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We show that persons with spinal cord injury (SCI) retain decodable neural correlates of attempted arm and hand movements. We investigated hand open, palmar grasp, lateral grasp, pronation, and supination in 10 persons with cervical SCI. Discriminative movement information was provided by the time-domain of low-frequency electroencephalography (EEG) signals. Based on these signals, we obtained a maximum average classification accuracy of 45% (chance level was 20%) with respect to the five investigated classes. Pattern analysis indicates central motor areas as the origin of the discriminative signals. Furthermore, we introduce a proof-of-concept to classify movement attempts online in a closed loop, and tested it on a person with cervical SCI. We achieved here a modest classification performance of 68.4% with respect to palmar grasp vs hand open (chance level 50%).

Dissociative disorders are frequent and clinically relevant conditions in psychiatric populations. Yet, their recognition in clinical practice is often poor. This study evaluated the performance of three well known and internationally used dissociation scales in screening for dissociative disorders. Consecutively treated out- and day care-patients ( n  = 160) from several psychiatric units in Switzerland completed the Dissociative Experiences Scale (DES), Somatoform Dissociation Questionnaire (SDQ-20), and Multidimensional Inventory for Dissociation (MID). The Structured Clinical Interview for DSM-IV Dissociative Disorders-Revised (SCID-D-R) was then administered. Test performance of the scales was analyzed by receiver operating characteristic curves. The diagnostic accuracy, represented by the area under the curve, did not differ significantly between the three summary scales. Cut-off scores for detecting at least 80 % of any dissociative disorder and dissociative disorder-not-otherwise-specified/dissociative identity disorder, respectively, were 12 and 20 for the DES, 30 and 33 for the SDQ-20, and 28 and 28 for the MID summary scale. The diagnostic accuracy of the DES subscale ‘absorption’ and the MID subscale ‘somatic symptoms’ was equal or slightly lower than the corresponding summary scale. The DES, SDQ-20, and MID summary scales are suitable in screening for dissociative disorders in general psychiatric out- and day care-patients. Adequate cut-off scores in the German-adapted DES are lower than in non-German versions. Screening with the DES subscale ‘absorption’ and the MID subscale ‘somatic symptoms’ could be more efficient without the loss of diagnostic accuracy.

A BCI user awareness of an error is associated with a cortical signature named error-related potential (ErrP). The incorporation of ErrPs' detection in BCIs can improve BCIs' performance. This work is three-folded. First, we investigate if an ErrP classifier is transferable from able-bodied participants to participants with spinal cord injury (SCI). Second, we test this generic ErrP classifier with SCI and control participants, in an online experiment without offline calibration. Third, we investigate the morphology of ErrPs in both groups of participants. We used previously recorded electroencephalographic (EEG) data from able-bodied participants to train an ErrP classifier. We tested the classifier asynchronously, in an online experiment with 16 new participants: 8 participants with SCI and 8 able-bodied control participants. The experiment had no offline calibration and participants received feedback regarding the ErrPs' detection from its start. The generic classifier was not trained with the user's brain signals. Still, its performance was optimized during the online experiment with the use of personalized decision thresholds. Participants with SCI presented a non-homogenous ErrP morphology, and four of them did not present clear ErrP signals. The generic classifier performed above chance level in participants with clear ErrP signals, independently of the SCI (11 out of 16 participants). Three out of the five participants that obtained chance level results with the generic classifier would have not benefited from the use of a personalized classifier. This work shows the feasibility of transferring an ErrP classifier from able-bodied participants to participants with SCI, for asynchronous detection of ErrPs in an online experiment without offline calibration, which provided immediate feedback to the users.

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms 1 – 3 . However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease 4 – 6 . Synaptic signalling of upper-layer excitatory neurons—which are evolutionarily expanded in humans 7 and linked to cognitive function 8 —is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date. Single-nucleus transcriptomes of frontal cortex and choroid plexus samples from patients with COVID-19 reveal pathological cell states that are similar to those associated with human neurodegenerative diseases and chronic brain disorders.

While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.

Aging is a key risk factor for chronic diseases of the elderly. MicroRNAs regulate post-transcriptional gene silencing through base-pair binding on their target mRNAs. We identified nonlinear changes in age-related microRNAs by analyzing whole blood from 1334 healthy individuals. We observed a larger influence of the age as compared to the sex and provide evidence for a shift to the 5’ mature form of miRNAs in healthy aging. The addition of 3059 diseased patients uncovered pan-disease and disease-specific alterations in aging profiles. Disease biomarker sets for all diseases were different between young and old patients. Computational deconvolution of whole-blood miRNAs into blood cell types suggests that cell intrinsic gene expression changes may impart greater significance than cell abundance changes to the whole blood miRNA profile. Altogether, these data provide a foundation for understanding the relationship between healthy aging and disease, and for the development of age-specific disease biomarkers. Aging is a key risk factor for chronic diseases of the elderly. Here the authors perform large-scale miRNA profiling of blood from individuals of a range of ages and show that common diseases alter the physiological age-related blood microRNA profile.

