MYC phase separation selectively modulates the transcriptome.

Dysregulation and enhanced expression of MYC transcription factors (TFs) including MYC and MYCN contribute to the majority of human cancers. For example, MYCN is amplified up to several hundredfold in high-risk neuroblastoma. The resulting overexpression of N-myc aberrantly activates genes that are not activated at low N-myc levels and drives cell proliferation. Whether increasing N-myc levels simply mediates binding to lower-affinity binding sites in the genome or fundamentally changes the activation process remains unclear. One such activation mechanism that could become important above threshold levels of N-myc is the formation of aberrant transcriptional condensates through phase separation. Phase separation has recently been linked to transcriptional regulation, but the extent to which it contributes to gene activation remains an open question. Here we characterized the phase behavior of N-myc and showed that it can form dynamic condensates that have transcriptional hallmarks. We tested the role of phase separation in N-myc-regulated transcription by using a chemogenetic tool that allowed us to compare non-phase-separated and phase-separated conditions at equivalent N-myc levels, both of which showed a strong impact on gene expression compared to no N-myc expression. Interestingly, we discovered that only a small percentage (<3%) of N-myc-regulated genes is further modulated by phase separation but that these events include the activation of key oncogenes and the repression of tumor suppressors. Indeed, phase separation increases cell proliferation, corroborating the biological effects of the transcriptional changes. However, our results also show that >97% of N-myc-regulated genes are not affected by N-myc phase separation, demonstrating that soluble complexes of TFs with the transcriptional machinery are sufficient to activate transcription.

A conserved molecular logic for neurogenesis to gliogenesis switch in the cerebral cortex.

During development, neural stem cells in the cerebral cortex, also known as radial glial cells (RGCs), generate excitatory neurons, followed by production of cortical macroglia and inhibitory neurons that migrate to the olfactory bulb (OB). Understanding the mechanisms for this lineage switch is fundamental for unraveling how proper numbers of diverse neuronal and glial cell types are controlled. We and others recently showed that Sonic Hedgehog (Shh) signaling promotes the cortical RGC lineage switch to generate cortical oligodendrocytes and OB interneurons. During this process, cortical RGCs generate intermediate progenitor cells that express critical gliogenesis genes Ascl1, Egfr, and Olig2. The increased Ascl1 expression and appearance of Egfr+ and Olig2+ cortical progenitors are concurrent with the switch from excitatory neurogenesis to gliogenesis and OB interneuron neurogenesis in the cortex. While Shh signaling promotes Olig2 expression in the developing spinal cord, the exact mechanism for this transcriptional regulation is not known. Furthermore, the transcriptional regulation of Olig2 and Egfr has not been explored. Here, we show that in cortical progenitor cells, multiple regulatory programs, including Pax6 and Gli3, prevent precocious expression of Olig2, a gene essential for production of cortical oligodendrocytes and astrocytes. We identify multiple enhancers that control Olig2 expression in cortical progenitors and show that the mechanisms for regulating Olig2 expression are conserved between the mouse and human. Our study reveals evolutionarily conserved regulatory logic controlling the lineage switch of cortical neural stem cells.

The development and the genetic diseases of the ciliary body.

The ciliary body, located at the junction of the choroid and iris, is crucial in the development of the embryonic eye. Notch2 signalling, Wnt signalling, transforming growth factor ß (TGF-ß) signalling, and Pax6 signalling are critical for coordinating the ciliary body formation. These signalling pathways are coordinated with each other and participate in the ciliary body development, ensuring the precise formation and optimal functioning of the eye structure. Although rare, ciliary body hypoplasia, ciliary tumours, and genetic-related iritis indicate the intricate nature of ciliary body development. Given the ciliary body's important biological significance and potential medical relevance, we aim to provide a comprehensive overview of the developmental molecular mechanisms governing ciliary body formation and function. Here, we focus on the intricate signalling pathways governing ciliary body development and corresponding genetic ciliary diseases.

RPGR is a guanine nucleotide exchange factor for the small GTPase RAB37 required for retinal function via autophagy regulation.

