Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress

The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity. Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex. In line with a role in mitosis, phosphorylation at Serine 87 is suppressed in S-phase and is mainly detected in the MUS81 molecules associated with EME1. Loss of CK2-dependent MUS81 phosphorylation contributes modestly to chromosome integrity, however, expression of the phosphomimic form induces DSBs accumulation in S-phase, because of unscheduled targeting of HJ-like DNA intermediates, and generates a wide chromosome instability phenotype. Collectively, our findings describe a novel regulatory mechanism controlling the MUS81 complex function in human cells. Furthermore, they indicate that, genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis

Gastric Cancer Maximum Tumour Diameter Reduction Rate at CT Examination as a Radiological Index for Predicting Histopathological Regression after Neoadjuvant Treatment: A Multicentre GIRCG Study

Aim. To investigate the role of maximum tumour diameter (D-max) reduction rate at CT examination in predicting histopathological tumour regression grade (TRG according to the Becker grade), after neoadjuvant chemotherapy (NAC), in patients with resectable advanced gastric cancer (AGC). Materials and Methods. Eighty-six patients (53 M, mean age 62.1 years) with resectable AGC (≥T3 or N+), treated with NAC and radical surgery, were enrolled from 5 centres of the Italian Research Group for Gastric Cancer (GIRCG). Staging and restaging CT and histological results were retrospectively reviewed. CT examinations were contrast enhanced, and the stomach was previously distended. The D-max was measured using 2D software and compared with Becker TRG. Statistical data were obtained using “R” software. Results. The interobserver agreement was good/very good. Becker TRG was predicted by CT with a sensitivity and specificity, respectively, of 97.3% and 90.9% for Becker 1 (D-max reduction rate > 65.1%), 76.4% and 80% for Becker 3 (D-max reduction rate < 29.9%), and 70.8% and 83.9% for Becker 2. Correlation between radiological and histological D-max measurements was strongly confirmed by the correlation index (c.i.= 0.829). Conclusions. D-max reduction rate in AGC patients may be helpful as a simple and reproducible radiological index in predicting TRG after NAC

Axial spondyloarthritis in patients with recurrent fever attacks: data from the AIDA network registry for undifferentiated autoInflammatory diseases (USAIDs)

BeckgroundDespite the recent advances in the field of autoinflammatory diseases, most patients with recurrent fever episodes do not have any defined diagnosis. The present study aims at describing a cohort of patients suffering from apparently unexplained recurrent fever, in whom non-radiographic axial spondylarthritis (SpA) represented the unique diagnosis identified after a complete clinical and radiologic assessment.Materials and methodsPatients’ data were obtained from the international registry on Undifferentiated Systemic AutoInflammatory Diseases (USAIDs) developed by the AutoInflammatory Disease Alliance (AIDA) network.ResultsA total of 54 patients with recurrent fever episodes were also affected by non-radiographic axial SpA according to the international classification criteria. SpA was diagnosed after the start of fever episodes in all cases; the mean age at the diagnosis of axial SpA was 39.9 ± 14.8 years with a diagnostic delay of 9.3 years. The highest body temperature reached during flares was 42°C, with a mean temperature of 38.8 ± 1.1°C. The most frequent manifestations associated to fever were: arthralgia in 33 (61.1%) cases, myalgia in 24 (44.4%) cases, arthritis in 22 (40.7%) cases, headache in 15 (27.8%) cases, diarrhea in 14 (25.9%) cases, abdominal pain in 13 (24.1%) cases, and skin rash in 12 (22.1%) cases. Twenty-four (44.4%) patients have taken daily or on-demand non-steroidal anti-inflammatory drugs (NSAIDs) and 31 (57.4%) patients have been treated with daily or on demand oral glucocorticoids. Colchicine was used in 28 (51.8%) patients, while other conventional disease modifying anti-rheumatic drugs (cDMARDs) were employed in 28 (51.8%) patients. Forty (74.1%) patients underwent anti-tumor necrosis factor (TNF) agents and 11 (20.4%) were treated with interleukin (IL)-1 inhibitors. The response to TNF inhibitors on recurrent fever episodes appeared more effective than that observed with anti-IL-1 agents; colchicine and other cDMARDs were more useful when combined with biotechnological agents.ConclusionSigns and symptoms referring to axial SpA should be inquired in patients with apparently unexplained recurrent fever episodes. The specific treatment for axial SpA may lead to a remarkable improvement in the severity and/or frequency of fever episodes in patients with unexplained fevers and concomitant axial SpA

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Ligia italica (Isopoda, Oniscidea) as bioindicator of mercury pollution of marine rocky coasts.

