Zhang Etal Research Articles

Rescuing T cells from stiff tumors

In a recent issue of Cell, Zhang etal.1 demonstrate that mechanical features of a solid tumor can drive Tcells into dysfunctionality and identify pathways that revert this "exhausted" state.

A brainstem maestro conducting the somatic and autonomic motor symphony

Somatic and sympathetic tones fluctuate together seamlessly across daily behaviors. In this issue of Cell, Zhang etal. describe populations of spinal projecting neurons in the rostral ventromedial medulla (rVMM) that harmonize somatic motor function and sympathetic activation. The coordinated regulation plays a vital role in supporting behaviors associated with various arousal states.

Debate: More, not less social media content moderation? How to better protect youth mental health online.

This article challenges Zhang etal.'s claims that social media content moderation is proving detrimental to youth mental health and asserts that greater emphasis on the systemic risks posed by social media platforms is required. This commentary draws on my lived experience as a bereaved parent, empiricial evidence and ongoing public policy and regulatory debates. Greater attention should be paid to the effects of algorithmic recommendation systems, which can result in teenagers becoming rapidly exposed to large amounts of harmful content on social media sites such as Instagram, Pinterest and TikTok.

Show MERCI on mobile mitochondria

There is emerging evidence that mitochondria can move between cells, particularly from immune cells into cancers. Recent work from Zhang etal. in Cancer Cell employs single-cell RNA- and mitochondrial DNA-sequencing in co-culture experiments and patient tumor samples to detect mitochondrial transfer. However, the mechanisms, scale, and implications remain uncertain.

Comment on "An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy".

Recent clinical successes of immune checkpoint blockade (ICB) therapies represents a milestone as a novel anti-tumor strategy beyond surgery, radiotherapy, chemotherapy, and targeted therapy in cancer therapy. T cells, especially CD8+ T cells, play crucial roles in anti-tumor immune responses. However, most T cells in the tumor microenvironment express high inhibitory receptors, such as PD-1, TIM-3, and LAG-3, and decreased T cell response in response to stimuli. Applying ICB therapies, such as anti-PD-1, promotes T cell activation and increases cytotoxic T lymphocyte (CTL) response, leading to the enhanced anti-tumor immune response in patients with malignancy. Therefore, studies aimed to define novel targets that can restrain T cell terminal exhaustion are urgently required to provide new strategies for patients resistant to immunotherapy. The previously published study by Zhang etal. (An Injectable Hydrogel to Modulate T Cells for Cancer Immunotherapy, https://doi.org/10.1002/smll.202202663) introduces a new type of injectable hydrogel that can regulate the function of T cells, thereby improving their effectiveness in cancer immunotherapy. However, it remains to be discussed for its conclusion, as the flow cell assay of this article may not be proper.

Fructose sweetens the adipocyte-T cell alliance against tumors

Dietary fructose is implicated in tumorigenesis, but whether dietary fructose regulates antitumor immunity remains elusive. In this issue of Cell Metabolism, Zhang etal. show that dietary fructose promotes adipocyte-derived leptin production, which attenuates terminal exhaustion programming and boosts the effector function of CD8+ Tcells for improved tumor control.

Oxidized thioredoxin 1 places a leash on NLRP1 inflammasome activity.

The biology of the NACHT domain and leucine-rich repeat (NLR) and pyrin domain-containing 1 (NLRP1) inflammasome has perplexed researchers since this inflammasome was first described about two decades ago. The identification of oxidized thioredoxin 1 (TRX1) as a suppressor of NLRP1 recently linked cellular redox homeostasis to NLRP1 inflammasome signaling. Now, Zhang etal. present a molecular structure of TRX1-bound NLRP1 with unprecedented detail. This structure gives key insight into regulatory mechanisms governing NLRP1 activation and offers enormous potential for structure-based anti-inflammatory drug design.

Genetically informed therapy for lymphoma: the discomfiting benefit of lumping splits.

Zhang etal. report a randomized phase 2 trial for diffuse large B cell lymphoma (DLBCL) that compared standard of care (R-CHOP) to R-CHOP combined with one of 5 agents matched to an individual lymphoma's genetics. Overall, the matching strategy significantly outperformed R-CHOP, laying the foundation for a paradigm-shifting phase 3 trial.