Although the small GTPase RAB37 acts as an organizer of autophagosome biogenesis, the upstream regulatory mechanism of autophagy via guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange in maintaining retinal function has not been determined. We found that retinitis pigmentosa GTPase regulator (RPGR) is a guanine nucleotide exchange factor that activates RAB37 by accelerating GDP-to-GTP exchange. RPGR directly interacts with RAB37 via the RPGR-RCC1-like domain to promote autophagy through stimulating exchange. Rpgr knockout (KO) in mice leads to photoreceptor degeneration owing to autophagy impairment in the retina. Notably, the retinopathy phenotypes of Rpgr KO retinas are rescued by the adeno-associated virus-mediated transfer of pre-trans-splicing molecules, which produce normal Rpgr mRNAs via trans-splicing in the Rpgr KO retinas. This rescue upregulates autophagy through the re-expression of RPGR in KO retinas to accelerate GDP-to-GTP exchange; thus, retinal homeostasis reverts to normal. Taken together, these findings provide an important missing link for coordinating RAB37 GDP-GTP exchange via the RPGR and retinal homeostasis by autophagy regulation.

Phase separation of YAP-MAML2 differentially regulates the transcriptome.

Phase separation (PS) drives the formation of biomolecular condensates that are emerging biological structures involved in diverse cellular processes. Recent studies have unveiled PS-induced formation of several transcriptional factor (TF) condensates that are transcriptionally active, but how strongly PS promotes gene activation remains unclear. Here, we show that the oncogenic TF fusion Yes-associated protein 1-Mastermind like transcriptional coactivator 2 (YAP-MAML2) undergoes PS and forms liquid-like condensates that bear the hallmarks of transcriptional activity. Furthermore, we examined the contribution of PS to YAP-MAML2-mediated gene expression by developing a chemogenetic tool that dissolves TF condensates, allowing us to compare phase-separated and non-phase-separated conditions at identical YAP-MAML2 protein levels. We found that a small fraction of YAP-MAML2-regulated genes is further affected by PS, which include the canonical YAP target genes CTGF and CYR61, and other oncogenes. On the other hand, majority of YAP-MAML2-regulated genes are not affected by PS, highlighting that transcription can be activated effectively by diffuse complexes of TFs with the transcriptional machinery. Our work opens new directions in understanding the role of PS in selective modulation of gene expression, suggesting differential roles of PS in biological processes.

Signatures of tumor-associated macrophages correlate with treatment response in ovarian cancer patients.

Ovarian cancer (OC) ranks as the second leading cause of death among gynecological cancers. Numerous studies have indicated a correlation between the tumor microenvironment (TME) and the clinical response to treatment in OC patients. Tumor-associated macrophages (TAMs), a crucial component of the TME, exert influence on invasion, metastasis, and recurrence in OC patients. To delve deeper into the role of TAMs in OC, this study conducted an extensive analysis of single-cell data from OC patients. The aim is to develop a new risk score (RS) to characterize the response to treatment in OC patients to inform clinical treatment. We first identified TAM-associated genes (TAMGs) in OC patients and examined the protein and mRNA expression levels of TAMGs by Western blot and PCR experiments. Additionally, a scoring system for TAMGs was constructed, successfully categorizing patients into high and low RS subgroups. Remarkably, significant disparities were observed in immune cell infiltration and immunotherapy response between the high and low RS subgroups. The findings revealed that patients in the high RS group had a poorer prognosis but displayed greater sensitivity to immunotherapy. Another important finding was that patients in the high RS subgroup had a higher IC50 for chemotherapeutic agents. Furthermore, further experimental investigations led to the discovery that THEMIS2 could serve as a potential target in OC patients and is associated with EMT (epithelial-mesenchymal transition). Overall, the TAMGs-based scoring system holds promise for screening patients who would benefit from therapy and provides valuable information for the clinical treatment of OC.

High-throughput PRIME-editing screens identify functional DNA variants in the human genome.

Despite tremendous progress in detecting DNA variants associated with human disease, interpreting their functional impact in a high-throughput and single-base resolution manner remains challenging. Here, we develop a pooled prime-editing screen method, PRIME, that can be applied to characterize thousands of coding and non-coding variants in a single experiment with high reproducibility. To showcase its applications, we first identified essential nucleotides for a 716 bp MYC enhancer via PRIME-mediated single-base resolution analysis. Next, we applied PRIME to functionally characterize 1,304 genome-wide association study (GWAS)-identified non-coding variants associated with breast cancer and 3,699 variants from ClinVar. We discovered that 103 non-coding variants and 156 variants of uncertain significance are functional via affecting cell fitness. Collectively, we demonstrate that PRIME is capable of characterizing genetic variants at single-base resolution and scale, advancing accurate genome annotation for disease risk prediction, diagnosis, and therapeutic target identification.

