This paper presents an Internet-of-Things software infrastructure that enables energy management and simulation of new control policies in a city district. The proposed platform enables the interoperability and the correlation of (near-)real-time building energy profiles with environmental data from sensors as well as building and grid models. In a smart city context, this platform fulfills 1) the integration of heterogeneous data sources at the building and district level, and 2) the simulation of novel energy policies at the district level aimed at the optimization of the energy usage accounting also for its impact on building comfort. The platform has been deployed in a real-world district and a novel control policy for the heating distribution network has been developed and tested. Results are presented and discussed in the paper.

We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.

Long-range enhancers govern the temporal and spatial control of gene expression; however, the mechanisms that regulate enhancer activity during normal and malignant development remain poorly understood. Here, we demonstrate a role for aberrant chromatin accessibility in the regulation of MYC expression in T-cell lymphoblastic leukemia (T-ALL). Central to this process, the NOTCH1-MYC enhancer (N-Me), a long-range T cell–specific MYC enhancer, shows dynamic changes in chromatin accessibility during T-cell specification and maturation and an aberrant high degree of chromatin accessibility in mouse and human T-ALL cells. Mechanistically, we demonstrate that GATA3-driven nucleosome eviction dynamically modulates N-Me enhancer activity and is strictly required for NOTCH1-induced T-ALL initiation and maintenance. These results directly implicate aberrant regulation of chromatin accessibility at oncogenic enhancers as a mechanism of leukemic transformation. Significance: MYC is a major effector of NOTCH1 oncogenic programs in T-ALL. Here, we show a major role for GATA3-mediated enhancer nucleosome eviction as a driver of MYC expression and leukemic transformation. These results support the role of aberrant chromatin accessibility and consequent oncogenic MYC enhancer activation in NOTCH1-induced T-ALL. This article is highlighted in the In This Issue feature, p. 1631

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from seventeen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, Hi-C, and karyotyping. These data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. We expect these data to facilitate innovation for whole genome measurement technologies, de novo assembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic variants. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.

Children and adults with 22q11.2 deletion syndrome (22q11.2DS) experience cognitive and emotional challenges and face a markedly increased risk for schizophrenia (SCZ), yet how this deletion alters early human brain development remains unclear. Using cerebral cortex organoids derived from individuals with 22q11.2DS and SCZ, we identify cell-type-specific developmental abnormalities. Single-cell RNA sequencing and experimental validation reveal delayed cortical neuron maturation, with increased neural progenitor proliferation and a reduced proportion of more mature neurons. We observe disrupted molecular programs linked to neuronal maturation, sparser neurites, and blunted glutamate-induced Ca²⁺ responses. The aberrant transcriptional profile is enriched for neuropsychiatric risk genes. MicroRNA profiling suggests that DGCR8 haploinsufficiency contributes to these effects via dysregulation of genes that control the pace of maturation. Protein-protein interaction network analysis highlights complementary roles for additional deleted genes. Our study reveals consistent developmental and molecular defects caused by 22q11.2 deletions, offering insights into disease mechanisms and therapeutic strategies.