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The rise of sophisticated black-box machine learning models in Artificial Intelligence systems has prompted the need for explanation methods that reveal how these models work in an understandable way to users and decision makers. Unsurprisingly, the state-of-the-art exhibits currently a plethora of explainers providing many different types of explanations. With the aim of providing a compass for researchers and practitioners, this paper proposes a categorization of explanation methods from the perspective of the type of explanation they return, also considering the different input data formats. The paper accounts for the most representative explainers to date, also discussing similarities and discrepancies of returned explanations through their visual appearance. A companion website to the paper is provided as a continuous update to new explainers as they appear. Moreover, a subset of the most robust and widely adopted explainers, are benchmarked with respect to a repertoire of quantitative metrics.

Gene expression profiling in neurodegenerative diseases such as Alzheimer’s Disease (AD) is frequently performed using real-time quantitative polymerase chain reaction (RT-qPCR). The accuracy of this technique relies heavily on selecting suitable reference genes (RGs) for normalization and internal control. Ideally, RGs should maintain consistent transcription levels, unaffected by cellular or pathological changes. However, identifying stable RGs is challenging, particularly in diseases like AD, where gene expression fluctuates across disease stages. This study aimed to determine the most stable RGs in two brain regions - cortex (CTX) and hippocampus (HIPP) - of male and female 5XFAD mice, a model of familial AD. The stability of five commonly used RGs namely Gapdh, Ppia, Rer1, Rpl27 and Rps29, was evaluated using GeNorm, NormFinder, BestKeeper, and EndoGene algorithms across three AD stages: prodromal (2 months of age, mo), early (4 mo), and late (7 and 10 mo). Results revealed region-, sex-, and time-dependent differences in RG expression stability, reflecting the distinct vulnerability of CTX and HIPP to Aβ pathology. Using the two most stable RGs for normalization improved precision, reducing variability and increasing the significance level in target gene expression analyses. These findings emphasize the necessity of validating RGs under specific experimental conditions to ensure reliable RT-qPCR quantification in AD research.

BackgroundSteroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, randomized controlled trial was designed to test whether the monoclonal antibody rituximab is non-inferior to steroids in maintaining remission in juvenile forms of SDNS and how long remission may last (EudraCT:2008-004486-26).MethodsWe enrolled 30 children 4–15 years who had developed SDNS 6–12 months before and were maintained in remission with low prednisone doses (0.1–0.4 mg/Kg/day). Participants were randomized following a non-inferiority design to continue prednisone alone (n 15, controls) or to add a single intravenous infusion of rituximab (375 mg/m2, n 15 intervention). Prednisone was tapered in both arms after 1 month. Children assigned to the control arm were allowed to receive rituximab to treat disease relapse.ResultsProteinuria increased at 3 months in the prednisone group (from 0.14 to 1.5 g/day) (p < 0.001) and remained unchanged in the rituximab group (0.14 g/day). Fourteen children in the control arm relapsed within 6 months. Thirteen children assigned to rituximab (87%) were still in remission at 1 year and 8 (53%) at 4 years. Responses were similar in children of the control group who received rituximab to treat disease relapse. We did not record significant adverse events.ConclusionsRituximab was non-inferior to steroids for the treatment of juvenile SDNS. One in two children remains in remission at 4 years following a single infusion of rituximab, without significant adverse events. Further studies are needed to clarify the superiority of rituximab over low-dose corticosteroid as a treatment of SDNS.

BackgroundChildren with multidrug-resistant nephrotic syndrome (MRNS) are exposed to drug toxicity (steroids/calcineurin inhibitors (CNI)/mycophenolate mofetil (MMF)) and have an increased risk of kidney disease progression. In small case series, the fully humanized anti-CD20 antibody ofatumumab (OFA) induced remission in children with MRNS when at high dose (10,300 mg/1.73 m2) and partial remission at standard dose (1000 mg/1.73 m2).MethodsThis double-blind randomized placebo-controlled trial tested the efficacy of single infusion OFA in children with proven MRNS and initial chronic renal failure (eGFR [median/range] 119/38–155 ml/min/1.73 m2 in Placebo arm vs. 65/19–103 ml/min/1.73 m2 Intervention). Children who had been resistant to a combination of CNI and steroids, with or without MMF or rituximab, were randomized to receive single infusion OFA (1500 mg/1.73 m2) (Intervention arm) or normal saline (Placebo arm). We assessed complete or partial remission of proteinuria after 3 months (primary outcome), and after 6 and 12 months (secondary outcomes), as well as progression to end-stage kidney disease.ResultsAfter 13 of the planned 50 children (25%) were randomized, the data safety and monitoring board recommended study termination for futility. All 13 children remained nephrotic. Renal function worsened in 5 children (2 in Intervention arm, 3 in Placebo arm) who required renal replacement therapy during the study period. Circulating CD20 was reduced following OFA infusion and remained low for > 3 months.ConclusionsOFA given in one single infusion of 1500 mg/1.73 m2 doses does not induce remission in MRNS. Regimens based on higher OFA doses should be tested in clinical trials.Trial registrationhttps://clinicaltrials.gov: NCT02394106