Gut IgA: Never fear, the super inducers are here.

In this issue of Cell Host & Microbe, Zhang etal. show that long-term oral administration of a pectin-derived prebiotic broadly enhanced IgA responses to commensals in the small intestine. This effect required Tcells and involved Lachnospiraceae A2, suggesting that a few symbionts promote IgA responses to many commensals.

Multi-omics analysis of metastatic pancreatic cancer reveals an immunosuppressive landscape

Immune cell populations play key functional roles in tumor growth and metastasis, and multi-omic approaches can map cellular interactions to identify targets for highly immunosuppressive and treatment resistant cancers. In this issue of Med, Zhang etal.1 investigate the immune cell landscape of advanced pancreatic cancer to understand the mechanisms underlying liver metastasis.

Seek and you shall find-news on the quest for novel PET-degrading enzymes.

Plastic-degrading enzymes hold immense potential for eco-friendly recycling methods. However, the catalytic rates of current enzymes do not stack up against the mammoth task of degrading millions of tons of plastic waste per year. In the quest for more efficient polyethylene terephthalate (PET)-degrading enzymes, Zhang etal. report the discovery and characterization of PET40, a versatile PET-hydrolyzing esterase that is divergent from most characterized PETases. While PET40 has comparably low hydrolytic activity on PET, Zhang etal. demonstrate its broad activity on an expanded substrate pool. This sheds light on the potential ecological role of these esterases and suggests that PET might be only a recent addition to their substrate spectrum.

Lifting the curtain on loop extrusion barriers: Single-molecule insights into cohesin stalling

In this issue, Zhang etal.1 show that CTCF blocks cohesin-mediated loop extrusion in an orientation-dependent manner. Using single-molecule imaging assays, the authors find that dCas9 and R-loops can also stall extrusion.

A tale of two switches: Redox regulation of adenosine-5′-phosphosulfate kinase in humans and plants

The sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) is a near-universal component of sulfur metabolism. In a report by Zhang etal. in this issue of Structure, X-ray crystal structures of the APS kinase domains from human PAPS synthase reveal dynamic substrate recognition and a regulatory "redox switch" analogous to that previously described only in plant APS kinases.

Brain tumors on slice: A novel platform for personalized therapeutic screening

Mann and Zhang etal. developed a robust exvivo slice culture platform consisting of resected patient high- and low-grade glioma tissue engrafted onto rat organotypic brain slices, and interrogated tumor responses to clinically relevant therapeutics with a novel treatment-response algorithm.

Stress-induced condensate switch awakens sleeping viruses

In a recent Cell paper, Zhang etal. reveal that stress-induced changes in intra-condensates awaken dormant viruses. These results shed light on the delicate balance between viruses and their hosts, providing avenues for further research in the field.

Two heads are better than one: Cooperation of two CAPS domains in membrane binding

In this issue of Structure, Zhang etal. report their structural studies on the C2 and PH domains of Ca2+-dependent activator proteins for secretion (CAPS). The two domains form a tightly packed module and generate a continuous basic patch across both domains to substantially enhance CAPS binding to PI(4,5)P2-containing membranes.

First Report of Valsa nivea (Hoffm.) Fr.Causing Valsa Canker on Korla Pear (Pyrus sinkiangensis Yü) in the World.

