Nanostructured Carbon Nitride for Continuous-Flow Trifluoromethylation of (Hetero)arenes

Efficient catalytic methods for the trifluoromethy-lation of (hetero)arenes are of particular importance in organic and pharmaceutical manufacturing. However, many existing protocols rely on toxic reagents and expensive or sterically hindered homogeneous catalysts. One promising alternative to conduct this transformation involves the use of carbon nitride, a non-toxic photocatalyst prepared from inexpensive precursors. Nonetheless, there is still little understanding regarding the interplay between physicochemical features of this photocatalyst and the correspond-ing effects on the reaction rate. In this work, we elucidate the role of carbon nitride nanostructuring on the catalytic performance, understanding the effect of surface area and band gap tuning via metal insertion. Our findings provide new insights into the structure-function relationships of the catalyst, which we exploit to design a continuous-flow process that maximizes catalyst-light interaction, facilitates catalyst reusability, and enables intensified reaction scale-up. This is particularly significant given that photocatalyzed batch protocols often face challenges during industrial exploitation. Finally, we extrapolate the rapid and simplified continuous-flow method to the synthesis of a variety of functionalized heteroaromatics, which have numerous applications in the pharmaceutical and fine chemical industries

Protecting sensitive patient groups from imaging using ionizing radiation: effects during pregnancy, in fetal life and childhood

The frequency of imaging examinations requiring radiation exposure in children (especially CT) is rapidly increasing. This paper reviews the current evidence in radiation protection in pediatric imaging, focusing on the recent knowledge of the biological risk related to low doses exposure. Even if there are no strictly defined limits for patient radiation exposure, it is recommended to try to keep doses as low as reasonably achievable (the ALARA principle). To achieve ALARA, several techniques to reduce the radiation dose in radiation-sensitive patients groups are reviewed. The most recent recommendations that provide guidance regarding imaging of pregnant women are also summarized, and the risk depending on dose and phase of pregnancy is reported. Finally, the risk-benefit analysis of each examination, and careful communication of this risk to the patient, is emphasized

An iPSC-derived vascular model of Marfan syndrome identifies key mediators of smooth muscle cell death.

Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-β (TGF-β) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-β inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.This work was supported by Evelyn Trust, the NIHR Cambridge Biomedical Research Centre and the British Heart Foundation (FS/13/29/30024, RM/l3/3/30159, FS/11/77/29327).This is the author accepted manuscript. The final version is available from Nature Publishing Group via https://doi.org/10.1038/ng.372

A Novel Human Pluripotent Stem Cell-Derived Neural Crest Model of Treacher Collins Syndrome Shows Defects in Cell Death and Migration.

The neural crest (NC) is a transient multipotent cell population present during embryonic development. The NC can give rise to multiple cell types and is involved in a number of different diseases. Therefore, the development of new strategies to model NC in vitro enables investigations into the mechanisms involved in NC development and disease. In this study, we report a simple and efficient protocol to differentiate human pluripotent stem cells (HPSC) into NC using a chemically defined media, with basic fibroblast growth factor 2 (FGF2) and the transforming growth factor-β inhibitor SB-431542. The cell population generated expresses a range of NC markers, including P75, TWIST1, SOX10, and TFAP2A. NC purification was achieved in vitro through serial passaging of the population, recreating the developmental stages of NC differentiation. The generated NC cells are highly proliferative, capable of differentiating to their derivatives in vitro and engraft in vivo to NC specific locations. In addition, these cells could be frozen for storage and thawed with no loss of NC properties, nor the ability to generate cellular derivatives. We assessed the potential of the derived NC population to model the neurocristopathy, Treacher Collins Syndrome (TCS), using small interfering RNA (siRNA) knockdown of TCOF1 and by creating different TCOF1+/- HPSC lines through CRISPR/Cas9 technology. The NC cells derived from TCOF1+/- HPSC recapitulate the phenotype of the reported TCS murine model. We also report for the first time an impairment of migration in TCOF1+/- NC and mesenchymal stem cells. In conclusion, the developed protocol permits the generation of the large number of NC cells required for developmental studies, disease modeling, and for drug discovery platforms in vitro

Transcriptomics: A Step behind the Comprehension of the Polygenic Influence on Oxidative Stress, Immune Deregulation, and Mitochondrial Dysfunction in Chronic Kidney Disease.

