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Bispecific immune cell engagers, particularly bispecific T-cell engagers, show limited efficacy in solid tumors such as glioblastoma (GBM) due to systemic toxicities, poor T cell infiltration, and restricted drug penetration. We develop PL@mBiME, a multifunctional lipid nanoparticle (LNP) platform that enables brain tumor–targeted delivery and sustained in vivo expression of mRNA encoding a bispecific macrophage engager (BiME). The BiME simultaneously targets ErbB2 on glioma cells and CD206 on M2 macrophages, reprogramming macrophages toward pro-inflammatory M1 phenotype while promoting macrophage–tumor cell bridging, enhancing tumor cell phagocytosis and antigen presentation. PL@mBiME incorporates pH-responsive charge reversal to improve tumor accumulation and lysosomal escape as well as glutathione-triggered release of surface-conjugated PD-L1 antibody to amplify anti-tumor immunity. Across multiple GBM models, this coordinated activation of innate and adaptive immunity induces tumor regression, prolongs survival, and generates durable immune memory without significant toxicity. Bispecific immune cell engagers show limited efficacy in glioblastoma (GBM) therapy due to poor T cell infiltration and restricted drug penetration. Here this group reports a multifunctional lipid nanoparticle platform that enables brain tumor–targeted delivery and sustained in vivo expression of mRNA encoding a bispecific macrophage engager for GBM treatment.

As urbanization proceeds globally in recent decades, a nuanced understanding of the differential impacts of the urban heat island (UHI) effect across income country groups is crucial. Through an analysis of ~5 million urban grids from 2003 to 2018, we discovered that the average surface urban heat island intensity (SUHII) increased at a rate of 0.021 °C annually. Despite the extensive areas of SUHII increase in higher-income countries, particularly the US and China, it is the low and lower-middle-income countries that exhibited a more pronounced net increase in intensity. Specifically, 27% of urban grids in low-income countries witnessed the most substantial net increase during the daytime, while 19% of urban grids in lower-middle-income countries led the surge at nighttime. Higher-income countries’ SUHII growth reflects their pace of urbanization, but the trend of intensifying urban heat expands faster in lower-income economies. Such findings underscore an impending UHI challenge for lower-middle and low-income nations, emphasizing the need for targeted mitigation and adaptation strategies.

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING . The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for type-I interferon production. An isocaloric glutamine-rich diet abolishes STING-mediated effector cell expansion in tumours, weakening STING agonist-induced tumour control. Cancer cell-specific BATF2 expression promotes an Id2-centered T-cell effector signature, reduces T-cell exhaustion, and triggers spontaneous HNSCC rejection in a type-I interferon-dependent fashion. Utilizing syngeneic subcutaneous, orthotopic, and 24-week-long cigarette smoke carcinogen-induced HNSCC models, we demonstrate that host Batf2 deficiency results in increased infiltration of CD206 + myeloid cells and reduced effector CD8 + T-cells, accelerating the initiation of cancers. Overall, we reveal a tumour suppressor BATF2 whose loss is mediated by unique metabolic cues in the TME and drives cancer immune escape. STING–type-I interferon pathway regulates the immunogenicity of several cancer types, including head and neck squamous cell carcinoma. Here the authors describe that glutamine metabolism in the tumour microenvironment dampens the STING–type-I interferon pathway by epigenetically silencing the expression of BATF2, which functions as a tumour suppressor.

Soil salinization and autotoxicity are major abiotic stresses constraining melon production. The ACE gene family (also known as HOTHEAD, HTH) encodes flavin-containing oxidoreductases involved in stress responses and RNA cache-mediated non-Mendelian inheritance. This study presents a comprehensive genome-wide analysis of the ACE/HTH gene family in melon through integrated bioinformatic and experimental approaches. We identified 14 CmACE genes encoding proteins of 457–595 amino acids. This gene family underwent significant expansion through tandem duplication events, particularly on chromosome 5. Phylogenetic analysis grouped these genes into three distinct clades with conserved gene structures and motif compositions. Promoter analysis identified abundant stress- and hormone-responsive cis-elements, with ABRE elements being predominant. Expression analyses revealed that multiple CmACE genes, including CmACE3, CmACE5, CmACE6 and CmACE14, were significantly upregulated under salt-alkali and autotoxicity stresses, showing distinct tissue-specific and time-dependent expression patterns. Notably, CmACE3 and CmACE6 were strongly induced under both stresses, while the tandemly duplicated pair CmACE6 and CmACE7 exhibited divergent expression patterns, suggesting functional specialization. Our findings provide the first comprehensive characterization of the CmACE gene family in melon, revealing its evolutionary history and stress-responsive regulation. These results not only offer valuable genetic resources for breeding stress-resistant melons but also lay a foundation for future research into the potential role of this conserved gene family in integrating stress adaptation with epigenetic regulatory pathways in crops.

The Π -operator (Ahlfors–Beurling transform) plays an important role in solving the Beltrami equation. In this paper we define two Π -operators on the n-sphere. The first spherical Π -operator is shown to be an L2 isometry up to isomorphism. To improve this, with the help of the spectrum of the spherical Dirac operator, the second spherical Π operator is constructed as an isometric L2 operator over the sphere. Some analogous properties for both Π -operators are also developed. We also study the applications of both spherical Π -operators to the solution of the spherical Beltrami equations.

