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BackgroundChimeric Antigen Receptor (CAR) T cell therapies are innovative treatments against hematological malignancies, with increasing therapeutic indications. Despite their great efficacy, these therapies are hampered by high rates of neurotoxicity (immune effector cell–associated neurotoxicity (ICANS)). In the past few years, several risk factors have been associated with ICANS and grouped together in the attempt to build validated models able to predict neurologic complications. However, little is known about pre-existing neurologic conditions possibly related to the development of neurotoxicity.Methods and resultsIn our case series, including sixteen consecutive patients treated with CAR T cells, we observed that (i) neurotoxicity only occurred in the two patients who presented subtle clinical signs of frontal lobe impairment at baseline and (ii) neurologic manifestations of ICANS consisted of language disturbances and cortical frontal myoclonus, which were both manifestations of a frontal predominant dysfunction.DiscussionBased on our experience, we suggest that a pre-existing frontal lobe impairment, even if at a subclinical level, may eventually drive to ICANS, which in turn shows symptoms compatible with a frontal encephalopathy. It is remarkable that this focal neurotoxicity involved the same CNS regions that were responsible of subtle neurological signs at baseline. Future studies on larger numbers of patients are needed to confirm the possible role of baseline frontal lobe dysfunction as a predictor of ICANS, in order to enhance efforts to safely deliver CAR T cell therapy.

Short- and medium-term cardio-pulmonary sequelae after COVID-19 have been extensively studied. However, studies with longer follow-ups are required. This study aims to identify and characterise cardio-pulmonary sequelae, in patients hospitalised for SARS-CoV-2 pneumonia, at 24 months follow-up. This is a prospective, observational cohort study conducted on consecutive patients hospitalised for COVID-19 and acute respiratory failure. Patients were followed up at 24 months with complete pulmonary function tests (PFTs), 6-min walking test and a dyspnoea score (Modified Medical Research Council scale). A subgroup of patients with at least one clinical or functional sign suggestive of increased pulmonary pressures also underwent transthoracic echocardiography (TTE) to evaluate the presence of direct or indirect signs of pulmonary hypertension (PH). Ninety consecutive patients (74% men, median age 59.1 years) were enrolled in the study. In regard to PFTs, carbon monoxide diffusion capacity (DLCO) impairment was observed in 23 cases (26%), in all cases of mild entity. When considering the dyspnoea, 30 (34%) patients showed some degree of breathlessness. Forty patients underwent TTE. No patients had overt PH or chronic thromboembolic PH. However, all patients showed a hyperdynamic state of the right ventricle, and 8 (20%) patients had a decreased acceleration time on pulmonary valve, signs of increased pulmonary vasculature resistances and afterload elevation. At 24-month follow-up after severe COVID-19, DLCO and TTE prove to be the most sensitive tool to detect cardio-pulmonary sequelae. Dyspnoea is still present in about one-third of patients and requires a multidisciplinary approach.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a disorder mediated by autoantibodies against the GluN1 subunit of NMDAR. It occurs with severe neuropsychiatric symptoms that often improve with immunotherapy. Clinical studies and animal models based on patients’ antibody transfer or NMDAR immunization suggest that the autoantibodies play a major pathogenic role. Yet, there is an important need of models offering an all-inclusive neuro-immunobiology of the disease together with a clinical course long enough to facilitate the assessment of potential new treatments. Toward this end, eight-week-old female mice (C57BL/6J) were immunized (days 1 and 28) with GluN1356-385 peptide or saline with AddaVax adjuvant and pertussis toxin. After symptom development (∼day 35), subsets of mice were treated with an anti-CD20 (day 35), a positive allosteric modulator (PAM) of NMDAR (NMDAR-PAM, SGE-301) from days 45 to 71, or both. GluN1-antibody synthesis, epitope spreading, effects of antibodies on density and function of NMDAR, brain immunological infiltrates, microglial activation and NMDAR phagocytosis, and antibody synthesis in cultured inguinal and deep cervical lymph nodes (DCLN) were assessed with techniques including immunohistochemistry, calcium imaging, confocal and super-resolution microscopy, electrophysiology, or flow cytometry. Changes of memory and behaviour were assessed with a panel of behavioural tests, and clinical/subclinical seizures with brain-implanted electrodes. Immunized mice, but not controls, developed serum and CSF NMDAR-antibodies (IgG1 predominant) against the immunizing peptide and other GluN1 regions (epitope spreading) resulting in a decrease of synaptic and extrasynaptic NMDAR clusters and reduction of hippocampal plasticity. These findings were associated with brain inflammatory infiltrates, mainly B- and plasma cells, microglial activation, colocalization of NMDAR-IgG complexes with microglia, and presence of these complexes within microglial endosomes. Cultures of DCLC showed GluN1-antibody production. These findings were associated with psychotic-like behaviour (predominant at disease onset), memory deficit, depressive-like behaviour, abnormal movements (15% of mice), and lower threshold for developing pentylenetetrazole-induced seizures (hypoactivity, myoclonic jerks, continuous tonic-clonic) which correlated with regional cFOS expression. Most symptoms and neurobiological alterations were reversed by the anti-CD20 and PAM, alone or combined. Initial repopulation of B cells, by the end of the study, was associated with re-emergence of clinical-neurobiological alterations, which were abrogated by PAM. Overall, this model offers an all-inclusive neuro-immunobiology of the disease, allowing testing novel treatments, supporting the potential therapeutic role of NMDAR-PAM, and suggesting an immunological paradigm of systemic antigen presentation and brain NMDAR epitope spreading, which along the DCLN might contribute to fine-tune the polyclonal immune response.

