Humans and dolphins: Decline and fall of adult neurogenesis

Pre-clinical research is carried out on animal models, mostly laboratory rodents, with the ultimate aim of translating the acquired knowledge to humans. In the last decades, adult neurogenesis (AN) has been intensively studied since it is viewed as a tool for fostering brain plasticity, possibly repair. Yet, occurrence, location, and rate of AN vary among mammals: the capability for constitutive neuronal production is substantially reduced when comparing small-brained, short living (laboratory rodents) and large-brained, long-living species (humans, dolphins). Several difficulties concerning scarce availability of fresh tissues, technical limits and ethical concerns did contribute in delaying and diverting the achievement of the picture of neurogenic plasticity in large-brained mammals. Some reports appeared in the last few years, starting to shed more light on this issue. Despite technical limits, data from recent studies mostly converge to indicate that neurogenesis is vestigial, or possibly absent, in regions of the adult human brain where in rodents neuronal addition continues into adult life. Analyses carried out in dolphins, mammals devoid of olfaction, but descendant of ancestors provided with olfaction, has shown disappearance of neurogenesis in both neonatal and adult individuals. Heterogeneity in mammalian structural plasticity remains largely underestimated by scientists focusing their research in rodents. Comparative studies are the key to understand the function of AN and the possible translational significance of neuronal replacement in humans. Here, we summarize comparative studies on AN and discuss the evolutionary implications of variations on the recruitment of new neurons in different regions and different species

Humans and Dolphins: Decline and Fall of Adult Neurogenesis

Pre-clinical research is carried out on animal models, mostly laboratory rodents, with the ultimate aim of translating the acquired knowledge to humans. In the last decades, adult neurogenesis (AN) has been intensively studied since it is viewed as a tool for fostering brain plasticity, possibly repair. Yet, occurrence, location, and rate of AN vary among mammals: the capability for constitutive neuronal production is substantially reduced when comparing small-brained, short living (laboratory rodents) and large-brained, long-living species (humans, dolphins). Several difficulties concerning scarce availability of fresh tissues, technical limits and ethical concerns did contribute in delaying and diverting the achievement of the picture of neurogenic plasticity in large-brained mammals. Some reports appeared in the last few years, starting to shed more light on this issue. Despite technical limits, data from recent studies mostly converge to indicate that neurogenesis is vestigial, or possibly absent, in regions of the adult human brain where in rodents neuronal addition continues into adult life. Analyses carried out in dolphins, mammals devoid of olfaction, but descendant of ancestors provided with olfaction, has shown disappearance of neurogenesis in both neonatal and adult individuals. Heterogeneity in mammalian structural plasticity remains largely underestimated by scientists focusing their research in rodents. Comparative studies are the key to understand the function of AN and the possible translational significance of neuronal replacement in humans. Here, we summarize comparative studies on AN and discuss the evolutionary implications of variations on the recruitment of new neurons in different regions and different species

Undifferentiated connective tissue disease presenting with prevalent interstitial lung disease: Case report and review of literature

Undifferentiated connective tissue diseases (UCTDs) are clinical entities characterised by signs and symptoms suggestive of a systemic autoimmune disease, which do not fulfil the diagnostic criteria for a defined connective tissue disease. Lung involvement can complicate the course and management of the disease, often determining a worse outcome. Respiratory dysfunction as the first clinical manifestation has seldom been reported

Renal Fibrosis in Lupus Nephritis

Fibrosis can be defined as a pathological process in which deposition of connective tissue replaces normal parenchyma. The kidney, like any organ or tissue, can be impacted by this maladaptive reaction, resulting in persistent inflammation or long-lasting injury. While glomerular injury has traditionally been regarded as the primary focus for classification and prognosis of lupus nephritis (LN), increasing attention has been placed on interstitial fibrosis and tubular atrophy as markers of injury severity, predictors of therapeutic response, and prognostic factors of renal outcome in recent years. This review will discuss the fibrogenesis in LN and known mechanisms of renal fibrosis. The importance of the chronicity index, which was recently added to the histological categorization of LN, and its role in predicting treatment response and renal prognosis for patients with LN, will be explored. A better understanding of cellular and molecular pathways involved in fibrosis in LN could enable the identification of individuals at higher risk of progression to chronic kidney disease and end-stage renal disease, and the development of new therapeutic strategies for lupus patients

