In the present work, different hydrolases were adsorbed onto polypropylene beads to investigate their activity both in short-esters and polyesters synthesis. The software MODDE® Pro 13 (Sartorius) ...was used to develop a full-factorial design of experiments (DoE) to analyse the thermostability and selectivity of the immobilized enzyme towards alcohols and acids with different chain lengths in short-esters synthesis reactions. The temperature optima of Candida antarctica lipase B (CaLB), Humicola insolens cutinase (HiC), and Thermobifida cellulosilytica cutinase 1 (Thc_Cut1) were 85 °C, 70 °C, and 50 °C. CaLB and HiC preferred long-chain alcohols and acids as substrate in contrast to Thc_Cut1, which was more active on short-chain monomers. Polymerization of different esters as building blocks was carried out to confirm the applicability of the obtained model on larger macromolecules. The selectivity of both CaLB and HiC was investigated and best results were obtained for dimethyl sebacate (DMSe), leading to polyesters with a Mw of 18 kDa and 6 kDa. For the polymerization of dimethyl adipate (DMA) with BDO and ODO, higher molecular masses were obtained when using CaLB onto polypropylene beads (CaLB_PP) as compared with CaLB immobilized on macroporous acrylic resin beads (i.e., Novozym 435). Namely, for BDO the Mn were 7500 and 4300 Da and for ODO 8100 and 5000 Da for CaLB_PP and for the commercial enzymes, respectively. Thc_Cut1 led to polymers with lower molecular masses, with Mn < 1 kDa. This enzyme showed a temperature optimum of 50 °C with 63% of DMA and BDO when compared to 54% and 27%, at 70 °C and at 85 °C, respectively.
The SOX2 transcription factor is critical for neural stem cell (NSC) maintenance and brain development. Through chromatin immunoprecipitation (ChIP) and chromatin interaction analysis (ChIA-PET), we ...determined genome-wide SOX2-bound regions and Pol II-mediated long-range chromatin interactions in brain-derived NSCs. SOX2-bound DNA was highly enriched in distal chromatin regions interacting with promoters and carrying epigenetic enhancer marks. Sox2 deletion caused widespread reduction of Pol II-mediated long-range interactions and decreased gene expression. Genes showing reduced expression in Sox2-deleted cells were significantly enriched in interactions between promoters and SOX2-bound distal enhancers. Expression of one such gene, Suppressor of Cytokine Signaling 3 (Socs3), rescued the self-renewal defect of Sox2-ablated NSCs. Our work identifies SOX2 as a major regulator of gene expression through connections to the enhancer network in NSCs. Through the definition of such a connectivity network, our study shows the way to the identification of genes and enhancers involved in NSC maintenance and neurodevelopmental disorders.
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•Sox2-bound enhancers are enriched within long-range interactions in neural stem cells•SOX2 loss decreases chromatin interactivity genome-wide•Sox2-bound enhancers from interactions activate reporter genes in zebrafish forebrain•Socs3, a gene downregulated in Sox2 mutant NSCs, rescues their self-renewal
Bertolini et al. report that long-range chromatin interactions in neural stem cells (NSCs) are enriched in Sox2-bound enhancers; in Sox2-deleted NSCs, interactions are reduced. Genes downregulated in Sox2-deleted cells are enriched in interactions with enhancers normally Sox2-bound. Overexpression of Socs3, a gene downregulated in mutant NSCs, rescues long-term NSC self-renewal.
In this work we report the realization of the first low-threshold cryogenic detector that uses diamond as absorber for astroparticle physics applications. We tested two 0.175 g CVD diamond samples, ...each instrumented with a W-TES. The sensors showed transitions at about 25 mK. We present the performance of the diamond detectors and we highlight the best performing one, where we obtained an energy threshold as low as 16.8 eV. This promising result lays the foundation for the use of diamond for different fields of applications where low threshold and excellent energy resolution are required, as i.e. light dark matter searches and BSM physics with coherent elastic neutrino nucleus scattering.
