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Pyramidal cells (PCs) form the backbone of the layered structure of the neocortex, and plasticity of their synapses is thought to underlie learning in the brain. However, such long-term synaptic changes have been experimentally characterized between only a few types of PCs, posing a significant barrier for studying neocortical learning mechanisms. Here we introduce a model of synaptic plasticity based on data-constrained postsynaptic calcium dynamics, and show in a neocortical microcircuit model that a single parameter set is sufficient to unify the available experimental findings on long-term potentiation (LTP) and long-term depression (LTD) of PC connections. In particular, we find that the diverse plasticity outcomes across the different PC types can be explained by cell-type-specific synaptic physiology, cell morphology and innervation patterns, without requiring type-specific plasticity. Generalizing the model to in vivo extracellular calcium concentrations, we predict qualitatively different plasticity dynamics from those observed in vitro. This work provides a first comprehensive null model for LTP/LTD between neocortical PC types in vivo, and an open framework for further developing models of cortical synaptic plasticity. The study of learning algorithms in the neocortex requires comprehensive knowledge of synaptic plasticity between its diverse cell types, which is currently lacking. Chindemi et al. describe a modeling approach to fill these gaps in experimental literature, and predict the features of synaptic plasticity in vivo.

Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here we introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, we delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury. Spatially selective and temporally controlled stimulation of the spinal cord, together with rehabilitation, results in substantial restoration of locomotor function in humans with spinal cord injury.

Epidural electrical stimulation (EES) targeting the dorsal roots of lumbosacral segments restores walking in people with spinal cord injury (SCI). However, EES is delivered with multielectrode paddle leads that were originally designed to target the dorsal column of the spinal cord. Here, we hypothesized that an arrangement of electrodes targeting the ensemble of dorsal roots involved in leg and trunk movements would result in superior efficacy, restoring more diverse motor activities after the most severe SCI. To test this hypothesis, we established a computational framework that informed the optimal arrangement of electrodes on a new paddle lead and guided its neurosurgical positioning. We also developed software supporting the rapid configuration of activity-specific stimulation programs that reproduced the natural activation of motor neurons underlying each activity. We tested these neurotechnologies in three individuals with complete sensorimotor paralysis as part of an ongoing clinical trial ( www.clinicaltrials.gov identifier NCT02936453). Within a single day, activity-specific stimulation programs enabled these three individuals to stand, walk, cycle, swim and control trunk movements. Neurorehabilitation mediated sufficient improvement to restore these activities in community settings, opening a realistic path to support everyday mobility with EES in people with SCI. Implantation of a multielectrode paddle that allows personalized electrical stimulation to all regions of the spinal cord involved in leg and trunk movements rapidly restores motor function in patients with spinal cord injury with complete paralysis.

