Wang Etal Research Articles

Translating while under attack: Plant defense mRNAs find a way

In plants, pattern-triggered immunity shuts down global translation while allowing the translation of defense mRNAs. Wang etal. (2022) describe a previously unknown mechanism for how elements in the 5' UTR of these mRNAs can recruit the translation machinery to initiate protein synthesis.

The Warburg effect: Saturation of mitochondrial NADH shuttles triggers aerobic lactate fermentation

In this issue of Molecular Cell, Wang etal. investigate the Warburg effect in proliferating cells and demonstrate that lactate fermentation is a secondary mechanism activated after mitochondrial shuttles exceed their capacity to oxidize cytosolic NADH.

ErbB4+ spinal cord dorsal horn neurons process heat pain

How the spinal cord transmits heat signals from the periphery to the brain remains unclear. In this issue of Neuron, Wang etal. (2022) identify a population of spinal cord neurons functioning in this pathway.

Robust approach to combining multiple markers to improve surrogacy.

Identifying effective and valid surrogate markers to make inference about a treatment effect on long-term outcomes is an important step in improving the efficiency of clinical trials. Replacing a long-term outcome with short-term and/or cheaper surrogate markers can potentially shorten study duration and reduce trial costs. There is sizable statistical literature on methods to quantify the effectiveness of a single surrogate marker. Both parametric and nonparametric approaches have been well developed for different outcome types. However, when there are multiple markers available, methods for combining markers to construct a composite marker with improved surrogacy remain limited. In this paper, building on top of the optimal transformation framework of Wang etal. (2020), we propose a novel calibrated model fusion approach to optimally combine multiple markers to improve surrogacy. Specifically, we obtain two initial estimates of optimal composite scores of the markers based on two sets of models with one set approximating the underlying data distribution and the other directly approximating the optimal transformation function. We then estimate an optimal calibrated combination of the two estimated scores which ensures both validity of the final combined score and optimality with respect to the proportion of treatment effect explained by the final combined score. This approach is unique in that it identifies an optimal combination of the multiple surrogates without strictly relying on parametric assumptions while borrowing modeling strategies to avoid fully nonparametric estimation which is subject to the curse of dimensionality. Our identified optimal transformation can also be used to directly quantify the surrogacy of this identified combined score. Theoretical properties of the proposed estimators are derived, and the finite sample performance of the proposed method is evaluated through simulation studies. We further illustrate the proposed method using data from the Diabetes Prevention Programstudy.

Successful organoid-mediated generation of iPSC-derived CAR-T cells.

Artificial thymic organoids (ATOs) allow the selective differentiation of chimeric antigen receptor (CAR)-transduced human iPSCs into CAR-T cells. In this issue of Cell Stem Cell, Wang etal. now use ATOs to produce human CD19+ CAR-T cells that mimic conventional CAR-T cells and effectively control the progression of human CD19+ leukemia in an animal model.

Microbial metabolite as icebreaker for immunotherapy

Immunotherapy has limited success in triple-negative breast cancer (TNBC). In this issue of Cell Metabolism, Wang etal. found that microbial metabolite TMAO boosts CD8+ Tcell-mediated antitumor immunity by inducing pyroptosis in tumor cells, enhancing the efficacy of immunotherapy in TNBC (Wang etal., 2022).

Overcoming drug resistance, the natural way

Colistin is an antibiotic of last resort for treating Gram-negative bacterial infections, but resistance is spreading rapidly. In a recent issue of Nature, Wang etal. use genome mining to identify and synthesize a natural variant that bypasses colistin resistance and offers new hope for tackling antimicrobial resistance.

Excited to see you: New imaging approaches to detect ferrous iron in vivo

Ferroptosis is an iron-dependent form of cell death implicated in cancer and neurodegenerative diseases. In this issue of Cell Chemical Biology, Shao etal. (2022) and Wang etal. (2022) describe imaging techniques to monitor ferrous iron levels and iron-dependent lipid peroxidation, two key determinants of ferroptosis sensitivity.

Targeting p21 for diabetes: Another choice of senotherapy

Senotherapy, the elimination of senescent cells, is a cutting-edge treatment for aging-related and lifestyle diseases. In this issue of Cell Metabolism, Wang etal. report that p21Cip1 highly expressing cells, which represent a senescent cell population, occur in the adipose tissue during obesity. Targeting them genetically or pharmacologically attenuates insulin resistance, suggesting a possible therapeutic approach to treat the metabolic complications of obesity.

The meninges—a cradle and school for nurturing and educating developing B cells

B cell development is thought to be limited to the bone marrow. In this issue of Immunity, Wang etal. find that the meninges, the membranes that surround the brain and spinal cord, contain developing B cells, and they provide evidence that the B cells are there to be tolerized to central nervous system antigens.