In this study, we evaluated the possible role of Ligia italica as a bioindicator for the monitoring of heavy metals pollution in the suppralittoral zone of marine rocky coasts. Between 2004 and 2011 specimens of L. italica were collected along the Eastern Sicilian coasts from sites known for their high pollution levels as they are near to an area where in September 2001 a refinery plant discharged into the sea some waste containing Hg. Other specimens were collected from the Vendicari Natural Reserve located about 30 miles from the polluted sites and used as control area. On a consistent number of animals, the concentration in toto of As, Cd, Cr, Hg, Ni, Pb, V, was determined by Atomic Absorption Spectrometry. On other animals, investigations were carried out in order to check for ultrastructural alterations of the hepatopancreas, that is the main metals storage organ in isopods. Results revealed the presence, in the animals collected in 2004 from the polluted sites, of considerable concentrations of Hg and of lower concentrations of other metals such as As, Pb and V. The Hg bioaccumulation resulted in remarkable ultrastructural alterations of the two cellular types (B and S cells) in the epithelium of the hepatopancreas. Surprisingly, a moderate amount of Hg was also found in specimens collected in 2004 from the Vendicari Natural Reserve, proving that the Hg pollution can also spread many miles away. Animals collected from the polluted sites in the following years showed a progressively decreasing Hg content, reaching very low levels in those from the last sampling. Also, the ultrastructural alterations found in the hepatopancreas of the animals from the last sample were quite irrelevant. In conclusion, Ligia italica can represent a good bioindicator and the ultrastructure of the hepatopancreas could be used as ultrastructural biomarker of heavy metals pollution in the supralittoral zones

Serological, Virological Investigation and Hepatic Injury Evaluation for Hepatitis E Virus in Hunting Dogs

Hepatitis E virus (HEV) is a quasi-enveloped single-stranded positive-sense RNA virus belonging to the Orthohepevirus A genus within the Hepeviridae family. The most common transmission route of this virus is fecal&ndash;oral, although zoonotic transmission by contact with infected animals has also been described. In this study, 80 sera and rectal swabs were collected from dogs during the 2019/2020 and 2020/2021 wild boar hunting season in Tuscany. All dogs were submitted for serological screening to detect the presence of anti-HEV antibodies. To evaluate the circulation of HEV, rectal swabs from both seropositive dogs and dogs living in the same kennels were examined by One-Step RT-qPCR. In addition, the presence of markers of hepatic damage in dogs&rsquo; sera was investigated. Results indicated the presence of anti-HEV antibodies in 4/80 subjects (5%). However, neither HEV RNA nor signs of hepatic damage were found. In conclusion, although HEV can stimulate a specific immuno-response in dogs, this species does not seem to play an important role in HEV epidemiology

Ischemic Bowel Disease

Gastrointestinal tract ischemia and infarction comprises different clinical syndromes characterized by inadequate blood perfusion to the bowel. The age of onset depends on gender and the etiology of the ischemia, even if the majority of patients are over age 60. These disorders have been increasing over the past decade and constitute approximately 1–2 % of admissions for abdominal pain in the USA and 3.7 % of surgical intervention for acute abdomen in Italy. The increase in incidence can be attributed to various factors, including increased clinical awareness, aging population, and improvement in diagnostic imaging techniques. The mortality rate is very high, between 50 and 90 %, hence, timely diagnosis is essential to improve the outcome. The pathogenesis and symptoms of intestinal ischemia are extremely variable, and the diagnosis largely depends on clinical suspicion. A recent classification of ischemic bowel diseases, developed by the American Gastroenterological Association (AGA) in 2000, defines three clinical categories: acute mesenteric ischemia (AMI), chronic mesenteric ischemia (CMI) also known as intestinal angina, and ischemic colitis (IC)

Bowel Obstruction

Bowel obstruction is a common but difficult clinical problem in terms of appropriate and timely management. In clinical practice, radiologists play a key role not only in making the diagnosis but also in guiding physicians toward appropriate and timely management of many indeterminate cases and situations. In this chapter, small and large bowel obstruction is illustrated, from pathophysiology to imaging, emphasizing the role of multidetector computed tomography (MDCT) in the diagnosis and management of bowel obstruction. Furthermore, the place of allied imaging modalities such as plain film and ultrasonography is comprehensively illustrated

Tubule of the hepatopancreas of <i>Ligia italica</i> from the two polluted sites.

<p>A–D TEM. A) In many B cells the rough endoplasmic reticulum undergoes a marked swelling and vesiculation (arrow); large vacuoles (Lv), probably derived from the rough endoplasmic reticulum, are present around the nucleus. B) The lipid droplets of B cells are surrounded by scattered accumulations of electron-dense material that in some cells are particularly abundant (arrow). C) In many S cells the number of vesicles of heavy metals accumulation increases moderately. D) The major significant ultrastructural alteration concerning the S cells is, however, represented by the presence of numerous vesicles containing heterogeneous electron-dense material (Vs), that are most likely of lysosomal derivation. Scale bar: A, B = 2 μm; C = 0.5 μm; D = 1 μm.</p