The influence of non‐HLA antibodies directed against angiotensin II type 1 receptor (AT1R) on early renal transplant outcomes

Non‐HLA antibodies (Abs) targeting vascular receptors are thought to have an impact on renal transplant injury. Anti‐angiotensin II type 1‐receptor‐activating antibodies (anti‐AT1R) have been mentioned to stimulate a severe vascular rejection, but the pretransplant screening has not been introduced yet. The aim of our study was to assess the incidence and importance of anti‐AT1R antibodies and their influence on renal transplant in the 1st year of observation. We prospectively evaluated the presence of anti‐AT1R antibodies in 117 consecutive renal transplant recipients in pre‐ and post‐transplant screening. Anti‐AT1R antibodies were observed in 27/117 (23%) of the analyzed recipients already before transplantation. The function of renal transplant was considerably worse in anti‐AT1R(+) group. The patients with anti‐AT1R Abs >9 U/ml lost their graft more often. Biopsy‐proven AR was described in 4/27 (15%) pts in the anti‐AT1R(+) group and 13/90 (14.4%) in the anti‐AT1R(?) group, but more severe cases of Banff IIB or antibody‐mediated rejection (AMR) were more often observed in anti‐AT1R (+) 4/27 (15%) vs. 1/90 (1.1%) in anti‐AT1R(+) (P = 0.009). Patients with anti‐AT1R Abs level >9 U/ml run a higher risk of graft failure independently of classical immunological risk factors. The recipients with anti‐AT1R Abs developed more severe acute rejections described as IIB or AMR in Banff classification. More recipients among the anti‐AT1R‐positive ones lost the graft. Our study suggests monitoring of anti‐AT1R Abs before renal transplantation for assessment of immunologic risk profiles and the identification of patients highly susceptible to immunologic events, graft failure, and graft loss.     

Desmethyl Macrolides: Synthesis and Evaluation of 4-Desmethyl Telithromycin

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Ontogeny of the immune system in Acipenserid juveniles

Sturgeon aquaculture has increased considerably worldwide but little is known about their immunological development and competence in early life stages. Culture of larvae is one of the most critical stages in intensive sturgeon farming, often associated with high mortality rates. The objective of this study was to characterize the developmental morphology (light and transmission electron microscopy, LM and TEM) of the meningeal myeloid tissue, spleen and thymus in Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) from hatching until 5 months old (2895°C·day (dd)). The spleen was first visible on 541 dd larvae LM sections and the other two immune organs in 768 dd samples (approximately 400 and 600 dd after onset of feeding). Generally, younger fish had significantly higher percentages of undifferentiated cells (meningeal myeloid tissue and spleen) and effective adaptive immune competence would not be expected in these fish on the onset of feeding, but further functional immune assessment is needed.     

The irre Cell Recognition Module (IRM) Protein Kirre Is Required to Form the Reciprocal Synaptic Network of L4 Neurons in the Drosophila Lamina

Each neuropil module, or cartridge, in the fly's lamina has a fixed complement of cells. Of five types of monopolar cell interneurons, only L4 has collaterals that invade neighboring cartridges. In the proximal lamina, these collaterals form reciprocal synapses with both the L2 of their own cartridge and the L4 collateral branches from two other neighboring cartridges. During synaptogenesis, L4 collaterals strongly express the cell adhesion protein Kirre, a member of the irre cell recognition module (IRM) group of proteins (, J Neurogenet, 23, 48–67). The authors show by mutant analysis and gene knockdown techniques that L4 neurons develop their lamina collaterals in the absence of this cell adhesion protein. Using electron microscopy (EM), the authors demonstrate, however, that without Kirre protein these L4 collaterals selectively form fewer synapses. The collaterals of L4 neurons of various genotypes reconstructed from serial-section EM revealed that the number of postsynaptic sites was dramatically reduced in the absence of Kirre, almost eliminating any synaptic input to L4 neurons. A significant reduction of presynaptic sites was also detected in kirre⁰ mutants and gene knockdown flies using RNA interference. L4 neuron reciprocal synapses are thus almost eliminated. A presynaptic marker, Brp-short^GFP confirmed these data using confocal microscopy. This study reveals that removing Kirre protein specifically disrupts the functional L4 synaptic network in the Drosophila lamina.     

Increased level of serum prostaglandin-2 in early stage of esophageal squamous cell carcinoma

Introduction

Prostaglandin-2 (PGE-2), one of the products of cyclooxygenase-2 (COX-2) induced catalysis, may play a critical role in the carcinogenesis of esophageal squamous cell carcinoma (ESCC). We investigated the efficacy of using serum PGE-2 concentration as a biomarker for this cancer type.

Material and methods

Prostaglandin-2 levels were analyzed in the serum of 65 ESCC patients and in 47 healthy individuals. The concentrations of cyclooxygenase-2 (COX-2) were measured in tumor tissues and normal tissues obtained from 31 surgically treated ESCC patients.

Results

Serum PGE-2 concentration was significantly higher in ESCC patients than in control patients (p = 0.004), especially in the early stages (I + II) of cancer (p < 0.0001). We observed significant inverse relationships between serum PGE-2 levels and: tumor stage, primary tumor progression, lymph and distant metastasis. The COX-2 concentration was significantly elevated in tumors as compared to normal tissues (p = 0.008). A significant correlation between serum PGE-2 and tumor COX-2 was observed (rho = 0.46, p = 0.009). However, ROC analysis showed that serum PGE-2 may be a weak prognostic factor for ESCC.

