Middle-aged adults can start to be affected by some arterial diseases, such as abdominal aortic or popliteal artery aneurysms, lower extremity arterial disease, internal carotid or renal artery or subclavian artery stenosis. These vasculopathies are often paucisymptomatic before manifesting themselves with dramatic complications. Therefore, early detection of peripheral artery disease (PAD) and aneurysmal disease is fundamental to reduce the risk of major adverse cardiovascular and limb events. Furthermore, PAD carries a high correlation with silent coronary artery disease (CAD). This study focuses on the most common PADs and aneurysmal diseases, in the attempt to summarize some key points which should selectively drive screen. Since it is evident how we are not in the human and economic possibilities to instrumentally screening wide populations, deep knowledge of semeiotics and careful anamnesis must play a central role in our daily activity as physician. The presence of some risk factors for atherosclerosis, or an already known history of CAD, can raise the clinical suspecion of PAD or aneurysmal disease after a careful clinical history and a deep physical examination. The clinical suspicion must then be confirmed by a first-level ultrasound investigation and, if so, adequate treatments can be adopted to prevent dreadful complications.

Adult X-linked hypophosphatemia (XLH) patients present with specific symptoms, including enthesopathies (e.g., ossification of the longitudinal ligament (OPLL), osteophytes around the large joint, and enthesopathy in the Achilles tendon), the development of severe secondary and tertiary hyperparathyroidism (SHPT/THPT) and the subsequent progression of chronic kidney disease (CKD). In addition, these patients exhibit the typical phenotypes of osteomalacia, such as pseudofracture and fracture in weight-bearing bones, odontitis, and tooth abscess. The mechanism underlying enthesopathy development is unknown; however, a common underlying mechanism among XLH and autosomal recessive hypophosphatemic rickets, ARHR1.2, due to mutations in PHEX, DMP1, and ENPP1, is assumed. Clarification of the pathogenesis and drug discovery for this complication is an urgent issue to address, as many adult XLH patients suffer subsequent debilitating nervus symptoms or impingement syndrome, and existing treatments are ineffective. Severe SHPT and THPT are associated with conventional therapy, including active vitamin D and phosphate supplementation, and complicated and careful adjustment of the dosage by experienced clinicians is required to avoid SHPT/THPT. Burosumab is a very effective therapy without risk for the development of SHPT/THPT. However, the indication of this drug should be carefully considered along with the cost-effectiveness, guidelines or recommendations and health care system of each country.

Despite the long history of using protein sequences to infer the tree of life the potential for different parts of protein structures to retain historical signal remains unclear. We propose that it might be possible to improve analyses of phylogenomic datasets by incorporating information about protein structure; we test this idea using the position of the root of Metazoa (animals) as a model system. We examined the distribution of “strongly decisive” sites (alignment positions that support a specific tree topology) in a dataset comprising >1,500 proteins and almost 100 taxa. The proportion of each class of strongly decisive sites in different structural environments was very sensitive to the model used to analyze the data when a limited number of taxa were used but they were stable when taxa were added. As long as enough taxa were analyzed, sites in all structural environments supported the same topology (ctenophores sister to other animals) regardless of whether standard tree searches or decisive sites were used to select the optimal tree. However, the use of decisive sites revealed a difference between the support for minority topologies for sites in different structural environments; buried sites and sites in sheet and coil environments exhibited equal support for the minority topologies whereas solvent exposed and helix sites had unequal numbers of sites supporting the minority topologies. Given the plausible trees equal support for minority topologies is consistent with discordance among gene trees, making it possible the relatively slowly evolving buried (and sheet and coil) sites are giving an accurate picture of the true species tree as well as the amount of conflict among gene trees. Alternatively, the apparent support could reflect currently uncharacterized processes of molecular evolution. Regardless, it is clear that analyses of the deepest branches in the animal tree of life using sites in different structural environments are associated with a subtle data type effect that results in distinct phylogenetic signals.

Background: Recent developments in our understanding of the interactions between long non-coding RNA (lncRNA) and cellular components have improved treatment approaches for various human diseases including cancer, vascular diseases, and neurological diseases. Although investigation of specific lncRNAs revealed their role in the metabolism of cellular RNA, our understanding of their contribution to post-transcriptional regulation is relatively limited. In this study, we explore the role of lncRNAs in modulating alternative splicing and their impact on downstream protein-RNA interaction networks. Results: Analysis of alternative splicing events across 39 lncRNA wildtype and knockout RNA-sequencing datasets from three human cell lines: HeLa (Cervical Cancer), K562 (Myeloid Leukemia), and U87 (Glioblastoma), resulted in high confidence (fdr < 0.01) identification of 4432 skipped exon events and 2474 retained intron events, implicating 759 genes to be impacted at post-transcriptional level due to the loss of lncRNAs. We observed that a majority of the alternatively spliced genes in a lncRNA knockout were specific to the cell type, in agreement with the finding that genes affected by alternative splicing also displayed enriched functions in a cell type specific manner. To understand the mechanism behind this cell-type specific alternative splicing patterns, we analyzed RNA binding protein (RBP)-RNA interaction profiles across the spliced regions. Conclusions: Despite limited RBP binding data across cell lines, alternatively spliced events detected in lncRNA perturbation experiments were associated with RBPs binding in proximal intron-exon junctions, in a cell type specific manner. The cellular functions affected by alternative splicing were also affected in a cell type specific manner. Based on the RBP binding profiles in HeLa and K562 cells, we hypothesize that several lncRNAs are likely to exhibit a sponge effect in disease contexts, resulting in the functional disruption of RBPs due to altered titration of the RBPs from their target loci. We propose that such lncRNA sponges can extensively rewire the post-transcriptional gene regulatory networks by altering the protein-RNA interaction landscape in a cell-type specific manner.