Korla pear (Pyrus sinkiangensis Yü) is an important commercial fruit tree that originated in China (Zhou et al. 2020). In April 2020, a survey was conducted in Aksu region, Xinjiang (40°55'37"N, 80°28'42"E), China. Some Korla pear trees (>15 years old) exhibited symptoms of branch dieback and branch cankers. Cankers observed on the trunk and branches of the tree were sunken, dark ulcerative lesions sometimes exhibiting signs of stromata erumpent through the bark and exuding yellow to reddish-orange spore tendrils. Of the 180 plants surveyed, 80% were symptomatic. Thirty samples of symptomatic tissues of infected branches were taken to the laboratory. Bark and cortical wood samples containing necrotic and healthy tissue were excised with flame-sterilized scalpels, surface disinfected with 75% ethanol and 1% NaClO, placed on PDA plates, and incubated at 25°C. A total of 30 fungal isolates were obtained. Among them, 28 isolates were identified as Valsa mali var. pyri (Lu. 1992) based on morphological and molecular identification, and two isolates (ALE6T-GP21 and ALE7T-GP23) were identified as Valsa nivea (Hoffm.) Fr. Valsa nivea isolates had a fine villi form mycelium that was initially white, turned grayish-green over time and grew close to the medium surface. Cultures also contained black ostiolate pycnidia in a stroma that consisted of multiple irregular locules. Conidiophores were hyaline, occasionally branched at the bases and (15.50-)16.48-17.94(-18.50)×(1.00-)1.13-1.37(-1.50) μm (n=20). Conidiogenous cells were phialidic and subcylindrical that taper towards the apex. Conidia were hyaline, banana-like and (5.47-)6.13-6.97(-7.64)×(1.02-)1.06-1.20(-1.23) μm (n=10). The molecular characteristics are consistent with the previous description of V. nivea (Adams et al. 2006). The internal transcribed spacer (ITS), transcription elongation factor (tef-1α) and β-tubulin (Tub2) gene were sequenced using ITS1/ITS4, EF1-728F/EF1-986R and Bt2a/Bt2b primers, respectively (Zhang etal. 2014). BLAST (Basic Local Alignment Search Tool) searches against the NCBI database revealed that the ITS sequence had 99.83% homology (ON843984.1 and ON843987.1), tef-1α gene had 99.22% homology (MH015266.1 and MH015267.1), and the Tub2 sequence had 99.57% and 100% homologies (KT934364.1 and KT934364.1) with V. nivea sequences. The amplified sequences of ITS region (OK442665 and OK442666), tef-1α (OK510871 and OK510872) and Tub2 (OK510869 and OK510870) were deposited in the GenBank. A phylogenetic analysis was performed using MEGA7 that shows 100% bootstrap support that ALE6T-GP21 and ALE7T-GP23 were V. nivea. A pathogenicity trial was conducted with isolate ALE6T-GP21 inoculated onto 1-year-old shoots of 15-year-old Korla pear trees in Alar city, Xinjiang, China. Five shoots were inoculated by making 5-mm deep wounds using a sterile scalpel then inoculating with a 50 μL conidia suspension (1×106 mL-1). Additionally, five shoots served as the negative control and were inoculated in the same way using 50 μL ddH2O. The trees were kept under ambient conditions. Inoculated branches developed symptoms 18 days post inoculation, whereas the control branches showed no symptoms. V. niveawas re-isolated from the symptomatic areas and the isolate confirmed as ALE6T-GP21 by sequence analysis. Currently, the proven hosts of V. nivea are Populus, Elaeagnus, Juglans, Malus and Salix (Adams et al. 2006; Wang et al. 2020). To our knowledge, this is the first report of pathogenic V. nivea occurring on P. sinkiangensis in the world. It will provide a basis for research into the occurrence, distribution of V. nivea on Korla Pear.

T-cell epitopes of PLA2R1 in membranous nephropathy: another step toward antigen-based immunotherapies

The discovery of phospholipase A2 receptor 1 as the major target antigen in membranous nephropathy (MN) has initiated a decade of major advances in the understanding of MN pathophysiology and improvement of patient care. In this Issue, Zhang etal. identified potential T-cell epitopes of phospholipase A2 receptor 1 in patients with MN. The characterization of the pathogenic T- and B-cell epitopes on phospholipase A2 receptor 1 is an important step moving from the current unspecific immunosuppressive therapies toward antigen-specific MN treatments.

A triplex for intestinal protection: Neurons, microbes, and goblet cells

Diverse intestinal components (e.g., gut-associated neurons, immune cells, gut microbes, and epithelium) are intimately intertwined with each other to maintain homeostasis in the gut. In a recent issue of Cell, Zhang etal. (2022) and Yang etal. (2022) present complementary studies uncovering interactions between nociceptor neurons, gut epithelium, and the microbiome to protect intestinal tissue from inflammation.

Fields to fermentors: Brewing botanical chemotherapeutic precursors using genetically engineered yeast

Plants are a rich source of chemotherapeutics and other essential medicines, but plant-based drug supply chains are unsustainable. Writing in Nature, Zhang etal.1 demonstrated a proof-of-concept alternate source of the anticancer drug vinblastine by engineering yeast to convert sugar and amino acids into its direct precursors, catharanthine and vindoline.