Accurate diagnosis of bronchopulmonary Talaromyces marneffei infection in an anti-IFN-γ autoantibodies positive patient assisted by endobronchial ultrasound-guided TBNA and mNGS: a case report.

RATIONALE: T. marneffei is opportunistic and dimorphic fungus, which can cause systemic mycosis in human beings. It's being difficult to obtain histopathological or microbiological evidence in T. marneffei infection. We reported a rare non-HIV case of T. marneffei infection of bronchopulmonary and mediastinal lymph nodes which was diagnosed by EBUS-TBNA combined with mNGS. The high titer of anti-IFN-γ autoantibodies in serum was probably the cause of T. marneffei infection,which has yet to be fully known. PATIENT CONCERNS: A 56-year-old Chinese man presented with a 5-month history of intermittent low or high fever and dry cough, followed by fatigue, night sweating, and chest pain when coughing. A large hilar lesion in the left lung and multiple mediastinal lymph node enlargements were found on his chest CT scan. DIAGNOSES: The patient received EBUS-TBNA of hilar tissue and lymph node biopsy for mNGS at the second Ultrasonic bronchoscopy. No fungal hyphae or spores were found in the histopathology. There were high sequencing reads of T. marneffei in samples of lymph node fluid and bronchogenesis tissue detected by mNGS. His plasma anti-IFN-γ autoantibodies level was positive with a high titer at 1:2500↑. INTERVENTION: The patient went through atrial fibrillation at the first dose of amphotericin B liposomes and treated with voriconazole later. OUTCOMES: His fever, cough and dyspnea quickly disappeared since the fourth day of treatment. After six months, there was not any focus in his chest CT scans. But his plasma anti-IFN-γ autoantibodies remained unchanged. LESSONS: Complementing the traditional laboratory and bronchoscopy, mNGS combined with EBUS-TBNA facilitate rapid and precise diagnosis of bronchopulmonary mediastinal lymph nodes T. marneffei infection. Clinicians should be aware of anti-INF-γ autoantibodies in opportunistic infections of non-HIV patients.

High throughput PRIME editing screens identify functional DNA variants in the human genome.

Despite tremendous progress in detecting DNA variants associated with human disease, interpreting their functional impact in a high-throughput and base-pair resolution manner remains challenging. Here, we develop a novel pooled prime editing screen method, PRIME, which can be applied to characterize thousands of coding and non-coding variants in a single experiment with high reproducibility. To showcase its applications, we first identified essential nucleotides for a 716 bp MYC enhancer via PRIME-mediated saturation mutagenesis. Next, we applied PRIME to functionally characterize 1,304 non-coding variants associated with breast cancer and 3,699 variants from ClinVar. We discovered that 103 non-coding variants and 156 variants of uncertain significance are functional via affecting cell fitness. Collectively, we demonstrate PRIME capable of characterizing genetic variants at base-pair resolution and scale, advancing accurate genome annotation for disease risk prediction, diagnosis, and therapeutic target identification.

Engineered Extracellular Vesicles for Delivery of an IL-1 Receptor Antagonist Promote Targeted Repair of Retinal Degeneration.

Retinal degeneration (RD) is an irreversible blinding disease that seriously affects patients' daily activities and mental health. Targeting hyperactivated microglia and regulating polarization are promising strategies for treating the disease. Mesenchymal stem cell (MSC) transplantation is proven to be an effective treatment due to its immunomodulatory and regenerative properties. However, the low efficiency of cell migration and integration of MSCs remains a major obstacle to clinical use. The goal of this study is to develop a nanodelivery system that targets hyperactivated microglia and inhibits their release of proinflammatory factors, to achieve durable neuroprotection. This approach is to engineer extracellular vesicles (EVs) isolated from MSC, modify them with a cyclic RGD (cRGD) peptide on their surface, and load them with an antagonist of the IL-1 receptor, anakinra. Comparing with non-engineered EVs, it is observed that engineered cRGD-EVs exhibit an increased targeting efficiency against hyperactivated microglia and strongly protected photoreceptors in experimental RD cells and animal models. This study provides a strategy to improve drug delivery to degenerated retinas and offers a promising approach to improve the treatment of RD through targeted modulation of the immune microenvironment via engineered cRGD-EVs.

Identifying TNF and IL6 as potential hub genes and targeted drugs associated with scleritis: A bio-informative report.

