No abstract

Obesity usually induces systemic metabolic disturbances, including in the tumor microenvironment (TME). This is because adaptive metabolism related to obesity in the TME with a low level of prolyl hydroxylase-3 (PHD3) depletes the major fatty acid fuels of CD8+ T cells and leads to the poor infiltration and unsatisfactory function of CD8+ T cells. Herein, we discovered that obesity could aggravate the immunosuppressive TME and weaken CD8+ T cell-mediated tumor cell killing. We have thus developed gene therapy to relieve the obesity-related TME to promote cancer immunotherapy. An efficient gene carrier was prepared by modifying polyethylenimine with p-methylbenzenesulfonyl (abbreviated as PEI-Tos) together with hyaluronic acid (HA) shielding, achieving excellent gene transfection in tumors after intravenous administration. HA/PEI-Tos/p DNA (HPD) containing the plasmid encoding PHD3 (pPHD3) can effectively upregulate the expression of PHD3 in tumor tissues, revising the immunosuppressive TME and significantly increasing the infiltration of CD8+ T cells, thereby improving the responsiveness of immune checkpoint antibody-mediated immunotherapy. Efficient therapeutic efficacy was achieved using HPD together with αPD-1 in colorectal tumor and melanoma-bearing obese mice. This work provides an effective strategy to improve immunotherapy of tumors in obese mice, which may provide a useful reference for the immunotherapy of obesity-related cancer in the clinic.

In a 2013 article, I partitioned all musical contours into fifteen types and arranged them in a network called the minimally divergent contour network (MDCN). Within the MDCN, we can examine the similarity between any two contour types by measuring the shortest path between them. However, despite the methodological efficiency, none of the fifteen types considers nonconsecutive repeated contour pitches. Prompted by this issue, this article extends the MDCN to include nonconsecutive repeated contour pitches. To demonstrate the analytic utility of the extended MDCN, I examine works by Bright Sheng and György Kurtág.

To make post-tonal harmony more accessible, many music scholars derive various theories, which rely on the traditional notions of consonance and dissonance, to describe the quality of a chord. Most of these theories use the quality of an interval as the criterion to measure the proportion between the consonances and dissonances within a chord. All intervals can be categorized as either consonances or dissonances except for one-the tritone. Although traditionally in tonal music, the tritone was perceived as a dissonance; its quality in twentieth-century music, however, has been challenged by many scholars. It may sound like a dissonant (Paul Hindemith), a consonant ( Joseph Straus), or a neutral interval (Charles Seeger). If different viewpoints abound in the tritone's quality, do we hear it as adding the consonant or dissonant sound to a chord? Confronted with this issue, this article suggests an alternative way of perceiving all intervals-their space-and further proposes a method that assists us in hearing a chord in terms of its degree of compactness. Based on this method, we can experience the dynamics created by the confrontation between spatial and compact chords, and find post-tonal harmony more accessible.

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