Impact of DWI and ADC values in ovarian-adnexal reporting and data system (O-RADS) MRI score

Purpose: Introduce DWI and quantitative ADC evaluation in O-RADS MRI system and observe how diagnostic performance changes. Assess its validity and reproducibility between readers with different experience in female pelvic imaging. Finally, evaluate any correlation between ADC value and histotype in malignant lesions. Materials and methods: In total, 173 patients with 213 indeterminate adnexal masses (AMs) on ultrasound were subjected to MRI examination, from which 140 patients with 172 AMs were included in the final analysis. Standardised MRI sequences were used, including DWI and DCE sequences. Two readers, blinded to histopathological data, retrospectively classified AMs according to the O-RADS MRI scoring system. A quantitative analysis method was applied by placing a ROI on the ADC maps obtained from single-exponential DWI sequences. AMs considered benign (O-RADS MRI score 2) were excluded from the ADC analysis. Results: Excellent inter-reader agreement was found in the classification of lesions according to the O-RADS MRI score (K = 0.936; 95% CI). Two ROC curves were created to determine the optimal cut-off value for the ADC variable between O-RADS MRI categories 3-4 and 4-5, respectively, 1.411 × 10-3 mm2/sec and 0.849 × 10-3 mm2/sec. Based on these ADC values, 3/45 and 22/62 AMs were upgraded, respectively, to score 4 and 5, while 4/62 AMs were downgraded to score 3. ADC values correlated significantly with the ovarian carcinoma histotype (p value < 0.001). Conclusion: Our study demonstrates the prognostic potential of DWI and ADC values in the O-RADS MRI classification for better radiological standardisation and characterisation of AMs

Noncanonical sortase-mediated assembly of pilus type 2b in group B Streptococcus

Group B Streptococcus (GBS) expresses 3 structurally distinct pilus types (1, 2a, and 2b) identified as important virulence factors and vaccine targets. These pili are heterotrimeric polymers, covalently assembled on the cell wall by sortase (Srt) enzymes. We investigated the pilus-2b biogenesis mechanism by using a multidisciplinary approach integrating genetic, biochemical, and structural studies to dissect the role of the 2 pilus-2b-associated Srts. We show that only 1 sortase (SrtC1-2b) is responsible for pilus protein polymerization, whereas the second one (Srt2-2b) does not act as a pilin polymerase, but similarly to the housekeeping class A Srt (SrtA), it is involved in cell-wall pilus anchoring by targeting the minor ancillary subunit. Based on its function and sequence features, Srt2-2b does not belong to class C Srts (SrtCs), nor is it a canonical member of any other known family of Srts. We also report the crystal structure of SrtC1-2b at 1.9 Å resolution. The overall fold resembles the typical structure of SrtCs except for the N-terminal lid region that appears in an open conformation displaced from the active site. Our findings reveal that GBS pilus type 2b biogenesis differs significantly from the current model of pilus assembly in gram-positive pathogens.-Lazzarin, M., Cozzi, R., Malito, E., Martinelli, M., D'Onofrio, M., Maione, D., Margarit, I., and Rinaudo, C. D. Noncanonical sortase-mediated assembly of pilus type 2b in group B Streptococcus

Apo, Zn 2 + -bound and Mn 2 + -bound structures reveal ligand-binding properties of SitA from the pathogen Staphylococcus pseudintermedius

