The [1,2,4]Triazolo[4,3-a]pyridine as a New Player in the Field of IDO1 Catalytic Holo-Inhibitors

Inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) are considered a promising strategy in cancer immunotherapy as they are able to boost the immune response and to work in synergy with other immunotherapeutic agents. Despite the fact that no IDO1 inhibitor has been approved so far, recent studies have shed light on the additional roles that IDO1 mediates beyond its catalytic activity, conferring new life to the field. Here we present a novel class of compounds originated from a structure-based virtual screening made on IDO1 active site. The starting hit compound is a novel chemotype based on a [1,2,4]triazolo[4,3-a]pyridine scaffold, so far underexploited among the heme binding moieties. Thanks to the rational and in silico-guided design of analogues, an improvement of the potency to sub-micromolar levels has been achieved, with excellent in vitro metabolic stability and exquisite selectivity with respect to other heme-containing enzymes

Rehabilitative treatment of patients with covid-19 infection: The p.a.r.m.a. evidence based clinical practice protocol

Background: The impact of the SARS-CoV-2 on the National Health System (NHS) required a reorganization of the various levels of care, which also involved the rehabilitation reality. Aim of the work: A clinical practice review of the literature was conducted to provide operational-rehabilitation guidelines adapt-ed to the local reality and to the recent corporate reorganization in the context of the COVID-19 emergency. Methods: A practice review of the available scientific evidence was regularly conducted from the start of the COVID-19 pandemic to periodically update the clinical practice guidelines. Articles that met the following inclusion criteria were included: studies conducted on human adult subjects with COVID-19 infection, un-dergoing rehabilitation in any hospitalization setting. Results: The results of this clinical practice update were periodically discussed with colleagues and collaborators in a multi-professional team, in order to guarantee a good clinical practice protocol, named P.A.R.M.A. Conclusions: The P.A.R.M.A. protocol is the result of a periodic review literature update, which has allowed us to take charge of patients affected by COVID-19 ac-cording to the most up-to-date clinical evidences, guaranteeing a shared and uniform treatment within a local reality in an era of health emergency. (www.actabiomedica.it)

Management of Enthesitis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations

Objective. Enthesitis is a key pathological and clinical feature of psoriatic arthritis (PsA) in children and adults. Enthesitis is typically assessed clinically using several validated enthesitis scoring systems that have been used in clinical trials. Enthesitis treatment response has been reported as change in the total enthesitis score or the proportion of patients who achieved complete resolution. The majority of trials in PsA did not require patients to have enthesitis at study entry since enthesitis was evaluated only as a secondary outcome. Despite the inherent limitations of the clinical assessment of enthesitis, imaging of the entheses using ultrasound or magnetic resonance imaging has rarely been used in clinical trials to assess response to treatment of enthesitis. This systematic review summarizes existing evidence regarding pharmaceutical and nonpharmaceutical interventions for enthesitis in patients with PsA to facilitate an evidence-based update of the Group for Research and Assessment in Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for PsA. Methods. We performed a systematic literature review to identify 41 randomized clinical trials that reported enthesitis treatment response in patients with PsA. For each intervention, the response effect size was summarized and the quality of evidence was graded. Recommendations were then formulated for the various pharmacological and nonpharmacological therapies. Results. We included 41 randomized clinical trials in our review and graded each intervention. Conclusion. Several classes of systemic conventional and advanced therapies and local measures were recommended for active enthesitis in patients with PsA

GREENPEG exploration for pegmatite minerals to feed the energy transition: first steps towards the Green Stone Age

The GREENPEG project, which is funded by the European Commission Horizon 2020 Climate action, environment, resource efficiency and raw materials programme, aims to develop multimethod exploration toolsets for the identification of European, buried, small-scale (0.015 million m3 ) pegmatite ore deposits of the NbYF (NYF) and LiCsTa (LCT) chemical types. The project is being coordinated by the Natural History Museum of the University of Oslo and involves four exploration services/mining operators, one geological survey, one non-profit helix association of administration, industry and academia, two consulting companies and five academic institutions from eight European countries. The target raw materials are Li, high-purity quartz for silica and metallic Si, ceramic feldspar, rare earth elements, Ta, Be and Cs, which are naturally concentrated in granitic pegmatites. Silicon and Li are two of the most sought-after green technology metals as they are essential for photovoltaics and Li-ion batteries for electric cars, respectively. GREENPEG will change the focus of exploration strategies from large-volume towards small-volume, high-quality ores and overcome the lack of exploration technologies for pegmatite ore deposits by developing toolsets tailored to these ore types. This contribution focuses on the methods applied in the GREENPEG project and as such provides a potential pathway towards the Green Stone Age from the perspective of pegmatite-sourced minerals. (c) 2022 The Author(s)

Growth Arrest Specific Gene 6 Protein Concentration in Cerebrospinal Fluid Correlates with Relapse Severity in Multiple Sclerosis

Background. Growth arrest specific gene 6 (Gas6) protein enhances survival of oligodendrocytes and neurons, and it is involved in autoimmunity. Therefore, we aimed to verify whether cerebrospinal-fluid (CSF) Gas6 concentration may represent a biomarker of disease activity in multiple sclerosis. Methods. Sixty-five patients who underwent a spinal tap during relapse of relapsing/remitting multiple sclerosis (RR-MS)(McDonald-criteria) were studied. Forty patients affected by noninflammatory/nonautoimmune neurological diseases served as controls. Relapse was defined according to Schumacher criteria. Symptoms were grouped according to Kurtzke-Functional System (FS). Clinical characteristics of the relapse, duration, Expanded-Disability-Status Scale (EDSS) change, number of FS involved, completeness of recovery, age, steroid therapy, were categorised. Patients were followed at 6-month intervals to assess relapse rate and EDSS progression. Gas6 was measured (CSF, plasma) by in-house-enzyme-linked immunoassay (ELISA). Results. Higher CSF Gas6 concentrations were observed in relapses lasting ≤60 days (8.7 ± 3.9 ng/mL) versus >60 days (6.5 ± 2.6) or controls (6.5 ± 2.4; P = 0.05), with ≤2 FS involved (8.5 ± 3.8) versus >2 FS (5.6 ± 2.5) (P < 0.05) and EDSS change ≤2.5 points (8.8 ± 3.7) versus >2.5 (6.5 ± 3.5) (P = 0.04). Conversely, CSF Gas6 was not predictive of the completeness of recovery. Plasma and CSF concentrations were not related (R (2) = 0.0003), and neither were predictive of relapse rate or EDSS progression after first relapse. Conclusions. CSF concentration of Gas6 is inversely correlated with the severity of relapse in RR-MS patients but does not predict the subsequent course of the disease

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Purpose: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. / Methods: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. / Results: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. / Conclusion: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic–atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

De Novo and Bi-allelic Pathogenic Variants in NARS1 Cause Neurodevelopmental Delay Due to Toxic Gain-of-Function and Partial Loss-of-Function Effects.

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function

Eosinophils in glioblastoma biology

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review

SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects.

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development