controlled Trial.

BACKGROUND: Lactoferrin is a mammalian milk glycoprotein involved in innate immunity. Recent data show that bovine lactoferrin (bLF) prevents late-onset sepsis in preterm very low birth weight (VLBW) neonates. METHODS: This is a secondary analysis of data from a multicenter randomized controlled trial where preterm VLBW neonates randomly received bLF (100 mg/day; group A1), bLF + Lactobacillus rhamnosus GG (10(6) colony-forming units per day; group A2), or placebo (group B) for 6 weeks. Here we analyze the incidence rates of fungal colonization, invasive fungal infection (IFI), and rate of progression from colonization to infection in all groups. RESULTS: This study included 472 neonates whose clinical, nutritional, and demographical characteristics were similar. Overall, the incidence of fungal colonization was comparable (17.6%, 16.6%, and 18.5% in A1, A2, and B, respectively; P = .89 [A1] and .77 [A2]). In contrast, IFIs were significantly decreased in A1 and A2 (0.7% and 2.0%, respectively) compared with B (7.7%; P = .002 [A1] and .02 [A2]), and this was significantly true both in <1000 g (0.9% [A1] and 5.6% [A2], vs 15.0%) and in 1001 to 1500 g infants (0% and 0% vs 3.7%). The progression rate colonization-infection was significantly lower in the bLF groups: 3.7% (A1) and 12% (A2), vs 41.9%; P < .001 (A1) and P = .02 (A2). No IFI-attributable deaths occurred in the treatment groups, versus 2 in placebo. No adverse effects or intolerances occurred. CONCLUSIONS: Prophylactic oral administration of bLF reduces the incidence of IFI in preterm VLBW neonates. No effect is seen on colonization. The protective effect on IFI is likely due to limitation of ability of fungal colonies to progress toward invasion and systemic disease in colonized infants

Follistatin-like protein 1 sustains colon cancer cell growth and survival

Follistatin-like protein 1 (FSTL1) is a secreted glycoprotein, which controls several physiological and pathological events. FSTL1 expression is deregulated in many tumors, but its contribution to colon carcinogenesis is not fully understood. Here, we investigated the expression and functional role of FSTL1 in colorectal cancer (CRC). A significant increase of FSTL1 was seen in human CRC as compared to the surrounding non-tumor tissues and this occurred at both RNA and protein level. Knockdown of FSTL1 in CRC cells with a specific antisense oligonucleotide (AS) reduced expression of regulators of the late G1 phase, such as phosphorylated retinoblastoma protein, E2F-1, cyclin E and phospho-cyclin-dependent kinase-2, and promoted accumulation of cells in the G1 phase of the cell cycle thus resulting in diminished cell proliferation. Consistently, recombinant FSTL1 induced proliferation of normal intestinal epithelial cells through an ERK1/2-dependent mechanism. Cell cycle arrest driven by FSTL1 AS in CRC cells was accompanied by activation of caspases and subsequent induction of apoptosis. Moreover, FSTL1 knockdown made CRC cells more susceptible to oxaliplatin and irinotecan-induced death. Data indicate that FSTL1 is over-expressed in human CRC and suggest a role for this protein in favouring intestinal tumorigenesis