Acute Hypoxia Alters Extracellular Vesicle Signatures and the Brain Citrullinome of Naked Mole-Rats (<i>Heterocephalus glaber</i>)

Peptidylarginine deiminases (PADs) and extracellular vesicles (EVs) may be indicative biomarkers of physiological and pathological status and adaptive responses, including to diseases and disorders of the central nervous system (CNS) and related to hypoxia. While these markers have been studied in hypoxia-intolerant mammals, in vivo investigations in hypoxia-tolerant species are lacking. Naked mole-rats (NMR) are among the most hypoxia-tolerant mammals and are thus a good model organism for understanding natural and beneficial adaptations to hypoxia. Thus, we aimed to reveal CNS related roles for PADs in hypoxia tolerance and identify whether circulating EV signatures may reveal a fingerprint for adaptive whole-body hypoxia responses in this species. We found that following in vivo acute hypoxia, NMR: (1) plasma-EVs were remodelled, (2) whole proteome EV cargo contained more protein hits (including citrullinated proteins) and a higher number of associated KEGG pathways relating to the total proteome of plasma-EVs Also, (3) brains had a trend for elevation in PAD1, PAD3 and PAD6 protein expression, while PAD2 and PAD4 were reduced, while (4) the brain citrullinome had a considerable increase in deiminated protein hits with hypoxia (1222 vs. 852 hits in normoxia). Our findings indicate that circulating EV signatures are modified and proteomic content is reduced in hypoxic conditions in naked mole-rats, including the circulating EV citrullinome, while the brain citrullinome is elevated and modulated in response to hypoxia. This was further reflected in elevation of some PADs in the brain tissue following acute hypoxia treatment. These findings indicate a possible selective role for PAD-isozymes in hypoxia response and tolerance

An outbreak of aseptic meningitis due to echovirus 30 associated with attending school and swimming in pools

Summary Objectives To identify the risk factors of an outbreak of meningitis associated with echovirus 30-infection that occurred in Rome, Italy, in late 1997 among children from two different schools. Methods A case-control study was carried out. A case was defined as a child from either of the two schools, A or B, who presented meningitis-like (fever, headache and vomiting), diarrhea, or respiratory tract symptoms. All asymptomatic students were included in the analysis as controls. Results Among 446 pupils (80%) who answered the questionnaire, 68 met the case definition. Twenty pupils developed a meningitis-like illness. Echovirus 30 was isolated from cerebrospinal fluid (CSF) in four and from stools in six. Forty-eight pupils reported other symptoms. The attack rate was 10.8% in school A and 0.8% in school B for meningitis-like illness; it was 12% and 10%, respectively, for other enterovirus-like illnesses. The risk of meningitis-like illness was higher among children attending school A (crude OR=14.9; 95% CI=4.3–52.1), among children using any public pool (OR=3.8; 95% CI=1.5–9.9) and those using an outside swimming pool X (OR=13.4; 95% CI=2.7–65.8 versus no swimming pool and OR=8.3; 95% CI=1.1–62.6 versus other pools). The epidemic curve appears to suggest a person-to-person transmission. Conclusions The epidemic occurred by person-to-person transmission in a number of classrooms and at swimming pool X

Molecular survey of Ehrlichia canis and Coxiella burnetii infections in wild mammals of southern Italy

Ehrlichiosis and Q fever caused by the intracellular bacteria Ehrlichia canis and Coxiella burnetii, respectively, are tick-borne diseases with zoonotic potential and widespread geographical distribution. This study investigated the prevalence of both infections in wild mammals in southern Italy. Tissue samples obtained from the red fox (Vulpes vulpes), European badger (Meles meles), gray wolf (Canis lupus), beech marten (Martes foina), and crested porcupine (Hystrix cristata) were processed for molecular detection of both pathogens. E. canis was detected in 55 out of 105 (52 %) red foxes and three out of six gray wolves. Four sequence types were identified, three of which were found in the spleen and liver samples of red foxes and wolves, and one in the kidney of a red fox. None of the examined mammals was positive to C. burnetii type. This represents the first report of E. canis in free-ranging wolves worldwide, as well as the first evidence of this pathogen in red foxes in the peninsular Italy. Our results suggest that E. canis infection is common in free-ranging canids in southern Italy and that a sylvatic life cycle of this pathogen may occur

Structural modeling of altered CLCN1 conformation following a novel mutation in a patient affected by autosomal dominant myotonia congenita (Thomsen disease)

Myotonia congenita belongs to the group of non-dystrophic myotonia caused by mutations in _CLCN_1gene, and can be inherited either in autosomal dominant (Thomsen disease) or recessive (Becker disease) forms. Here we describe a 46-year-old male patient affected by myotonia congenita. Genetic analysis identified the mutation p.Val536Ile, and structural analysis suggests a pathological role for this variant. In fact, the presence of a bulky residue in the place of valine 536, such as leucine or isoleucine, may generate interactions with Tyr578, thus altering its function and impairing the dynamics of ion current. A mutation affecting the same aminoacid 536 (p.Val536Leu) has already been described, but in association with a second mutation (p.Phe167Leu). Therefore, these data highlight the importance of establishing the inheritance pattern for each variant of CLCN1 gene, that, joined with phenotype heterogeneity, may improve the diagnosis and genetic counseling in MC patients

