Picking a (neuroimmune) fight against fragile regulation of addiction.

T cells and their derived cytokines have been shown to modulate brain function. In this issue of Cell, Zhu, Yan, and colleagues demonstrate that opioid use impacts the crosstalk between the CNS and the peripheral immune system. Regulatory T cell (Treg)-derived IFN-γ signaling translates into synaptic weakening in the nucleus accumbens (NAc) to impart withdrawal-induced behavioral dysfunction.

The Neural Crest Pitches In to Remove Apoptotic Debris.

In this issue of Cell, Zhu et al. show that in the developing zebrafish, neural crest cells can act as professional phagocytes and directionally approach apoptotic cells to clear the larval nervous system from cell debris.

Tomato Multiomics Reveals Consequences of Crop Domestication and Improvement.

Genome-scale analyses of variation, gene expression, and metabolite accumulation in ancestral, early domesticates, and modern tomatoes by Zhu et al. identify genes underlying fruit chemistry and demonstrate that alleles affecting metabolic quality have been bred into modern varieties as a result of linkage drag. Similar metabolic hitchhikers are likely ubiquitous in other domesticated species.

Sunlight Brightens Learning and Memory.

Sunlight can alter mood, behavior, and cognition, but the cellular basis of this phenomenon remains to be fully elucidated. In this issue of Cell, Zhu et al. shed light on a UV-dependent metabolic pathway that leads to increased synaptic release of glutamate and enhanced motor learning and memory in mice.

An orphan no more: Nur77 senses cytosolic LPS.

Cytosolic LPS activates the NLRP3 inflammasome via a gasdermin D (GSDMD)-dependent mechanism. In this issue of Immunity, Zhu et al.1 provide insight into the events linking these two steps, identifying the orphan nuclear receptor Nur77 as a mediator of NLRP3 activation that senses LPS and GSDMD-dependent accumulation of cytosolic mtDNA.

Fragile-like regulatory T cells modulate opioid withdrawal in humans and mice.

Opioid use alters peripheral immune functions via unknown mechanisms. In a recent issue of Cell, Zhu et al. report increased fragile-like regulatory T cells in patients with opioid use disorder and in morphine-treated mice. In mice, Treg cell-derived interferon-γ within the brain promotes withdrawal-associated alterations in synapses.

Meet the authors: Ying Lu, Donghoon Lee, and Yanan Zhu.

We talk to co-first authors Donghoon Lee and Yanan Zhu and co-corresponding author Ying Lu about their paper "Molecular mechanism for activation of the 26S proteasome by ZFAND5" (this issue of Molecular Cell), the challenges of the project, their scientific pathways, and the late Dr. Alfred Goldberg.

Dual-specificity RNA aptamers: A sweet new tool for studying O-GlcNAc biology.

Zhu and Hart1 use dual-specificity RNA aptamers to recruit cellular O-GlcNAc transferase (OGT) and induce O-GlcNAc on target proteins like ß-catenin, revealing that O-GlcNAc stabilizes ß-catenin and enhances its transcriptional activity.

How the circadian nuclear orphan receptor REV-ERBα represses transcription: Temporal and spatial phase separation combined.

In this issue of Molecular Cell, Zhu et al.1 demonstrate that REV-ERBα and its co-repressor NCOR1 are assembled into daytime-dependent liquid droplets that constitute hubs in which the transcription of multiple REV-ERBα target genes is simultaneously repressed.

A no-Wnt situation for alveolar macrophage self-renewal.

Alveolar macrophages (AMs) are central to defense against respiratory pathogens. Impediments in restoring AMs after infection increase the risk for superinfection, which is associated with significant morbidity and mortality worldwide. In this issue of Immunity, Zhu et al. report a Wnt-ß-catenin-HIF-1α axis in AMs that promotes an inflammatory phenotype while restricting proliferation and self-renewal.

ecDNA party bus: Bringing the enhancer to you.

