Nature Biomedical Engineering最新文献

The massive parallelization of neuronal intracellular recording, which enables the measurement of synaptic signals across a neuronal network, and thus the mapping and characterization of synaptic connections, is an open challenge, with the state of the art being limited to the mapping of about 300 synaptic connections. Here we report a 4,096 platinum/platinum-black microhole electrode array fabricated on a complementary metal-oxide semiconductor chip for parallel intracellular recording and thus for synaptic-connectivity mapping. The microhole–neuron interface, together with current-clamp electronics in the underlying semiconductor chip, allowed a 90% average intracellular coupling rate in rat neuronal cultures, generating network-wide intracellular-recording data with abundant synaptic signals. From these data, we extracted more than 70,000 plausible synaptic connections among more than 2,000 neurons and catalogued them into electrical synaptic connections and into inhibitory, weak/uneventful excitatory and strong/eventful excitatory chemical synaptic connections, with an estimated overall error rate of about 5%. This scale of synaptic-connectivity mapping and the ability to characterize synaptic connections is a step towards the functional connectivity mapping of large-scale neuronal networks.

The difficulty of delivering genes to the kidney has limited the translation of genetic medicines, particularly for the more than 10% of the global population with chronic kidney disease. Here we show that new variants of adeno-associated viruses (AAVs) displaying robust and widespread transduction in the kidneys of mice, pigs and non-human-primates can be obtained by evolving capsid libraries via cross-species cycling in different kidney models. Specifically, the new variants, AAV.k13 and AAV.k20, were enriched from the libraries following sequential intravenous cycling through mouse and pig kidneys, ex vivo cycling in human organoid cultures, and ex vivo machine perfusion in isolated kidneys from rhesus macaques. The two variants transduced murine kidneys following intravenous administration, with selective tropism for proximal tubules, and led to markedly higher transgene expression than parental AAV9 vectors in proximal tubule epithelial cells within human organoid cultures and in autotransplanted pig kidneys. Following ureteral delivery, AAV.k20 efficiently transduced kidneys in pigs and macaques. The AAV.k13 and AAV.k20 variants are promising vectors for therapeutic gene-transfer applications in kidney diseases and transplantation.

Correction to: Nature Biomedical Engineering https://doi.org/10.1038/s41551-024-01297-1, published online 6 December 2024.

The utility of urinary tests for the monitoring of the treatment efficacy and adverse events of anticancer therapies is constrained by the low concentration of relevant urinary biomarkers. Here we report, using mice with lung cancer and treated with chemotherapy, of a urinary fluorescence test for the concurrent monitoring of the levels of a tumour biomarker (cathepsin B) and of a biomarker of chemotherapy-induced kidney injury (N-acetyl-β-d-glucosaminidase). The test involves two intratracheally administered urinary reporters leveraging caged bioorthogonal click handles for the biomarker-dependent activation of ‘clickability’ and renal clearance, and the bioorthogonal click reaction of each renally cleared reporter with paired fluorescence indicators in the collected urine. In mouse models of chemotherapy-treated orthotopic lung cancer and of cisplatin-induced kidney injury, lower urinary fluorescence signals (which can be measured by a smartphone camera) for tumour and kidney injury levels positively correlated with animal weight gain and survival time. Biomarker-activated bioorthogonal click reactivity and renal clearance combined with bioorthogonally triggered fluorescence in vitro may enable specific, sensitive and rapid urinary assays for the monitoring of other physiopathological processes.

Correction to: Nature Biomedical Engineering https://doi.org/10.1038/s41551-024-01281-9, published online 11 November 2024.

Correction to: Nature Biomedical Engineering https://doi.org/10.1038/s41551-024-01313-4, published online 4 December 2024.