Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits.

Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.

The emergence of aspect-oriented programming (AOP) languages has provided software designers with new mechanisms and strategies for decomposing programs into modules and composing modules into systems. What we do not yet fully understand is how best to use such mechanisms consistent with common modularization objectives such as the comprehensibility of programming code, its parallel development, dependability, and ease of change. The main contribution of this work is a new form of information hiding interface for AOP that we call the crosscut programming interface, or XPI. XPIs abstract crosscutting behaviors and make these abstractions explicit. XPIs can be used, albeit with limited enforcement of interface rules, with existing AOP languages, such as AspectJ. To evaluate our notion of XPIs, we have applied our XPI-based design methodology to a medium-sized network overlay application called Hypercast. A qualitative and quantitative analysis of existing AO design methods and XPI-based design method shows that our approach produces improvements in program comprehensibility, in opportunities for parallel development, and in the ease with which code can be developed and changed.

Background On May 8, 2018, the China National Medical Products Administration (NMPA) approved anlotinib, an orally administered anti-angiogenesis inhibitor, for the treatment of patients with advanced non-small cell lung cancer (NSCLC) who have progressed after treatment with two or more lines of prior systemic chemotherapy. Main body of the abstract China NMPA reviewed and inspected a regional double-blinded, placebo-controlled, Phase III trial comparing the overall survival (OS) of NSCLC patients between the anlotinib and placebo arms. A total of 437 patients were randomized (2:1) to receive either anlotinib ( n = 294) or placebo ( n = 143) once daily on a 2-week on and 1-week off schedule. Patients with epidermal growth factor receptor ( EGFR ) or activating anaplastic lymphoma kinase ( ALK ) genomic tumor aberrations should have disease progression on NMPA-approved therapy. Anlotinib is the first NMPA-approved drug for patients with advanced NSCLC who have progressed on at least two lines of prior systemic chemotherapies in China. The approval was based on a statistically and clinically significant improvement in median OS with anlotinib (9.46 months) compared with placebo [6.37 months; hazard ratio (HR]) = 0.70, 95% confidence interval (CI) = 0.55–0.89; two-sided log-rank P = 0.002]. The confirmed objective response rate (ORR) was 9.2% in the anlotinib arm and 0.7% in the placebo arm. The median duration of response (DoR) was 4.83 months, with a 95% CI of 3.31–6.97 months. The toxicity profile of anlotinib was consistent with that of known anti-angiogenesis inhibitors. Common adverse drug reactions (ADRs) in anlotinib-treated patients included hypertension (67.4%), hand–foot syndrome (43.9%), hemoptysis (14.0%), thyroid stimulating hormone (TSH) elevation (46.6%), and corrected QT interval (QTc) prolongation (26.2%). Short conclusion Anlotinib demonstrated a clinically significant OS prolongation as a novel therapeutic option for advanced or metastatic NSCLC following at least two lines of chemotherapy.

The wide use and continuous abrasion of rubber-related products appears to be leading to an incredible release of p-phenylenediamine (PPD) antioxidants in the environment. However, no related research has been conducted on the pollution characteristics and potential health risks of PM 2.5 -bound PPDs. We report for the first time the ubiquitous distributions of six emerging PPDs and a quinone derivative, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPDQ), in PM 2.5 from urban areas of China. Atmospheric contamination levels of PM 2.5 -bound PPDs were found to be mostly in pg m −3 amounts between 2018 and 2019. Urban vehicle rubber tire abrasion was found to probably contribute to the PPDs in PM 2.5 and accounted for their significant spatiotemporaldependent concentration variations. Furthermore, 6PPDQ, an emerging oxidation product of 6PPD in the environment, was first quantified (pg m −3 ) with a total detection rate of 81% in the urban PM 2.5 , demonstrating its broad existence. On the basis of the determined ambient concentrations, the annual intakes of PPDs and 6PPDQ for adults were not low, indicating their possible human health risks induced by long-term exposure. This study confirms the widespread occurrence of PPDs and 6PPDQ in PM 2.5 , showing that the pollution of such compounds in urban air should not be underestimated.