Recent work from Zhu et al. (2021) reveals that extrachromosomal DNA circles harboring enhancers can serve as mobile regulatory elements that interact with chromosomal oncogenes, stimulating high-level gene activity and contributing to tumor heterogeneity and cancer progression.

Closing the structure-to-function gap for LRRK2.

Variations in the LRRK2 gene represent one of the strongest genetic factors for Parkinson's disease (PD). It has become clear that structural knowledge of the encoded large multidomain LRRK2 protein will cast light on its biological function. The new study from Myasnikov, Zhu, et al. provides a high-resolution structure of the full-length LRRK2.

The Yolk Sac Feeds Pancreatic Tumors.

In this issue of Immunity, Zhu et al. (2017) report that tumor-associated macrophages in a mouse model of pancreatic ductal adenocarcinoma (PDAC) originate from both the yolk sac (YS) and bone marrow. Differential ablation of these populations indicates that only the YS-derived macrophages promote PDAC progression and growth.

Argonaute10 as a miRNA locker.

The stability and translation efficiency of many messenger RNAs is regulated by microRNAs (miRNAs), which exert their effects through associated Argonaute proteins. In this issue, Zhu, Zhang, and colleagues reveal that plants also exploit miRNA binding by Argonautes as a sequestering mechanism that prevents miRNAs from fulfilling their normal roles.

Shedding light on rechargeable Na/Cl2 battery.

Advancing new ideas of rechargeable batteries represents an important path to meeting the ever-increasing energy storage needs. Recently, we showed rechargeable sodium/chlorine (Na/Cl2) (or lithium/chlorine Li/Cl2) batteries that used a Na (or Li) metal negative electrode, a microporous amorphous carbon nanosphere (aCNS) positive electrode, and an electrolyte containing dissolved aluminum chloride and fluoride additives in thionyl chloride [G. Zhu et al., Nature 596, 525-530 (2021) and G. Zhu et al., J. Am. Chem. Soc. 144, 22505-22513 (2022)]. The main battery redox reaction involved conversion between NaCl and Cl2 trapped in the carbon positive electrode, delivering a cyclable capacity of up to 1,200 mAh g-1 (based on positive electrode mass) at a ~3.5 V discharge voltage [G. Zhu et al., Nature 596, 525-530 (2021) and G. Zhu et al., J. Am. Chem. Soc. 144, 22505-22513 (2022)]. Here, we identified by X-ray photoelectron spectroscopy (XPS) that upon charging a Na/Cl2 battery, chlorination of carbon in the positive electrode occurred to form carbon-chlorine (C-Cl) accompanied by molecular Cl2 infiltrating the porous aCNS, consistent with Cl2 probed by mass spectrometry. Synchrotron X-ray diffraction observed the development of graphitic ordering in the initially amorphous aCNS under battery charging when the carbon matrix was oxidized/chlorinated and infiltrated with Cl2. The C-Cl, Cl2 species and graphitic ordering were reversible upon discharge, accompanied by NaCl formation. The results revealed redox conversion between NaCl and Cl2, reversible graphitic ordering/amorphourization of carbon through battery charge/discharge, and probed trapped Cl2 in porous carbon by XPS.

Mycobiota dysbiosis: a new nexus in intestinal tumorigenesis.

While there is growing evidence that perturbation of the gut microbiota can result in a variety of pathologies including gut tumorigenesis, the influence of commensal fungi remains less clear. In this issue, Zhu et al (2021) show that mycobiota dysbiosis stimulates energy metabolism changes in subepithelial macrophages promoting colon cancer via enhancing innate lymphoid cell activity. These findings provide insights into a role of the gut flora in intestinal carcinogenesis and suggest opportunities for adjunctive antifungal or immunotherapeutic strategies to prevent colorectal cancer.

A hybrid constrained continuous optimization approach for optimal causal discovery from biological data.