Diamond operated as a cryogenic calorimeter is an excellent target for direct detection of low-mass dark matter candidates. Following the realization of the first low-threshold cryogenic detector ...that uses diamond as absorber for astroparticle physics applications, we now present the resulting exclusion limits on the elastic spin-independent interaction cross-section of dark matter with diamond. We measured two 0.175 g CVD (Chemical Vapor Deposition) diamond samples, each instrumented with a Transition Edge Sensor made of Tungsten (W-TES). Thanks to the energy threshold of just 16.8 eV of one of the two detectors, we set exclusion limits on the elastic spin-independent interaction of dark matter particles with carbon nuclei down to dark matter masses as low as 0.122 GeV/c
2
. This work shows the scientific potential of cryogenic detectors made from diamond and lays the foundation for the use of this material as target for direct detection dark matter experiments.
Dual acting anti-inflammatory drugs Leone, S; Ottani, A; Bertolini, A
Current topics in medicinal chemistry,
02/2007, Letnik:
7, Številka:
3
Journal Article
Recenzirano
Drugs able to inhibit both cyclooxygenases (COX-1 and COX-2) and 5-lipoxygenase (5-LOX) (dual acting anti-inflammatory drugs) have been designed in order to obtain compounds that retain the activity ...of classical nonsteroidal anti-inflammatory drugs (NSAIDs) while avoiding their main drawbacks. The classical NSAIDs display their anti-inflammatory action mainly through inhibition of COX and one of their main drawbacks is the curtailed production of gastroprotective prostaglandins (PGs) being associated with the concurrent increased production of the gastro-damaging and bronchoconstrictive leukotrienes (LTs). Leukotrienes and cysteinyl-leukotrienes are moreover pro-inflammatory and increase microvascular permeability. One of the leukotrienes (LTB(4)) is the most potent chemotactic agent and it induces chemotaxis of eosinophils, neutrophils and monocytes in the inflamed tissue, increases superoxide generation and proinflammatory cytokines production. It is further advantageous for a drug to have both COX and 5-LOX inhibiting activities because prostaglandins enhance leukotriene-mediated inflammation. Various structural families of dual inhibitors have been designed and several compounds are currently undergoing clinical development. In the post-COX-2 selective inhibitors era, these dual acting inhibitors may turn out to be promising new drugs to treat inflammatory diseases and possibly other diseases. Indeed, both COX-2 and 5-LOX are also involved in the development and progression of several types of cancer; in these conditions, selective inhibition of COX-2 alone may lead to a shunt of arachidonic acid metabolism towards the leukotriene pathway, and therefore the blockade of both COX-2 and 5-LOX may produce a better anticancer response. In addition, the dual inhibition of both COX and 5-LOX is neuroprotective by suppressing toxic actions of reactive microglia and macrophages, that are increased in aging brain and in age-related degenerative conditions, particularly Alzheimer's and Parkinson's diseases. Finally, the blockade of 5-LOX does not impair the synthesis of lipoxins (LXs), which are mainly produced by further lipoxygenation of 15-HPETE, and which have potent anti-inflammatory properties and can be considered as stop-signal mediators. Leukocyte 15-LOX and platelet 12-LOX by intercellular mechanism via leukocyte/platelet cell-cell interaction convert 15-HPETE into lipoxins.
This study analyses 371 yearly series of 1-day precipitation maxima extracted from a data set of high-quality homogenized rain gauge records covering an area of about 25,000 km
2
in the western part ...of northern-central Italy that includes eastern Liguria and northern Tuscany and is very prone to severe floods and shallow landslides. Return levels of 1-day extreme precipitation (corresponding to 10-, 50-, and 100-year return periods as predicted by a generalized extreme value distribution (GEV)) are estimated both for station sites and for the nodes of a high-resolution grid (30 arcsec). GEV parameters are estimated by regional frequency analysis using the station-year approach. Grid-point index floods are estimated from yearly cumulative precipitation normals exploiting the very high correlation existing at local scale between station index flood and the corresponding yearly precipitation normals. Results clearly show the high vulnerability of this region to extreme precipitation events and highlight the different role played by total annual precipitation normals and by both scale and shape parameters in regulating the longer period return levels. The results presented in this paper allow better estimating the climatology of extreme events in the study area, contributing to a more effective hazard assessment at different spatial and temporal scales.