Besides causing financial losses and damage to the brand’s reputation, counterfeiting can threaten the health system and global security. In this context, physical unclonable functions (PUFs) have been proposed to overcome limitations of current anti-counterfeiting technologies. Here, we report on artificial fingerprints that can be directly engraved on a wide range of substrates through self-assembled block-copolymer templating as nanoscale PUFs for secure authentication and identification. Results show that morphological features can be exploited to encode fingerprint-like nanopatterns in binary code matrices representing a unique bit stream of information characterized by high uniqueness and entropy. A strategy based on computer vision concepts for authentication/identification in real-world scenarios is reported. Long-term reliable operation and robust authentication/identification against thermal treatment at cryogenic and high temperatures of the PUF have been demonstrated. These results pave the way for the realization of PUFs embracing the inherent stochasticity of self-assembled materials at the nanoscale. Physical unclonable functions have been proposed to overcome limitations of current anti-counterfeiting technologies. Here, the authors report the development of nanoscale artificial fingerprints as physical unclonable functions for secure authentication and identification.

Modern computation based on von Neumann architecture is now a mature cutting-edge science. In the von Neumann architecture, processing and memory units are implemented as separate blocks interchanging data intensively and continuously. This data transfer is responsible for a large part of the power consumption. The next generation computer technology is expected to solve problems at the exascale with 10 18 calculations each second. Even though these future computers will be incredibly powerful, if they are based on von Neumann type architectures, they will consume between 20 and 30 megawatts of power and will not have intrinsic physically built-in capabilities to learn or deal with complex data as our brain does. These needs can be addressed by neuromorphic computing systems which are inspired by the biological concepts of the human brain. This new generation of computers has the potential to be used for the storage and processing of large amounts of digital information with much lower power consumption than conventional processors. Among their potential future applications, an important niche is moving the control from data centers to edge devices. The aim of this roadmap is to present a snapshot of the present state of neuromorphic technology and provide an opinion on the challenges and opportunities that the future holds in the major areas of neuromorphic technology, namely materials, devices, neuromorphic circuits, neuromorphic algorithms, applications, and ethics. The roadmap is a collection of perspectives where leading researchers in the neuromorphic community provide their own view about the current state and the future challenges for each research area. We hope that this roadmap will be a useful resource by providing a concise yet comprehensive introduction to readers outside this field, for those who are just entering the field, as well as providing future perspectives for those who are well established in the neuromorphic computing community.