No pharmacological therapy has been shown with certainty to improve the cardiovascular prognosis in patients with kidney failure on chronic haemodialysis. We aimed to investigate the effects of the steroidal mineralocorticoid receptor antagonist spironolactone on cardiovascular outcomes in patients on haemodialysis who are at high risk of cardiovascular events. ALCHEMIST was an investigator-initiated, multicentre, double-blind, randomised, placebo-controlled, event-driven trial conducted at 64 university hospitals, general hospitals, and non-profit or private practice dialysis centres in France, Belgium, and Monaco. Adult patients aged 18 years and older with kidney failure on chronic haemodialysis with at least one cardiovascular comorbidity or risk factor were enrolled into a 4-week run-in period on open-label oral spironolactone 25 mg every other day. Participants were randomly assigned (1:1) to oral spironolactone titrated to 25 mg per day or placebo. The randomisation sequence was computer generated and stratified by centre in blocks of 4 or 6, and permutation of treatments within each block. The random assignment was double-blinded. The primary endpoint was time to first major adverse cardiovascular event (cardiovascular death, non-fatal myocardial infarction, acute coronary syndrome, stroke, or hospitalisation for heart failure) and was analysed in the intention-to-treat population. We also performed an updated meta-analysis of double-blind, randomised controlled trials of mineralocorticoid receptor antagonists in patients on haemodialysis incorporating data from ALCHEMIST. The study was registered with ClinicalTrials.gov, NCT01848639. Between June 13, 2013, and Nov 24, 2020, 1442 patients were locally screened for eligibility. 823 patients were included in the trial and 794 entered the run-in period. 644 patients were randomly assigned to spironolactone (n=320) or placebo (n=324). 444 (69%) patients were men and 200 (31%) were women. The trial was stopped prematurely due to lack of funding from the sponsor. Median follow-up was 32·6 months (IQR 17·3–48·4). The primary endpoint occurred in 78 (24%) of 320 patients in the spironolactone group (10·66 per 100 patient-years [95% CI 8·54–13·31]) and 79 (24%) of 324 patients in the placebo group (10·70 per 100 patient-years [8·59–13·35]; hazard ratio [HR] 1·00 [95% CI 0·73–1·36]; p=0·98). Hyperkalaemia above 6 mmol/L was reported in 135 (42%) patients in the spironolactone group and 134 (41%) in the placebo group (HR 1·12 [95% CI 0·88–1·43]). In the meta-analysis, mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality or non-fatal cardiovascular events and did not increase the odds of hyperkalaemia events (serum potassium concentration >6 mmol/L). In patients with kidney failure on haemodialysis and with high risk of adverse cardiovascular outcomes, spironolactone did not reduce the incidence of major cardiovascular events. The updated meta-analysis shows that mineralocorticoid receptor antagonists did not reduce all-cause or cardiovascular mortality. Therefore, off-label use of spironolactone in this setting is not supported by available evidence. French Ministry of Health.

Bursts of activity in networks of neurons are thought to convey salient information and drive synaptic plasticity. Here we report that network bursts also exert a profound effect on Spike-Timing-Dependent Plasticity (STDP). In acute slices of juvenile rat somatosensory cortex we paired a network burst, which alone induced long-term depression (LTD), with STDP-induced long-term potentiation (LTP) and LTD. We observed that STDP-induced LTP was either unaffected, blocked or flipped into LTD by the network burst, and that STDP-induced LTD was either saturated or flipped into LTP, depending on the relative timing of the network burst with respect to spike coincidences of the STDP event. We hypothesized that network bursts flip STDP-induced LTP to LTD by depleting resources needed for LTP and therefore developed a resource-dependent STDP learning rule. In a model neural network under the influence of the proposed resource-dependent STDP rule, we found that excitatory synaptic coupling was homeostatically regulated to produce power law distributed burst amplitudes reflecting self-organized criticality, a state that ensures optimal information coding.

Long-term potentiation (LTP) and long-term depression (LTD) of pyramidal cell connections are among the key mechanisms underlying learning and memory in the brain. Despite their important role, only a few of these connections have been characterized in terms of LTP/LTD dynamics, such as the one between layer 5 thick-tufted pyramidal cells (L5-TTPCs). Comparing the available evidence on different pyramidal connection types reveals a large variability of experimental outcomes, possibly indicating the presence of connection-type-specific mechanisms. Here, we show that a calcium-based plasticity rule regulating L5-TTPC synapses holds also for several other pyramidal-to-pyramidal connections in a digital model of neocortical tissue. In particular, we show that synaptic physiology, cell morphology and innervation patterns jointly determine LTP/LTD dynamics without requiring a different model or parameter set for each connection type. We therefore propose that a similar set of plasticity mechanisms is shared by seemingly very different neocortical connections and that only a small number of targeted experiments is required for generating a complete map of synaptic plasticity dynamics int he neocortex. Competing Interest Statement The authors have declared no competing interest.