Synopsis The Gram-positive bacterium Staphylococcus pseudintermedius is a leading cause of canine bacterial pyoderma, resulting in worldwide morbidity in dogs. S. pseudintermedius also causes life-threatening human infections. Furthermore, methicillin-resistant S. pseudintermedius is emerging, resembling the human health threat of methicillin-resistant Staphylococcus aureus. Therefore it is increasingly important to characterize targets for intervention strategies to counteract S. pseudintermedius infections. Here we used biophysical methods, mutagenesis, and X-ray crystallography, to define the ligand-binding properties and structure of SitA, an S. pseudintermedius surface lipoprotein. SitA was strongly and specifically stabilized by Mn 2 + and Zn 2 + ions. Crystal structures of SitA complexed with Mn 2 + and Zn 2 + revealed a canonical class III solute-binding protein with the metal cation bound in a cavity between Nand C-terminal lobes. Unexpectedly, one crystal contained both apo-and holo-forms of SitA, revealing a large sidechain reorientation of His 64 , and associated structural differences accompanying ligand binding. Such conformational changes may regulate fruitful engagement of the cognate ABC (ATP-binding cassette) transporter system (SitBC) required for metal uptake. These results provide the first detailed characterization and mechanistic insights for a potential therapeutic target of the major canine pathogen S. pseudintermedius, and also shed light on homologous structures in related staphylococcal pathogens afflicting humans

Computed Tomography Structured Reporting in the Staging of Lymphoma: A Delphi Consensus Proposal

Abstract Structured reporting (SR) in radiology is becoming increasingly necessary and has been recognized recently by major scientific societies. This study aims to build structured CT-based reports for lymphoma patients during the staging phase to improve communication between radiologists, members of multidisciplinary teams, and patients. A panel of expert radiologists, members of the Italian Society of Medical and Interventional Radiology (SIRM), was established. A modified Delphi process was used to develop the SR and to assess a level of agreement for all report sections. The Cronbach's alpha (Cα) correlation coefficient was used to assess internal consistency for each section and to measure quality analysis according to the average inter-item correlation. The final SR version was divided into four sections: (a) Patient Clinical Data, (b) Clinical Evaluation, (c) Imaging Protocol, and (d) Report, including n = 13 items in the "Patient Clinical Data" section, n = 8 items in the "Clinical Evaluation" section, n = 9 items in the "Imaging Protocol" section, and n = 32 items in the "Report" section. Overall, 62 items were included in the final version of the SR. A dedicated section of significant images was added as part of the report. In the first Delphi round, all sections received more than a good rating (≥3). The overall mean score of the experts and the sum of score for structured report were 4.4 (range 1-5) and 1524 (mean value of 101.6 and standard deviation of 11.8). The Cα correlation coefficient was 0.89 in the first round. In the second Delphi round, all sections received more than an excellent rating (≥4). The overall mean score of the experts and the sum of scores for structured report were 4.9 (range 3-5) and 1694 (mean value of 112.9 and standard deviation of 4.0). The Cα correlation coefficient was 0.87 in this round. The highest overall means value, highest sum of scores of the panelists, and smallest standard deviation values of the evaluations in this round reflect the increase of the internal consistency and agreement among experts in the second round compared to first round. The accurate statement of imaging data given to referring physicians is critical for patient care; the information contained affects both the decision-making process and the subsequent treatment. The radiology report is the most important source of clinical imaging information. It conveys critical information about the patient's health and the radiologist's interpretation of medical findings. It also communicates information to the referring physicians and records this information for future clinical and research use. The present SR was generated based on a multi-round consensus-building Delphi exercise and uses standardized terminology and structures, in order to adhere to diagnostic/therapeutic recommendations and facilitate enrolment in clinical trials, to reduce any ambiguity that may arise from non-conventional language, and to enable better communication between radiologists and clinicians

Neutralizing activity and T Cell response after bivalent fifth dose of mRNA vaccine in person living with HIV