The emergence of acquired resistance to EGFR-TKIs is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after frontline osimertinib treatment failure because of a secondary mutation. We also established acquired re-sistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020 resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial to mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome sec-ondary mutations after front-line osimertinib. We found that off-target mechanisms that cause re-sistance to earlier generation TKIs will also cause resistance to 4G TKIs.

The spread of the infection caused by the new coronavirus SARS-CoV-2 (COVID-19) became pandemic on March 11, 2020. From the time of the first cases (in November 2019, Wuhan, China), to date, a large number of COVID-19 observations have been accumulated in different age groups of patients both in China and abroad. Published scientific data allows us to conclude that children suffer from COVID-19 much less often than adults and tolerate the disease in a milder form, often appear to be asymptomatic. There is currently no final answer why children are less susceptible to this virus; however, scientists are increasingly inclined to consider a complex effect of the immune response and components of the renin-angiotensin system (RAS), which according to recent studies affects not only the cardiovascular system, but is also responsible for the activation of inflammatory reactions. A hypothesis of genetic predisposition to the development of severe forms of COVID-19 has recently been made. We conducted a search for publications in the databases and showed current scientific ideas about COVID-19 pathogenesis and factors influencing the disease development in childhood. Childhood immunity may have several protective features against SARS-CoV-2: immaturity of particular elements of the innate immune response, constitutional lymphocytosis with a shift towards anti-inflammatory Th2-response, as well as "trained" immunity. The influence of renin-angiotensin system reactions in this review is shown from two perspectives: expression of ACE2 receptors and polymorphisms of certain genes of this system. It was established that ACE2 transmembrane protein is not only the entry point for the virus but also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1-7), which has vasodilating properties. Higher ACE2 content in children compared with adults helps maintain balance in the renin-angiotensin system and prevents the development of complications. It was also shown that the presence of certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) could determine the imbalance inside the RAS, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift towards vasoconstrictor, proliferative and profibrotic mechanisms.

Modern surface analysis techniques are expanding significantly possibilities in description and attribution of historical artifacts. The present study is aimed to compare analytical ability of the X-ray fluorescent analysis (XRF) typically applied for studies ceramic art items with novel surface analysis methods: time-of-flight secondary ions mass spectroscopy (SIMS) and X-ray photoelectron spectroscopy (XPS) that were applied on measurements of elemental compositions of powder raw materials for porcelain fabrication: pegmatite P-1, Vesco-prima clay, kaolin, bone earth, dolomite, and feldspar. It was shown that SIMS successfully measures light elements unnoticeable for XRF such as lithium, beryllium, boron and heavy impurities not found out by XRF such as cobalt, cerium, copper, rubidium, vanadium. XPS has found thorium in the kaolin sample that was not detected by SIMS and XRF. The paper provides also values of chemical shifts of some XPS lines observed in materials under examination. The obtained information on relations of basic and impurity elements revealed by XRF and SIMS together with XPS chemical shifts data could be used to expose contemporary falsifications of historical porcelain and to attribute porcelain items during conservation process.

Although the existing paradigm states that CMV reactivation is under control of cellular immune response, the role of humoral counterpart is underestimated. Anti-CMV positive woman after conditioning with Bu-Flu-ATG underwent stem cell transplantation from fully matched, seronegative sibling donor. In immunodeficient recipient fast and significant decrease of specific immune response was observed but reconstitution of marrow-derived B and NK cells was prior thymic origin T cells. The lowest CMV-IgG(89 U/ml) was observed just before CMV viremia. Noteworthy, the sole and exclusive factor of CMV-specific immune response is a residual recipient antibody class IgG. The CMV-quantiferon increase was observed later, but in the first phase immune reconstitution of the PHA-induced IFNγ release was significantly lower than that CMV-induced. It corresponds with NK cells increase at the top of lymphocyte reconstitution and undetected CMV-specific CD8 cells by pentamer technique. Most of NK cells are CD16+, thus are stimulated by residual IgG. In immunocompetent donor the cellular and humoral immune response increases in parallel manner but symptoms of CMV mononucleosis were observed till the increase of specific IgG. Our observations shed light on a unique host-CMV interaction: indicate that significant decrease of CMV-IgG is a good predictor for CMV reactivation during secondary immunodeficiency.