In this dissertation, we studies Π-operators in different spaces using Clifford algebras. This approach generalizes the Π-operator theory on the complex plane to higher dimensional spaces. It also allows us to investigate the existence of the solutions to Beltrami equations in different spaces. Motivated by the form of the Π-operator on the complex plane, we first construct a Π-operator on a general Clifford-Hilbert module. It is shown that this operator is an L2 isometry. Further, this can also be used forsolving certain Beltrami equations when the Hilbert space is the L2 spaceof a measure space. This idea is applied to examples of some conformally flat manifolds, the real projective space, cylinders, Hopf manifolds and n-dimensional hyperbolic upper half space. It is worth pointing out that the proof for the L2 isometry of Π-operatoron the unit sphere is different from the idea mentioned above. In that idea, it requires the Dirac operator and its dual operator commute to prove the L2 isometry of the Π-operator. However, this is no longer true for thespherical Dirac operator. Hence, we use the spectrum of spherical Dirac operator to overcome this problem. Since the real projective space can be defined as a projection from the unit sphere, Π-operator theory in the real projective space can be induced from the one on the unit sphere. Similarly, Π-operator theory on cylinders (Hopf manifolds) is derived from the one on n-dimensional Euclidean space via a projection map. Classical Clifford analysis is centered at the study of functions on n-dimensional Euclidean space taking values in Clifford numbers. In contrast, Clifford analysis in higher spin spaces is the study of functions on n-dimensional Euclidean space taking values in arbitrary irreducible representations of the Spin group. At the end of this thesis, we construct an L2 isometric Π-operatorin higher spin spaces. Further, we provide an Ahlfors-Beurling type inequality in higher spin spaces to conclude the thesis.

Rarita-Schwinger fields are solutions to the relativistic field equation of spin-\\(3/2\\) fermions in four dimensional flat spacetime, which are important in supergravity and superstring theories. Bure s et al. generalized it to arbitrary spin \\(k/2\\) in 2002 in the context of Clifford algebras. In this article, we introduce the higher spin \\(\\)-operator related to the Rarita-Schwinger operator. Further, we investigate norm estimates, mapping properties and the adjoint operator of the higher spin \\(\\)-operator. As an application, a higher spin Beltrami equation is introduced, and existence and uniqueness of solutions to this higher spin Beltrami equation is established by the norm estimate of the higher spin \\(\\)-operator.

Rarita-Schwinger fields are solutions to the relativistic field equation of spin-\\(3/2\\) fermions in four dimensional flat spacetime, which are important in supergravity and superstring theories. Bure s et al. generalized it to arbitrary spin \\(k/2\\) in 2002 in the context of Clifford algebras. In this article, we introduce the higher spin \\(\\)-operator related to the Rarita-Schwinger operator. Further, we investigate norm estimates, mapping properties and the adjoint operator of the higher spin \\(\\)-operator. As an application, a higher spin Beltrami equation is introduced, and existence and uniqueness of solutions to this higher spin Beltrami equation is established by the norm estimate of the higher spin \\(\\)-operator.

The \\(\\)-operator, also known as Ahlfors-Beurling transform, plays an important role in solving the existence of locally quasiconformal solutions of Beltrami equations. In this paper, we first construct the \\(\\)-operator on a general Clifford-Hilbert module. This \\(\\)-operator is also an \\(L^2\\) isometry. Further, it can also be used for solving certain Beltrami equations when the Hilbert space is the \\(L^2\\) space of a measure space. Then, we show that this technique can be applied to construct the classical \\(\\)-operator in the complex plane and some other examples on some conformally flat manifolds, which are constructed by \\(U/\\), where \\(U\\) is a simply connected subdomain of either \\(R^n\\) or \\(S^n\\), and \\(\\) is a Kleinian group acting discontinuously on \\(U\\). The \\(\\)-operators on those manifolds also preserve the isometry property in certain \\(L^2\\) spaces, and their \\(L^p\\) norms are bounded by the \\(L^p\\) norms of the \\(\\)-operators on \\(R^n\\) or \\(S^n\\), depending on where \\(U\\) lies. The applications of the \\(\\)-operator to solutions of the Beltrami equations on those conformally flat manifolds are also discussed. At the end, we investigate the \\(\\)-operator theory in the upper-half space with the hyperbolic metric.

Squamous cell carcinomas (SCC) are often preceded by potentially malignant precursor lesions, most of which remain benign. The terminal exhaustion phenotypes of effector T-cells and the accumulation of myeloid-derived suppressor cells (MDSC) have been thoroughly characterized in established SCC. However, it is unclear what precancerous lesions harbor a bona fide high risk for malignant transformation and how precancerous epithelial dysplasia drives the immune system to the point of no return. Here we show that expression of SRY-box transcription factor 2 (SOX2) in precancerous lesions imparts an irreversible risk that recruits suppressive myeloid cells by promoting the release of CCL2. We developed a unique genetically engineered mouse model (GEMM) to recapitulate the malignant transformation of epithelial dysplasia to SCC in the oral mucosa with high histologic and phenotypic fidelity. Using a combination of longitudinal human specimens and the Sox2-GEMM, we found that the myeloid cells in precancerous epithelial dysplasia exhibit a distinctive dichotomous profile featuring high levels of IL-1α-SLC2A1 and low levels of type-I interferon (IFN-I) signatures, which occurs before SCC emerges histologically. Brief priming of myeloid cells with IL-1α desensitizes them to IFN-I agonists and makes myeloid-derived suppressor cells (MDSC) even more suppressive of T-cell activation. Mechanistically, IL-1 activation represses the expression of DHHC3/7 enzymes, which are responsible for the palmitoylation of stimulator of interferon genes (STING). Early blockade of IL1 signaling using pharmacologic and genetic approaches similarly reduces MDSC and SLC2A1 myeloid cells, suppresses epithelial dysplasia transformation, and extends survival. This work establishes a previously unrecognized SOX2-CCL2-IL1 pathway that leads to irreversible immune escape when precancerous epithelial lesions transform.