Loss of cholinergic neurons as well as α4β2* (* = containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer's disease (AD). Specifically, amyloid β (Aβ), the principal pathogenic factor of AD, is a high affinity ligand for nAChRs. Yet, the pathophysiological role of nAChRs in AD is not well established. In the present study, we have investigated the effects of the loss of α4* nAChRs on the histological alterations of the Tg2576 mouse model of AD (APPswe) crossing hemizygous APPswe mice with mice carrying the genetic inactivation of α4 nAChR subunit (α4KO). A global decrease in Aβ plaque load was observed in the forebrain of APPswe/α4KO mice in comparison with APPswe mice, that was particularly marked in neocortex of 15 month-old mice. At the same age, several alterations in synaptophysin immunoreactivity were observed in cortico-hippocampal regions of APPswe mice that were partially counteracted by α4KO. The analysis of the immunoreactivity of specific astroglia (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule, Iba1) markers showed an increase in the number as well as in the area occupied by these cells in APPswe mice that were partially counteracted by α4KO. Overall, the present histological study points to a detrimental role of α4* nAChRs that may be specific for Aβ-related neuropathology.

Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy-number variations in S100B, a pro-inflammatory damage-associated molecular pattern (DAMP), have been associated with ASD, and increased serum S100B has been found in ASD. Interestingly, it has been shown that increased S100B levels affect zinc homeostasis in vitro. Thus, here, we investigated the influence of increased S100B levels in vitro and in vivo during pregnancy in mice regarding zinc availability, the zinc-sensitive SHANK protein networks associated with ASD, and behavioral outcomes. We observed that S100B affects the synaptic SHANK2 and SHANK3 levels in a zinc-dependent manner, especially early in neuronal development. Animals exposed to high S100B levels in utero similarly show reduced levels of free zinc and SHANK2 in the brain. On the behavioral level, these mice display hyperactivity, increased stereotypic and abnormal social behaviors, and cognitive impairment. Pro-inflammatory factors and zinc-signaling alterations converge on the synaptic level revealing a common pathomechanism that may mechanistically explain a large share of ASD cases.

Alzheimer's disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs induces neuroprotection in the early stages of AD. We investigated the neuroprotective role of MCs in two transgenic mouse models of severe AD using 5 and 7 month-old (mo) 5XFAD mice and 9 and 12 mo 3xTg mice. These mice were subjected to a chronic stimulation of MC receptors (MCRs) with MC analogue Nle4-D-Phe7-α-melanocyte stimulating hormone (NDP-α-MSH, 340 μg/kg, i.p.). Mouse behavior and ex-vivo histological and biochemical analyses were performed after 50 days of treatment. Our analysis demonstrated an improvement in cognitive abilities of AD mice at late stage of AD progression. We also showed that these protective effects are associated with decreased levels of hyperphosphorylated Tau but not with Aβ burden, that was unaffected in the hippocampus and in the cortex of AD mice. In addition, an age-dependent NDP effect on glial reactivity was observed only in 3xTg mice whereas a global downregulation of p38 mitogen-activated protein kinase was selectively observed in 7 mo 5XFAD and 14 mo 3xTg mice. Our results suggest that MCR stimulation by NDP-α-MSH could represent a promising therapeutic strategy in managing cognitive decline also at late stage of AD, whereas the effects on neuroinflammation may be restricted to specific stages of AD progression.

In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1–5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor–sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.

Non-destructive and rapid tools are required for predicting the optimum harvest window and for monitoring fruit quality during postharvest period. This study tested a portable, experimental visible/near-infrared (vis/NIR) spectrophotometer, more versatile and handy than traditional vis/NIR instruments, to measure phytonutrients active in human health and important in fruit storability. Parameters determining sensorial and quality properties of the fruit were also analyzed. The vis/NIR measurement was carried out in field using apples of “Golden Delicious” and “Stark Red Delicious” on tree. Calibration models were developed using PLS regression based on second derivative spectra. For “Golden Delicious” apple, the cross-validation R 2 for soluble solids content (SSC), chlorophyll, titratable acidity (TA), flesh firmness, total phenols, carotenoids, and ascorbic acid were 0.72, 0.86, 0.52, 0.44, 0.09, 0.77, and 0.50, respectively. The corresponding RMSECV were 0.78 °Brix, 0.50 nmol/cm 2 , 0.59 g/L, 6.08 N, 0.10 mg/g, 0.08 nmol/cm 2 , and 0.83 mg/100 g, respectively. For “Stark Red Delicious” similar calibration statistics were found for SSC, TA, flesh firmness, chlorophyll, and ascorbic acid content. A better calibration performance was achieved for total phenols, while for carotenoids it was less accurate. Cross-validation R 2 for “Stark Red Delicious” total anthocyanins, total flavonoids, and non-anthocyanic flavonoids were 0.67, 0.86, and 0.77, respectively. The corresponding RMSECV were 0.12, 0.14, and 0.15 mg/g, respectively. It was concluded that the portable vis/NIR instrument performed similarly to bench top or portable vis/NIR instruments reported in the literature.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener’s), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.