MOTIVATION: Understanding causal effects is a fundamental goal of science and underpins our ability to make accurate predictions in unseen settings and conditions. While direct experimentation is the gold standard for measuring and validating causal effects, the field of causal graph theory offers a tantalizing alternative: extracting causal insights from observational data. Theoretical analysis has shown that this is indeed possible, given a large dataset and if certain conditions are met. However, biological datasets, frequently, do not meet such requirements but evaluation of causal discovery algorithms is typically performed on synthetic datasets, which they meet all requirements. Thus, real-life datasets are needed, in which the causal truth is reasonably known. In this work we first construct such a large-scale real-life dataset and then we perform on it a comprehensive benchmarking of various causal discovery methods. RESULTS: We find that the PC algorithm is particularly accurate at estimating causal structure, including the causal direction which is critical for biological applicability. However, PC does only produces cause-effect directionality, but not estimates of causal effects. We propose PC-NOTEARS (PCnt), a hybrid solution, which includes the PC output as an additional constraint inside the NOTEARS optimization. This approach combines PC algorithm's strengths in graph structure prediction with the NOTEARS continuous optimization to estimate causal effects accurately. PCnt achieved best aggregate performance across all structural and effect size metrics. AVAILABILITY AND IMPLEMENTATION: https://github.com/zhu-yh1/PC-NOTEARS.

In search of the mechanism that shapes the neutrophil's nucleus.

The organization of the genome within the confines of the nuclear compartment is considered a key contributor to transcription and DNA replication, repair, and recombination. A typical higher eukaryotic cell has a spherical nucleus that is ∼10 µm in diameter. This is not the case for a neutrophil, a short-lived innate immune cell with an unusual multilobular nuclear structure that may serve purposes outside nuclear functions. In this issue of Genes & Development, Zhu and colleagues (pp. 141-153) investigate the neutrophil's genome organization and the mechanisms that contribute to its unique nuclear shape.

Retraction: "Long noncoding RNA ITGB2-AS1 promotes growth and metastasis through miR-4319/RAF1 axis in pancreatic ductal adenocarcinoma".

Retraction: "Long noncoding RNA ITGB2-AS1 promotes growth and metastasis through miR-4319/RAF1 axis in pancreatic ductal adenocarcinoma" by Ming Yang, Qi Qin, Junling Zhu, Yao Guo, Tao Yin, Heshui Wu, Chunyou Wang, J Cell Physiol 2020; 10.1002/jcp.29471. The above article, published online on 20 January 2020 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jcp.29471) has been retracted by agreement between the authors, the journal's Editors in Chief, Alexander Hutchison, and Wiley Periodicals LLC. The retraction has been agreed due to concerns related to the data presented in the article. Several flaws and inconsistencies between results presented and experimental methods described were found. Additionally, some figure elements have been published elsewhere in a different scientific context. Thus, the conclusions of this article are considered to be invalid by the editors.

RETRACTION: Downregulation of microRNA-23b Protects Against Ischemia-Reperfusion Injury via p53 Signaling Pathway by Upregulating MDM4 in Rats.

RETRACTION: Z. Zhao, J.-Z. Guan, M. Wu, G.-H. Lai, and Z.-L. Zhu. Downregulation of microRNA-23b Protects Against Ischemia-Reperfusion Injury via p53 Signaling Pathway by Upregulating MDM4 in Rats. Journal of Cellular Biochemistry 120, no. 3 (2019): 4599-4612, https://doi.org/10.1002/jcb.27748. The above article, published online on 9 December 2018 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Christian Behl; and Wiley Periodicals LLC. The retraction has been agreed due to concerns raised by third parties on the data presented in the article. Several flaws and inconsistencies between results presented and experimental methods described were found. Furthermore, the same sample used to depict the immunofluorescence staining in Figure 5B was found to have been used in a different scientific context in a previous publication from a different author group. Thus, the editors consider the conclusions of this article to be invalid.