ObjectiveTo evaluate the value of synthetic magnetic resonance imaging (MRI) and T2 mapping in distinguishing between different types of fillers in soft tissues.Materials and methodsEx vivo fillers of buttock soft tissues (silicone, collagen, and different types of hyaluronic acid) were scanned using a synthetic MRI sequence at 1.5 and 3 T and an optimized T2 mapping sequence to measure the T2 relaxation times of the fillers ex vivo. Three patients addressed to assess complications with buttock fillers underwent MRI with the standard morphological sequences and an additional synthetic MRI sequence; T2 mapping was not performed for the patients. Two patients had silicone fillers, whereas the exact filler composition for the third patient was unknown.ResultsMeasurements of T1 and T2 relaxation times of ex vivo fillers at 1.5 and 3 T using synthetic MRI showed that the silicone, collagen, and hyaluronic acid had distinct relaxation time characteristics. In vivo, the synthetic MRI correctly identified silicone in the two patients with known silicone fillers, showing low T1 and T2 values, whereas in the third patient with an unknown filler type, the synthetic MRI suggested a collagen filler, with intermediate relaxation time values.ConclusionQuantitative sequences have the potential to differentiate between filler types in a noninvasive fashion.

Background: Paraneoplastic neurological syndromes (PNS) are defined by the presence of cancer and exclusion of other known causes of the neurological symptoms, but this criterion does not separate “true” PNS from neurological syndromes that are coincidental with a cancer. Objective: To provide more rigorous diagnostic criteria for PNS. Methods: An international panel of neurologists interested in PNS identified those defined as “classical” in previous studies. The panel reviewed the existing diagnostic criteria and recommended new criteria for those in whom no clinical consensus was reached in the past. The panel reviewed all reported onconeural antibodies and established the conditions to identify those that would be labelled as “well characterised”. The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study. Results: The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: “definite” and “possible”. Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of “classical” syndrome and “well characterised” onconeural antibody. Conclusions: The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases.

In Gram-negative bacteria and eukaryotic organelles, β-barrel proteins of the outer membrane protein 85-two-partner secretion B (Omp85-TpsB) superfamily are essential components of protein transport machineries. The TpsB transporter FhaC mediates the secretion of Bordetella pertussis filamentous hemagglutinin (FHA). We report the 3.15 Å crystal structure of FhaC. The transporter comprises a 16-stranded β barrel that is occluded by an N-terminal α helix and an extracellular loop and a periplasmic module composed of two aligned polypeptide-transport-associated (POTRA) domains. Functional data reveal that FHA binds to the POTRA 1 domain via its N-terminal domain and likely translocates the adhesin-repeated motifs in an extended hairpin conformation, with folding occurring at the cell surface. General features of the mechanism obtained here are likely to apply throughout the superfamily.

Francois Le Loarer, Franck Tirode and colleagues identify a new class of undifferentiated thoracic sarcomas characterized by inactivation of SMARCA4 , which encodes an ATPase subunit of BAF chromatin-remodeling complexes. They further show that these tumors exhibit transcriptional profiles similar to those of other BAF-deficient malignancies. While investigating cohorts of unclassified sarcomas by RNA sequencing, we identified 19 cases with inactivation of SMARCA4 , which encodes an ATPase subunit of BAF chromatin-remodeling complexes 1 , 2 . Clinically, the cases were all strikingly similar, presenting as compressive mediastino-pulmonary masses in 30- to 35-year-old adults with a median survival time of 7 months. To help define the nosological relationships of these tumors, we compared their transcriptomic profiles with those of SMARCA4 -mutated small-cell carcinomas of the ovary, hypercalcemic type (SCCOHTs) 3 , 4 , 5 , SMARCB1 -inactivated malignant rhabdoid tumors 6 (MRTs) and lung carcinomas (of which 10% display SMARCA4 mutations 7 ). Gene profiling analyses demonstrated that these tumors were distinct from lung carcinomas but related to MRTs and SCCOHTs. Transcriptome analyses, further validated by immunohistochemistry, highlighted strong expression of SOX2, a marker that supports the differential diagnosis of these tumors from SMARCA4 -deficient lung carcinomas. The prospective recruitment of cases confirmed this new category of 'SMARCA4-deficient thoracic sarcomas' as readily recognizable in clinical practice, providing opportunities to tailor their therapeutic management.