Chronic kidney disease (CKD) is an increasing and global health problem with a great economic burden for healthcare system. Therefore to slow down the progression of this condition is a main objective in nephrology. It has been extensively reported that microinflammation, immune system deregulation, and oxidative stress contribute to CKD progression. Additionally, dialysis worsens this clinical condition because of the contact of blood with bioincompatible dialytic devices. Numerous studies have shown the close link between immune system impairment and CKD but most have been performed using classical biomolecular strategies. These methodologies are limited in their ability to discover new elements and enable measuring the simultaneous influence of multiple factors. The "omics" techniques could overcome these gaps. For example, transcriptomics has revealed that mitochondria and inflammasome have a role in pathogenesis of CKD and are pivotal elements in the cellular alterations leading to systemic complications. We believe that a larger employment of this technique, together with other "omics" methodologies, could help clinicians to obtain new pathogenetic insights, novel diagnostic biomarkers, and therapeutic targets. Finally, transcriptomics could allow clinicians to personalize therapeutic strategies according to individual genetic background (nutrigenomic and pharmacogenomic). In this review, we analyzed the available transcriptomic studies involving CKD patients

Mitochondria: a new therapeutic target in chronic kidney disease.

Cellular metabolic changes during chronic kidney disease (CKD) may induce higher production of oxygen radicals that play a significant role in the progression of renal damage and in the onset of important comorbidities. This condition seems to be in part related to dysfunctional mitochondria that cause an increased electron "leakage" from the respiratory chain during oxidative phosphorylation with a consequent generation of reactive oxygen species (ROS). ROS are highly active molecules that may oxidize proteins, lipids and nucleic acids with a consequent damage of cells and tissues. To mitigate this mitochondria-related functional impairment, a variety of agents (including endogenous and food derived antioxidants, natural plants extracts, mitochondria-targeted molecules) combined with conventional therapies could be employed. However, although the anti-oxidant properties of these substances are well known, their use in clinical practice has been only partially investigated. Additionally, for their correct utilization is extremely important to understand their effects, to identify the correct target of intervention and to minimize adverse effects. Therefore, in this manuscript, we reviewed the characteristics of the available mitochondria-targeted anti-oxidant compounds that could be employed routinely in our nephrology, internal medicine and renal transplant centers. Nevertheless, large clinical trials are needed to provide more definitive information about their use and to assess their overall efficacy or toxicity

Personalization of the Immunosuppressive Treatment in Renal Transplant Recipients: The Great Challenge in "Omics" Medicine.

Renal transplantation represents the most favorable treatment for patients with advanced renal failure and it is followed, in most cases, by a significant enhancement in patients' quality of life. Significant improvements in one-year renal allograft and patients' survival rates have been achieved over the last 10 years primarily as a result of newer immunosuppressive regimens. Despite these notable achievements in the short-term outcome, long-term graft function and survival rates remain less than optimal. Death with a functioning graft and chronic allograft dysfunction result in an annual rate of 3%-5%. In this context, drug toxicity and long-term chronic adverse effects of immunosuppressive medications have a pivotal role. Unfortunately, at the moment, except for the evaluation of trough drug levels, no clinically useful tools are available to correctly manage immunosuppressive therapy. The proper use of these drugs could potentiate therapeutic effects minimizing adverse drug reactions. For this purpose, in the future, "omics" techniques could represent powerful tools that may be employed in clinical practice to routinely aid the personalization of drug treatment according to each patient's genetic makeup. However, it is unquestionable that additional studies and technological advances are needed to standardize and simplify these methodologies

How has peritoneal dialysis changed over the last 30 years: experience of the Verona dialysis center

The last decade has witnessed considerable improvement in dialysis technology and changes in clinical management of patients in peritoneal dialysis (PD) with a significant impact on long term clinical outcomes. However, the identification of factors involved in this process is still not complete.METHODS:Therefore, to assess this objective, we retrospectively analyzed clinical records of 260 adult patients who started PD treatment from 1983 to 2012 in our renal unit. For the analysis, we divided them into three groups according to the time of starting dialysis: GROUP A (n: 62, 1983-1992), GROUP B (n: 66, 1993-2002) and GROUP C (n: 132, 2003 to 2012).RESULTS:Statistical analysis revealed that patients included in the GROUP C showed a reduction in mean patients' age (p = 0.03), smoking habit (p = 0.001), mean systolic blood pressure (p < 0.0001) and an increment in hemoglobin levels (p < 0.0001) and residual diuresis (p = 0.016) compared to the other two study groups. Additionally, patients included in GROUP C, mainly treated with automated peritoneal dialysis, showed a reduced risk of all-causes mortality and a decreased risk to develop acute myocardial infarction and cerebrovascular disease. Patients' age, diabetes mellitus and smoking habit were all positively associated with a significant increased risk of mortality in our PD patients, while serum albumin levels and residual diuresis were negatively correlated.CONCLUSIONS:Therefore, the present study, revealed that in the last decade there has been a growth of our PD program with a concomitant modification of our patients' characteristics. These changes, together with the evident technical advances, have caused a significant improvement of patients' survival and a decrement of the rate of hospitalization. Moreover, it reveals that our pre-dialysis care, modifying the above-mentioned factors, has been a major cause of these clinical improvements