Background: Scleritis is a serious inflammatory eye disease that can lead to blindness. The etiology and pathogenesis of scleritis remain unclear, and increasing evidence indicates that some specific genes and proteins are involved. This study aimed to identify pivotal genes and drug targets for scleritis, thus providing new directions for the treatment of this disease. Methods: We screened candidate genes and proteins associated with scleritis by text-mining the PubMed database using Python, and assessed their functions by using the DAVID database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to identify the functional enrichment of these genes and proteins. Then, the hub genes were identified with CytoHubba and assessed by protein-protein interaction (PPI) network analysis. And the serum from patients with active scleritis and healthy subjects were used for the validation of hub genes. Finally, the DGIdb database was used to predict targeted drugs for the hub genes for treating scleritis. Results: A total of 56 genes and proteins were found to be linked to scleritis, and 65 significantly altered pathways were identified in the KEGG analysis (FDR < 0.05). Most of the top five pathways involved the categories "Rheumatoid arthritis," "Inflammatory bowel disease", "Type I diabetes mellitus," and "Graft-versus-host disease". TNF and IL6 were considered to be the top 2 hub genes through CytoHubba. Based on our serum samples, hub genes are expressed at high levels in active scleritis. Five scleritis-targeting drugs were found among 88 identified drugs. Conclusions: This study provides key genes and drug targets related to scleritis through bioinformatics analysis. TNF and IL6 are considered key mediators and possible drug targets of scleritis. Five drug candidates may play an important role in the diagnosis and treatment of scleritis in the future, which is worthy of the further experimental and clinical study.

Highly Efficient Photodynamic Therapy with Mitochondria-Targeting Aggregation-Induced Emission Photosensitizer for Retinoblastoma.

Retinoblastoma (RB) is an aggressive eye cancer in infancy and childhood, lethal by metastasis if left untreated. Currently, the survival rate and the chance of saving vision depend on the severity of the disease. In this work, a highly efficient photodynamic ophthalmic therapy for RB is reported by employing an isoquinolinium-based aggregation-induced-emission (AIE) photosensitizer (PS) TPE-IQ-2O for photodynamic inactivation (PDI). TPE-IQ-2O is an efficient mitochondria-targeting photosensitizer as an efficient guided photodynamic therapy (PDT) agent against cancer cells. Maximizing cancer-selectively damage to tumors with minimized side effects on normal tissue is essential for effective anticancer PDT and provides long-lasting protection against metastasis. In addition, TPE-IQ-2O can effectively reduce the degree of tissue inflammation by inhibiting the expression of related inflammatory factors. TPE-IQ-2O also exhibits excellent biocompatibility with a neglectable hemolysis effect on mouse red blood cells and almost no killing effect on mammalian cells, which enables its potential applications in the treatment of RB.

Application of SYNTAX and its Derivative Scores in the Selection of Revascularization Strategies for Complex Coronary Heart Disease.

Complex coronary heart disease (CHD) has become a hot spot in medicine due to its complex coronary anatomy, variable clinical factors, difficult hemodynamic reconstruction, and limited effect of conservative drug treatment. Identifying complex CHD and selecting optimal treatment methods have become more scientific as revascularization technology has improved, and coronary risk stratification scores have been introduced. SYNTAX and its derivative scores are decision-making tools that quantitatively describe the characteristics of coronary lesions in patients based on their complexity and severity. The SYNTAX and its derivative scores could assist clinicians in rationalizing the selection of hemodynamic reconstruction treatment strategies, and have demon-strated outstanding value in evaluating the prognosis of patients with complex CHD undergoing revascularization treatment. The authors in this article summary the practical application of SYNTAX and its derivative scores in complex CHD in order to deepen the understanding of the relationship between the choice of different revascularization strategies and SYNTAX and its derived scores in complex CHD and provide a further reference for clinical treatment of complex CHD.

The risk variant rs11836367 contributes to breast cancer onset and metastasis by attenuating Wnt signaling via regulating NTN4 expression.

Most genome-wide association study (GWAS)-identified breast cancer-associated causal variants remain uncharacterized. To provide a framework of understanding GWAS-identified variants to function, we performed a comprehensive study of noncoding regulatory variants at the NTN4 locus (12q22) and NTN4 gene in breast cancer etiology. We find that rs11836367 is the more likely causal variant, disrupting enhancer activity in both enhancer reporter assays and endogenous genome editing experiments. The protective T allele of rs11837367 increases the binding of GATA3 to the distal enhancer and up-regulates NTN4 expression. In addition, we demonstrate that loss of NTN4 gene in mice leads to tumor earlier onset, progression, and metastasis. We discover that NTN4, as a tumor suppressor, can attenuate the Wnt signaling pathway by directly binding to Wnt ligands. Our findings bridge the gaps among breast cancer-associated single-nucleotide polymorphisms, transcriptional regulation of NTN4, and breast cancer biology, which provides previously unidentified insights into breast cancer prediction and prevention.