OBJECTIVES: To investigate immunogenicity of SARS-CoV-2 vaccine third booster (3BD; fifth dose) with bivalent vaccine original/BA4/5 vaccine in people living with HIV (PLWH). STUDY DESIGN: This is an observational cohort study to evaluate the outcomes of SARS-CoV-2 vaccination (HIV-VAC study). We analyzed microneutralization assay and IFN-γ production in 48 PLWH on ART with CD4 count <200 cell/mm3 and/or previous AIDS according to immunization status: vaccinated PLWH who had a previous SARS-CoV-2 infection (hybrid immunization, HI) vs. those only vaccinated (non-hybrid immunization, nHI) and current CD4 count RESULTS: After 15 days from its administration (T1), the 3BD bivalent mRNA vaccine elicited a statistically significant increase of neutralizing antibodies (nAbs) geometric mean titers (GMTs) from T0 to T1 against W-D614G (fold-increase 4.8; p<0.0001), BA.5 (8.6 p<0.0001), BQ.1.1 (6.4, p<0.0001) and XBB.1 (6.5, p<0.0001). When compared to BA.5, nAbs GMTs against BQ.1.1 and XBB.1 decreased by 3.5 and 4.1-fold, respectively. After controlling for age, years from AIDS diagnosis, CD4 count at administration and CD4 count nadir, the fold change reduction in nAbs response to other VoCs as compared to BA.1, was larger in participants with HI vs. those nHI: 0.59 lower (95%CI 0.36, 0.97, p=0.04) for BQ.1.1 and 0.67 lower (95% CI: 0.47, 0.96, p=0.03) for XBB.1.In contrast, the analysis carried little evidence for an association between current CD4 count and response to the fifth dose of bivalent vaccine. Furthermore, cell-mediated immunity remained stable. CONCLUSIONS: Our data support the current recommendation of offering bivalent mRNA vaccine booster doses to PLWH with low CD4 count or previous AIDS at first vaccination, especially in those who never previously acquired SARS CoV2 and regardless of current CD4 count

SARS-CoV-2 Infection in Spondyloarthritis Patients Treated With Biotechnological Drugs: A Study on Serology

ObjectiveSerology could help to define the real extent of SARS-CoV-2 diffusion, especially in individuals considered at higher risk of COVID-19, such as spondyloarthritis (SpA) patients undergoing immunosuppressant. Our aim was to detect, by serology, previous SARS-CoV-2 contact in SpA, compared to health care workers (HCW), and healthy controls.MethodsSera from consecutive patients affected by SpA undergoing cytokine-targeted therapy, HCW and healthy controls from 2015 were analysed through chemiluminescent analytical system for the presence of IgG and IgM anti-SARS-CoV-2. Positive patients (IgM or IgG, or both) additionally underwent real-time Polymerase-Chain-Reaction (RT-PCR) to test for active infection. Serology was repeated at 3-months in SpA. Data across 3 groups were compared by Kruskal Wallis/Chi-square, and between 2 groups by Wilcoxon rank test/Chi-Square. P ≤ 0.05 were considered significant.Results200 SpA, 95 HCW and 101 controls were recruited. Positive serology was found in 25(12.5%) SpA, 8(8.4%) HCW, 0(0%) controls (p=0.001). SpA patients with positive serology more frequently reported COVID-19-like symptoms than those with negative serology (20% vs. 4%, p=0.009) and 2 had COVID-19 as confirmed by RT-PCR, non severe. No HCW reported symptoms or had positive RT-PCR. In SpA patients, at 3 months, mean IgM titres decreased from 2.76 ± 2.93 to 2.38 ± 2.95 (p=0.001), while IgG titres from 0.89 ± 3.25 to 0.31 ± 0.87 (p=ns).ConclusionsSerology revealed that exposure to SARS-CoV-2 in SpA patients and HCW was higher than expected based on reported symptoms. In SpA, anti-cytokine therapy could act as a protective factor for a severe disease course. However, a seroconversion was not observed at 3-months