Network alignment is a fundamental task in network analysis. In the biological field, where the protein–protein interaction (PPI) is represented as a graph, network alignment allowed the discovery of underlying biological knowledge such as conserved evolutionary pathways and functionally conserved proteins throughout different species. A recent trend in network science concerns network embedding, i.e., the modelling of nodes in a network as a low-dimensional feature vector. In this survey, we present an overview of current PPI network embedding alignment methods, a comparison among them, and a comparison to classical PPI network alignment algorithms. The results of this comparison highlight that: (i) only five network embeddings for network alignment algorithms have been applied in the biological context, whereas the literature presents several classical network alignment algorithms; (ii) there is a need for developing an evaluation framework that may enable a unified comparison between different algorithms; (iii) the majority of the proposed algorithms perform network embedding through matrix factorization-based techniques; (iv) three out of five algorithms leverage external biological resources, while the remaining two are designed for domain agnostic network alignment and tested on PPI networks; (v) two algorithms out of three are stated to perform multi-network alignment, while the remaining perform pairwise network alignment.

The short-lived turquoise killifish Nothobranchius furzeri (Nfu) is a valid model for aging studies. Here, we investigated its age-associated cardiac function. We observed oxidative stress accumulation and an engagement of microRNAs (miRNAs) in the aging heart. MiRNA-sequencing of 5 week (young), 12–21 week (adult) and 28–40 week (old) Nfu hearts revealed 23 up-regulated and 18 down-regulated miRNAs with age. MiR-29 family turned out as one of the most up-regulated miRNAs during aging. MiR-29 family increase induces a decrease of known targets like collagens and DNA methyl transferases (DNMTs) paralleled by 5´methyl-cytosine (5mC) level decrease. To further investigate miR-29 family role in the fish heart we generated a transgenic zebrafish model where miR-29 was knocked-down. In this model we found significant morphological and functional cardiac alterations and an impairment of oxygen dependent pathways by transcriptome analysis leading to hypoxic marker up-regulation. To get insights the possible hypoxic regulation of miR-29 family, we exposed human cardiac fibroblasts to 1% O 2 levels. In hypoxic condition we found miR-29 down-modulation responsible for the accumulation of collagens and 5mC. Overall, our data suggest that miR-29 family up-regulation might represent an endogenous mechanism aimed at ameliorating the age-dependent cardiac damage leading to hypertrophy and fibrosis.

Sarcomas are rare, mesenchymal tumors, representing about 10–15% of all childhood cancers. GD2 is a suitable target for chimeric antigen receptor (CAR) T-cell therapy due to its overexpression in several solid tumors. In this preclinical study, we investigated the potential use of iCasp9.2A.GD2.CAR-CD28.4–1BBζ (CAR.GD2) T-cells as a treatment option for patients who have GD2-positive sarcomas and we sought to identify factors shaping hostile tumor microenvironment in this setting. GD2 expression was evaluated by flow-cytometry on primary tumor biopsies of pediatric sarcoma patients. GD2 expression in sarcoma cells was also evaluated in response to an enhancer of zeste homolog 2 (EZH2) inhibitor (Tazemetostat). The antitumor activity of CAR.GD2 T-cells was evaluated both in vitro and in vivo preclinical models of orthotopic and/or metastatic soft-tissue and bone sarcomas. GD2 expression was detected in 55% of the primary tumors. Notably, the Osteosarcoma and Alveolar Rhabdomyosarcomas subtypes exhibited the highest GD2 expression levels, while Ewing sarcoma showed the lowest. CAR.GD2 T-cells show a significant tumor control both in vitro and in vivo models of GD2-expressing tumors. Pretreatment with an EZH2 inhibitor (Tazemetostat) upregulating GD2 expression, sensitizes GD2 dim sarcoma cells to CAR.GD2 T-cells cytotoxic activity. Moreover, in mouse models of disseminated Rhabdomyosarcomas and orthotopic Osteosarcoma, CAR.GD2 T-cells showed both a vigorous anti-tumor activity and long-term persistence as compared to un-transduced T-cells. The presence of immunosuppressive murine myeloid-derived suppressor (MDSC) cells significantly reduces long-term anti-tumour activity of infused CAR.GD2 T-cells. Tumor-derived G-CSF was found to be one of the key factors driving expansion of immunosuppressive murine and human MDSC, thus indirectly limiting the efficacy of CAR.GD2 T-cells. Our preclinical data strongly suggest that CAR.GD2 T-cells hold promise as a potential therapeutic option for the treatment of patients with GD2-positive sarcomas. Strategies to tackle hostile immunosuppressive MDSC are desirable to optimize CAR.GD2 T-cell activity.