Conclusions

Our results suggest that an elevated concentration of serum PGE-2 in the early stages of cancer may possibly be associated with tumor initiation and cancer development in ESCC. The exact role of these findings in early detection of this highly lethal cancer requires further research.     

Drug-likeness of linear pentamidine analogues and their impact on the hERG K+ channel – correlation with structural features

This work presents drug-likeness and the cardiotoxicity profiles of six potent pentamidine analogs 1–6 and three new compounds 7–9 as chemotherapeutics for therapy of Pneumocystis jiroveci pneumonia. A combination of experimental and computational approaches was used in the cardiotoxicity examination. The hERG trafficking and functionality of the hERG currents were tested by western blot analyses, immunofluorescent staining procedures, and patch-clamp electrophysiological assays. Cardiotoxicity combined with blocking the hERG K⁺ channel was predicted, and then simulated by docking to the CSM-TM model 732 protein. Location of pentamidines in the proximity of Leu622, Thr623, Ser649, Tyr652, Ala653, and Phe656, and the high energies of interactions were in accordance with probable blocking of the hERG channel. However, in the biochemical experiments, no significant changes in I_hERG densities and a minor effect on hERG maturation were observed. Predicted metabolic transformation of pentamidines with S atoms in the aliphatic linker leads to oxidation of one S atom, but those with the phenyl sulfanilide moiety can be oxidized to chinones. The tested pentamidines characterized by the presence of sulfur atoms or sulfanilide groups, have favorable drug-likeness parameters and are promising lead structures in the development of new potent chemotherapeutics against PJP.

The pentamidines with S atoms or sulfanilide groups in the linker have favorable drug-likeness parameters and low toxicity.     

Economic stress of people 50 + in European countries in the Covid-19 pandemic–do country policies matter?

The Covid-19 pandemic caused lockdown of economies, which in turn led to the worsening of the economic situation of many households. During the first wave of the Covid-19 pandemic governments undertook various measures to support economies and societies, including jobs protection along with financial support provision to people who suffered financial loss during the economic crisis. We analyse the economic situation of older Europeans, depending on their socio-economic status as well as country of residence characteristics, including economic and labour market changes during the first phase of the pandemic, the strictness of government policies but also the country development level using the Human Development Index. We use the results of the Survey of Health, Ageing, and Retirement in Europe (SHARE), including the SHARE Corona Telephone Survey, which was conducted during the first wave of the Covid-19 pandemic. Our results indicate that individual characteristics have a higher impact on individual economic stress, compared to country characteristics. However, country’s response to the consequences of the Covid-19 pandemic, but also the overall level of development influences the economic situation and ability to cope with the economic risks people aged 50 and over face. People in more developed countries have smaller difficulties in making ends meet, while the economic crisis and more stringent policies reduce chances to receive financial support and increase economic risks.     

Role of Beta-Carotene in Lung Cancer Primary Chemoprevention: A Systematic Review with Meta-Analysis and Meta-Regression

Lung cancer is one of the most common neoplasms globally, with about 2.2 million new cases and 1.8 million deaths annually. Although the most important factor in reducing lung cancer risk is lifestyle change, most patients favour the use of supplements, for example, rather than quitting smoking or following a healthy diet. To better understand the efficacy of such interventions, a systematic review was performed of data from randomized controlled trials concerning the influence of beta-carotene supplementation on lung cancer risk in subjects with no lung cancer before the intervention. The search corpus comprised a number of databases and eight studies involving 167,141 participants, published by November 2021. The findings indicate that beta-carotene supplementation was associated with an increased risk of lung cancer (RR = 1.16, 95% CI = 1.06–1.26). This effect was even more noticeable among smokers and asbestos workers (RR = 1.21, 95% CI = 1.08–1.35) and non-medics (RR = 1.18, 95% CI = 1.07–1.29). A meta-regression found no relationship between the beta-carotene supplementation dose and the size of the negative effect associated with lung cancer risk. Our findings indicate that beta-carotene supplementation has no effect on lung cancer risk. Moreover, when used as the primary chemoprevention, beta-carotene may, in fact, increase the risk of lung cancer.     

NiO–Ba0.95Ca0.05Ce0.9Y0.1O3−δ as a Modified Anode Material Fabricated by the Tape Casting Method

The development of new chemically resistant anodes for protonic ceramic fuel cells (PCFCs) is urgently required to avoid the costly deep hydrogen purification method. Ba_0.95Ca_0.05Ce_0.9Y_0.1O_3−δ (5CBCY), which is more chemically resistant than BaCaCe_0.9Y_0.1O_3−δ, was here tested as a component of a composite NiO–5CBCY anode material. A preparation slurry comprising 5CBCY_, NiO, graphite, and an organic medium was tape cast, sintered and subjected to thermal treatment in 10 vol.% H₂ in Ar at 700 °C. Differential thermal analysis, thermogravimetry, quadrupole mass spectrometry, X-ray diffraction analysis, scanning electron microscopy, the AC four-probe method and electrochemical impedance spectroscopy were used for the investigation. The electrical conductivity of the Ni–5CBCY in H₂–Ar at 700 °C was 1.1 S/cm. In the same gas atmosphere but with an additional 5 vol.% CO₂, it was slightly lower, at 0.8 S/cm. The Ni–5CBCY cermet exhibited repeatable electrical conductivity values during Ni-to-NiO oxidation cycles and NiO-to-Ni reduction in the 5CBCY matrix, making it sufficient for preliminary testing in PCFCs.