“Spazio Huntington”: Tracing the Early Motor, Cognitive and Behavioral Profiles of Kids with Proven Pediatric Huntington Disease and Expanded Mutations > 80 CAG Repeats

The “Spazio Huntington—A Place for Children” program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD (PHD). We met 25 at risk kids in two years, four of whom with PHD and highly expanded (HE) mutations beyond 80 CAG repeats. We rated motor, neuropsychological and behavioral changes in all PHD kids by the Unified HD Rating Scale (UHDRS)-total motor score (TMS) and additional measures of (1) cognitive level (Leiter International Performance Scale), (2) adaptive functioning (Adaptive Behavior Assessment Systems), (3) receptive language (Peabody Picture Vocabulary Test) and (4) behavioral abnormalities (Child Behavior Check List and Children’s Yale–Brown Obsessive Compulsive Scale). All PHD kids showed a severe progression of neurological and psychiatric manifestations including motor, cognitive and behavioral changes. The magnetic resonance imaging contributed to confirm the suspicious clinical observation by highlighting very initial striatum abnormalities in PHD. Spazio Huntington is a program to prospectively study PHD, the most atypical face of HD, and may represent the basis to recruit PHD patients in future clinical trials

Unveiling role of sphingosine-1-phosphate receptor 2 as a brake of epithelial stem cell proliferation and a tumor suppressor in colorectal cancer

ackgroundSphingosine-1-phosphate receptor 2 (S1PR2) mediates pleiotropic functions encompassing cell proliferation, survival, and migration, which become collectively de-regulated in cancer. Information on whether S1PR2 participates in colorectal carcinogenesis/cancer is scanty, and we set out to fill the gap.MethodsWe screened expression changes of S1PR2 in human CRC and matched normal mucosa specimens [N =76]. We compared CRC arising in inflammation-driven and genetically engineered models in wild-type (S1PR2(+/+)) and S1PR2 deficient (S1PR2(-/-)) mice. We reconstituted S1PR2 expression in RKO cells and assessed their growth in xenografts. Functionally, we mimicked the ablation of S1PR2 in normal mucosa by treating S1PR2(+/+) organoids with JTE013 and characterized intestinal epithelial stem cells isolated from S1PR2(-/-)Lgr5-EGFP- mice.ResultsS1PR2 expression was lost in 33% of CRC; in 55%, it was significantly decreased, only 12% retaining expression comparable to normal mucosa. Both colitis-induced and genetic Apc(+/min) mouse models of CRC showed a higher incidence in size and number of carcinomas and/or high-grade adenomas, with increased cell proliferation in S1PR2(-/-) mice compared to S1PR2(+/+) controls. Loss of S1PR2 impaired mucosal regeneration, ultimately promoting the expansion of intestinal stem cells. Whereas its overexpression attenuated cell cycle progression, it reduced the phosphorylation of AKT and augmented the levels of PTEN.ConclusionsIn normal colonic crypts, S1PR2 gains expression along with intestinal epithelial cells differentiation, but not in intestinal stem cells, and contrasts intestinal tumorigenesis by promoting epithelial differentiation, preventing the expansion of stem cells and braking their malignant transformation. Targeting of S1PR2 may be of therapeutic benefit for CRC expressing high Lgr5.Graphical Abstract. Schematic drawing of the role of S1PR2 in normal mucosa and colorectal cancer. In the normal mucosa, S1PR2 is highly expressed by differentiated cells at the upper region of both colon and intestinal crypts (S1PR2 ON), but not by the undifferentiated stem cell at the base of the crypts (S1PR2 OFF), in which acts as a negative proliferative regulator promoting epithelial differentiation. Its loss leads to the expansion of stem cells and reduced levels of PTEN and Axin-2, two negative regulators respectively of PI3K/AKT and Wnt signaling that control beta -catenin signaling. The translocation of beta -catenin into the nucleus promotes the transcription of target genes involved in the proliferation and malignant transformation. Thereby, S1PR2 works in the intestine as a tumor suppresso

Where does this image take you? A visual tale from a workshop on geographical imaginations

This work is authored by a group of Ph.D. students and academics who attended a workshop on visual methodologies in the framework of the Scuola di alta formazione in geografia organised by AGeI (Association of Italian Geographers), 2022 edition. By visually reporting the workshop activities we aim at reflecting on the creative power of images in expanding geographical imaginations and its potential in the teaching of geography. The paper is shaped as a visual essay in which images and text do not refer directly to each other but rather aim at creating an imaginative reading flow