Coordinated Transcriptional and Catabolic Programs Support Iron-Dependent Adaptation to RAS-MAPK Pathway Inhibition in Pancreatic Cancer.

The mechanisms underlying metabolic adaptation of pancreatic ductal adenocarcinoma (PDA) cells to pharmacologic inhibition of RAS-MAPK signaling are largely unknown. Using transcriptome and chromatin immunoprecipitation profiling of PDA cells treated with the MEK inhibitor (MEKi) trametinib, we identify transcriptional antagonism between c-MYC and the master transcription factors for lysosome gene expression, the MiT/TFE proteins. Under baseline conditions, c-MYC and MiT/TFE factors compete for binding to lysosome gene promoters to fine-tune gene expression. Treatment of PDA cells or patient organoids with MEKi leads to c-MYC downregulation and increased MiT/TFE-dependent lysosome biogenesis. Quantitative proteomics of immunopurified lysosomes uncovered reliance on ferritinophagy, the selective degradation of the iron storage complex ferritin, in MEKi-treated cells. Ferritinophagy promotes mitochondrial iron-sulfur cluster protein synthesis and enhanced mitochondrial respiration. Accordingly, suppressing iron utilization sensitizes PDA cells to MEKi, highlighting a critical and targetable reliance on lysosome-dependent iron supply during adaptation to KRAS-MAPK inhibition. SIGNIFICANCE: Reduced c-MYC levels following MAPK pathway suppression facilitate the upregulation of autophagy and lysosome biogenesis. Increased autophagy-lysosome activity is required for increased ferritinophagy-mediated iron supply, which supports mitochondrial respiration under therapy stress. Disruption of ferritinophagy synergizes with KRAS-MAPK inhibition and blocks PDA growth, thus highlighting a key targetable metabolic dependency. See related commentary by Jain and Amaravadi, p. 2023. See related article by Santana-Codina et al., p. 2180. This article is highlighted in the In This Issue feature, p. 2007.

Artificial Intelligence-Assisted Microcatheter Shaping for Intracranial Aneurysm Coiling: A Preliminary Study.

BACKGROUND: To evaluate the efficacy of artificial intelligence (AI) technology-assisted microcatheter shaping for coil embolization of intracranial aneurysms. METHODS: From June 2019 to May 2021, 30 aneurysms in 24 patients were treated with coiling embolization using computer software-assisted microcatheter shaping at our institution. All patients underwent digital subtraction angiography (DSA) before coiling embolization. After three-dimensional (3D) rotational angiography, digital imaging and communications in medicine (DICOM) data were extracted and imported into computer software based on an AI algorithm. 3D images of the parent artery and aneurysm were constructed with the software and data including the central axis of the parent artery, aneurysm location, aneurysm size, and 3D structure were automatically obtained. The optimal microcatheter path was calculated and the shape of the mandrel was automatically generated. Surgeons shaped the mandrel and microcatheter following the AI-generated template and completed the endovascular procedure. RESULTS: All patients successfully completed the endovascular procedure without perioperative complications. The microcatheters shaped as per the AI template accurately entered the aneurysm sacs in 1 attempt; 15 aneurysms required no microguidewire assistance in catheterizing the aneurysm sac and 15 did. The stability of the microcatheters during the procedures was satisfactory. No rebound incidence was observed and no reshaping was necessary. CONCLUSIONS: The AI-assisted microcatheter shaping technology provides a new method to generate the optimal shape for the mandrel and microcatheter during endovascular procedures. The technology facilitates microcatheter accuracy and stability during coiling embolization and provides technical support for surgeons.

Electrochemical detection of Sudan red series azo dyes: Bibliometrics based analysis.

Sudan red azo dyes are banned from food because of their carcinogenic properties. It is necessary to establish a method for the detection of Sudan azo dyes in food. Among them, electrochemical sensing technology has become a very potential analytical method for food detection because of its fast, sensitive and low price. In this paper, we analyze the electrochemical detection of Sudan red azo dyes by bibliometric method. A total of 161 articles were analyzed from 2007 to 2021. The geographical and institutional distribution of these papers is used to understand the form of collaboration on this topic. Keyword analysis in these papers is used to understand the different directions in which the topic is studied at different stages. The results show that the topic reached its peak in 2015. The development of novel materials with excellent electrochemical activity has promoted the research on this topic. As detection limits continue to be lowered and sensors continue to be optimized, this topic currently does not continue to attract much attention.