SNX10 and caspase-5 sort out endosomal LPS for a gut-wrenching Slug-fest.

Endosomes are important cellular compartments for sorting internalized cargo and immune sensing. In this issue, Wang etal describe a novel signaling pathway induced by endocytosed bacterial outer membrane vesicles, where sorting nexin 10 and caspase-5 act at the endosome to promote cytosolic exposure of LPS and initiate signaling to alter epithelial layer integrity. This study presents the first example of a specialized function for caspase-5, distinct from the inflammasome function executed by the closely related paralog caspase-4.

MFN2 Stabilization: A Bridge for Endoplasmic Reticulum Stress Sensitivity in Melanoma

In a new article in the Journal of Investigative Dermatology, Wang etal. (2021) report that mitochondrial quality control modulates responses to endoplasmic reticulum (ER) stress in melanoma. They implicate a linear pathway of XBP1, MARCH5, and MFN2 that act together to regulate mitochondrial fission and mitophagy and ultimately mediate melanoma cell sensitivity to ER stress. This work informs therapeutic combinations and biomarker strategies for targeting melanoma organellar homeostasis as well as for life‒death decisions.

Ironing-Out the Details: New Strategies for Combining Ferroptosis Inhibitors with Immunotherapy in Melanoma

Escape from ferroptosis is an important determinant of metastasis and immune evasion in melanoma. In a new article of the Journal of Investigative Dermatology, Wang etal. (2021) identify the CAMKK2‒adenosine monophosphate-activated protein kinase‒NRF2 signaling axis as a negative regulator of ferroptosis and showed that inhibiting CAMKK2 increases the efficacy of anti-PD-1 therapy. These findings offer new opportunities for the development of ferroptosis-inducing therapies to use in combination with immune checkpoint agents.

Ca2+ kickstarts antiviral RNAi

RNAi is a major plant antiviral strategy. However, the mechanisms triggering RNAi are unknown. In this issue of Cell Host & Microbe, Wang etal. (2021) demonstrate that wound-induced calcium signaling induces RNAi activation. As a counter-defense, a viral suppressor of RNAi (VSR) interferes with players in calcium signaling.

New methods for the additive hazards model with the informatively interval-censored failure time data.

The additive hazards model is one of the most commonly used models for regression analysis of failure time data and many inference procedures have been developed for it under various situations. In particular, Wang etal. (2018a, Computational Statistics and Data Analysis, 125, 1-9) discussed the situation where one observes informatively interval-censored data and proposed a likelihood estimation approach. However , it involves estimation of the unknown baseline cumulative hazard function and thus may be time-consuming . Corresponding to this, we propose two new procedures, an estimating equation-based one and an empirical likelihood-based one, and both do not need estimation of the cumulative hazard function and can be easily implemented. The asymptotic properties of the proposed methods are established and an extensive simulation study suggests that they work well in practical situations. An application is alsoprovided.

Stochastic initiation of DNA replication across the human genome

Wang etal. (2021) comprehensively map DNA replication initiation events across the human genome using single-molecule optical resolution mapping and find that initiation events are randomly distributed across broad initiation zones that are only utilized in a stochastic fashion across a population of cells.

Before and after farming: The genetic structure of South China and Southeast Asia

In this issue of Cell, Wang etal. harness ancient DNA methods to produce and analyze new genomic data from 31 individuals from South China, dated between 500 and 10,000-12,000 years ago. The study reveals a complex interplay between groups of three different genetic ancestries and provides a new perspective on interactions and agricultural dispersals in South China and Southeast Asia.

ILC damage, and I’ll repair it

In this issue of Immunity, Wang etal. report that the recognition of lysophosphatidyl serine via the receptor GPR43 confers type 3 innate lymphoid cells with the capacity to sense damage-induced cell death, which in turn triggers interleukin-22-dependent tissue repair.

The hypothalamus coordinates diverse escape strategies from threat

The neural circuits orchestrating complex behavioral response strategies to threat are not understood. In this issue of Neuron, Wang etal. (2021) establish the hypothalamic dorsal premammillary nucleus as a critical node that communicates with thalamic and midbrain regions to coordinate diverse escape strategies.

Hair of the mouse: A skin bacteria “cocktail” gets follicles back on their feet

Microbes can boost cutaneous immune defense and skin reparative capacity. However, mechanistic understanding, especially of the latter, remains sparse. In this issue of Cell Host & Microbe, Wang etal. (2021) shed light on this, demonstrating that bacteria contribute to hair follicle neogenesis after skin wounding via keratinocyte-intrinsic IL-1R1 signaling.