•This phase II trial shows that ablative SBRT for thoracic nodes metastases is safe and effective.•A risk-adaptive strategy that prioritizes organs at risk is a good compromise.•SBRT can defer the ...need for systemic therapy with a median time of 19,8 months.
Oligometastases in mediastinal nodes are increasingly prevalent, posing challenges for treatment with stereotactic body radiotherapy (SBRT) due to proximity to organs at risk (OARs). We report the results of a single prospective observational phase II trial on ablative SBRT for medically inoperable thoracic nodes metastases (NCT02970955).
Since 2017, patients with < 3 nodal metastases were evaluated by the tumor board and included if deemed inoperable. SBRT was delivered using risk adaptive approach based on number, site and size of metastatic nodes (50 Gy/5fractions, 60 Gy/8fractions, 70 Gy/10 fractions). Planning target volume (PTV) partial underdosage was allowed. The primary end point was local control (LC) at 12 months. Secondary end points were: acute and late toxicities, overall survival (OS), progression free survival (PFS), and time to next systemic therapy (TTNS).
Between 03/2017–11/2021, 32 patients (41 nodal metastases) were included. NSCLC (13pts), breast (5pts) and colorectal cancer (4pts) were the most represented primary tumour. In 66 % cases, partial PTV undercoverage was necessary. LC at 1 and 2 years was 93.5 % and 82.3 %, respectively. Treatment was well-tolerated with no acute or late toxicity ≥ G3. Median OS was 59.7 months. OS at 1 and 2 years was 96.9 % and 83.8 % respectively. Median PFS was 12.2 months. PFS at 1 and 2 years was 53.1 % and 31.3 %, respectively.
This trial supported the feasibility and safety of ablative SBRT for thoracic nodes metastases thanks to risk adaptive approach allowing to delay of new systemic therapies. Larger studies are needed to confirm these observations.
Diptera (Insecta) are able to transmit approximately 200 pathogenic microorganisms to humans and animals, causing more than 65 diseases, including bovine mastitis, which constitutes a major cause of ...economic losses in the dairy industry. In this scenario, 217 adult specimens of Diptera were collected from nine farms and identified to the family and/or species level. Of the 11 families recorded, Muscidae was the most prevalent (152 out of 217; 70%). All Diptera specimens were subjected to microbiological culture using conventional and selective media, and isolates were then identified at the species level by mass spectrometry. In total, 275 microorganisms were identified, with a predominance of pathogens related to environmental bovine mastitis (166/275 = 60·4%), that is, Enterococcus species (70/275 = 25·4%) and Escherichia coli (49/275 = 17·8%). Nontraditional agents related to bovine mastitis (called miscellaneous) were detected in 28% (77/275), as well as microorganisms with well‐known zoonotic behaviour (e.g. Bacillus cereus). This is study contributes with knowledge of diversity of microorganisms carried by Diptera in the dairy environment, including pathogens associated with environmental and contagious bovine mastitis, and agents with human relevance. To our knowledge, a three‐part chromogenic selective medium used to microbial culture of milk on farms was used for the first time to identification of pathogens in Diptera.
Significance and Impact of the Study: The high diversity of Diptera (Insecta) species (>157 000) worldwide, feeding habits, and the access to contaminated environments, make these insects potential vector‐borne of more than 200 pathogens to humans and animals. Here, 217 adult specimens of Diptera were collected in the environment of nine dairy farms with a history of clinical mastitis. From these, 275 microorganisms were identified, with a predominance of pathogens related to environmental bovine mastitis (Enterococcus spp. and Escherichia coli), in addition to agents with well‐known zoonotic nature (e.g. Bacillus cereus), indicating that control of this insect in dairy farms pose relevance in human and animal health.
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