Application of interdisciplinary collaborative hospice care for terminal geriatric cancer patients: a prospective randomized controlled study.

BACKGROUND: Hospice care (HC) is specialized medical care for terminal patients who are nearing the end of life. Interdisciplinary collaborative hospice care (ICHC) is where experts from different disciplines and patients/caregivers form a treatment team to establish shared patient care goals. However, the ICHC efficacy has not been frequently studied in the terminal geriatric cancer patient (TGCP) population. This study aimed to gain insight into ICHC provided to TGCPs by an ICHC team and identify factors to ameliorate multidimensional HC. METHODS: 166 TGCPs were randomized by a computer-generated random number table using an allocation ratio of 1:1. The patients were divided into the ICHC group and life-sustaining treatment (LST) group. The scores of these questionnaires, such as EORTC, QLQ-C30, Hamilton anxiety scale, the median survival time (MST), symptoms improvement, the median average daily cost of drugs (MADDC), the median total cost of drugs (MTDC) in the last 2 days, and medical care satisfaction were observed in both groups. RESULTS: After treatment, the improvement of emotional function and symptoms in the ICHC group were statistically higher than those in the LST group (P < 0.05). The MADDC and the MTDC in the last 2 days were statistically lower in the ICHC group than those in the LSTs group (P < 0.01). In addition, the overall satisfaction situation and the cooperation ability in the ICHC group were statistically higher than those in the LST group (P < 0.01). CONCLUSION: The ICHC could provide TGCPs with coordinated, comfortable, high-quality, and humanistic care.

Accuracy, Sensitivity, and Specificity of the LLIS and ULL27 in Detecting Breast Cancer-Related Lymphedema.

INTRODUCTION: Breast cancer-related lymphedema occurs in up to 30% of women following axillary lymph node dissection (ALND) and less commonly following sentinel lymph node biopsy. To quantify disability in these patients, patient-reported outcome measures (PROMs) have proven useful; however, given the overlap of symptoms between ALND and lymphedema, examination of their accuracy, sensitivity, and specificity in detecting lymphedema in breast cancer patients undergoing ALND is needed. METHODS: The Lymphedema Life Impact Scale (LLIS) and the Upper Limb Lymphedema 27 scale (ULL27) were administered to patients who had undergone ALND at least 2 years prior and either did or did not develop lymphedema. Survey responses and the degree of disability were compared to generate receiver operator characteristic (ROC) curves, and the sensitivity and specificity of PROMs to diagnose lymphedema were analyzed. RESULTS: Both PROMs were highly accurate, sensitive, and specific for detecting lymphedema. The LLIS had an accuracy of 97%, sensitivity of 100%, and specificity of 84.8% at a cutoff of ≥ 5.88 overall percent impairment score (higher scores indicate worse disability). The ULL27 had an accuracy of 93%, sensitivity of 88.6%, and specificity of 90.9% at a cutoff of ≤ 83.3 global score (lower scores indicate worse disability). CONCLUSIONS: The LLIS and the ULL27 appear to be highly specific for lymphedema and capable of differentiating it from symptoms resulting from ALND alone. Our findings suggest that use of these questionnaires with a threshold may be effective for diagnosing lymphedema, potentially reducing the need for frequent clinic visits and time-consuming measurements.

Transcriptional network orchestrating regional patterning of cortical progenitors.

We uncovered a transcription factor (TF) network that regulates cortical regional patterning in radial glial stem cells. Screening the expression of hundreds of TFs in the developing mouse cortex identified 38 TFs that are expressed in gradients in the ventricular zone (VZ). We tested whether their cortical expression was altered in mutant mice with known patterning defects (Emx2, Nr2f1, and Pax6), which enabled us to define a cortical regionalization TF network (CRTFN). To identify genomic programming underlying this network, we performed TF ChIP-seq and chromatin-looping conformation to identify enhancer-gene interactions. To map enhancers involved in regional patterning of cortical progenitors, we performed assays for epigenomic marks and DNA accessibility in VZ cells purified from wild-type and patterning mutant mice. This integrated approach has identified a CRTFN and VZ enhancers involved in cortical regional patterning in the mouse.