Background Prostate cancer (PCa) is the second most common cancer affecting men globally, especially those aged 50 years and above. Despite substantial progress in terms of both prognosis and therapy, PCa remains a significant health concern, necessitating the identification of novel therapeutic targets. Innate lymphoid cells (ILCs) have emerged as critical modulators of tumor immunity, exhibiting both pro- and antitumoral effects. However, little is known yet about their contribution in PCa. This study investigated the phenotypic and functional profiles of ILC subsets in the peripheral blood mononuclear cells (PBMCs) of patients with PCa stratified by Gleason score. Methods PBMCs were isolated by Lymphoprep. ILC frequency and activity were evaluated by flow cytometry. The levels of ILC-activating cytokines were analyzed by multiplex assay in the serum of healthy donors (HDs) and patients with PCa. To evaluate the crosstalk between ILC2s and cancer cells, PC3 and DU145 human PCa cell lines were used. Results We found a stage-dependent increase in the protumoral ILC2 frequency and a concurrent decrease in antitumoral ILC1s in patients with PCa compared with healthy controls. Interestingly, the frequency of ILC2s was higher in patients with elevated prostate-specific antigen (PSA) values, suggesting their potential as molecular predictor for defining the risk category of patients with PCa at diagnosis. Importantly, patients with PCa exhibited hyperactivated ILC2s, characterized by elevated interleukin (IL)-13 and IL-5 production, while ILC1s displayed reduced tumor necrosis factor (TNF)-α and interferon (IFN)-γ secretion. Furthermore, serum levels of ILC2-activating cytokines IL-33, IL-18, and prostaglandin D2 (PGD2) were elevated in patients with PCa. In vitro co-culture experiments demonstrated that PCa cell lines, capable of secreting these cytokines, could directly enhance ILC2 activity. Likewise, ILC2-derived IL-13 promoted PCa cell migration and invasion. Conclusions Collectively, our findings highlight a dysregulated ILC profile in PCa, characterized by ILC2 dominance and heightened activity at the expense of ILC1s, suggesting both ILC1s and ILC2s as potential therapeutic targets for PCa treatment. Graphical Abstract

Treatment with plasma of an early developmental stage, human umbilical cord, revitalizes the hippocampus and improves cognitive function in aged mice. Human umbilical cord blood enhances cognition Aging leads to changes in cognitive function that can lead to neurological disorders. Tony Wyss-Coray and colleagues show that human umbilical cord plasma is able to revitalize the hippocampus and improve cognitive function in aged mice. They find that tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor, is enriched in human cord plasma, young mouse plasma and young mouse hippocampi. It enters the brain following systemic administration and is necessary for the cognitive benefits conferred by cord plasma. Systemic TIMP2 is also essential for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, suggesting that TIMP2 has a role in normal hippocampal function. Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation 1 , an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation 2 , 3 , 4 and downregulated in the aged brain 5 , 6 , 7 , 8 . In addition to revitalizing other aged tissues 9 , 10 , 11 , 12 , 13 , exposure to factors in young blood counteracts age-related changes in these central nervous system parameters 14 , 15 , 16 , although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown 17 . We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

Ageing is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death 1 . Despite rapid advances over recent years, many of the molecular and cellular processes that underlie the progressive loss of healthy physiology are poorly understood 2 . To gain a better insight into these processes, here we generate a single-cell transcriptomic atlas across the lifespan of Mus musculus that includes data from 23 tissues and organs. We found cell-specific changes occurring across multiple cell types and organs, as well as age-related changes in the cellular composition of different organs. Using single-cell transcriptomic data, we assessed cell-type-specific manifestations of different hallmarks of ageing—such as senescence 3 , genomic instability 4 and changes in the immune system 2 . This transcriptomic atlas—which we denote Tabula Muris Senis , or ‘Mouse Ageing Cell Atlas’—provides molecular information about how the most important hallmarks of ageing are reflected in a broad range of tissues and cell types. A single-cell transcriptomic atlas across the lifespan of the mouse, denoted Tabula Muris Senis , provides molecular information about the hallmarks of ageing in a range of tissues and cell types.

The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability 1 – 3 . Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins 4 , 5 . Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery. Tagging and tracking the blood plasma proteome as a discovery tool reveals widespread endogenous transport of proteins into the healthy brain and the pharmacologically modifiable mechanisms by which the brain endothelium regulates this process with age.