TRPV1 analgesics disturb core body temperature via a biased allosteric mechanism involving conformations distinct from that for nociception.

Efforts on developing transient receptor potential vanilloid 1 (TRPV1) drugs for pain management have been hampered by deleterious hypo- or hyperthermia caused by TRPV1 agonists/antagonists. Here, we compared the effects of four antagonists on TRPV1 polymodal gating and core body temperature (CBT) in Trpv1+/+, Trpv1-/-, and Trpv1T634A/T634A. Neither the effect on proton gating nor drug administration route, hair coverage, CBT rhythmic fluctuations, or inflammation had any influence on the differential actions of TRPV1 drugs on CBT. We identified the S4-S5 linker region exposed to the vanilloid pocket of TRPV1 to be critical for hyperthermia associated with certain TRPV1 antagonists. PSFL2874, a TRPV1 antagonist we discovered, is effective against inflammatory pain but devoid of binding to the S4-S5 linker and inducing CBT changes. These findings implicate that biased allosteric mechanisms exist for TRPV1 coupling to nociception and CBT regulation, opening avenues for the development of non-opioid analgesics without affecting CBT.

Chronic cough relief by allosteric modulation of P2X3 without taste disturbance.

P2X receptors are cation channels that sense extracellular ATP. Many therapeutic candidates targeting P2X receptors have begun clinical trials or acquired approval for the treatment of refractory chronic cough (RCC) and other disorders. However, the present negative allosteric modulation of P2X receptors is primarily limited to the central pocket or the site below the left flipper domain. Here, we uncover a mechanism of allosteric regulation of P2X3 in the inner pocket of the head domain (IP-HD), and show that the antitussive effects of quercetin and PSFL2915 (our nM-affinity P2X3 inhibitor optimized based on quercetin) on male mice and guinea pigs were achieved by preventing allosteric changes of IP-HD in P2X3. While being therapeutically comparable to the newly licensed P2X3 RCC drug gefapixant, quercetin and PSFL2915 do not have an adverse effect on taste as gefapixant does. Thus, allosteric modulation of P2X3 via IP-HD may be a druggable strategy to alleviate RCC.

Hippo/YAP signaling choreographs the tumor immune microenvironment to promote triple negative breast cancer progression via TAZ/IL-34 axis.

Growing evidence suggests that the bidirectional interactions between cancer cells and their surrounding environment, namely the tumor microenvironment (TME), contribute to cancer progression, metastasis, and resistance to treatment. Intense investigation of the Hippo pathway, which controls multiple central cellular functions in tumorigenesis, was focused on cancer cells. However, the role of the Hippo pathway in modulating tumor-stromal interactions in triple-negative breast cancer remains largely unknown. Therefore, this study focused on revealing the effects of Hippo-YAP/TAZ signaling on the immune microenvironment. Our findings reveal that the activity of the Hippo pathway is associated with worse disease outcomes in TNBC and could increase TAM infiltration through the TAZ/IL-34 axis, leading to an immunosuppressive microenvironment and impairing the treatment efficacy of anti-PD-L1. Thus, the TAZ/IL-34 axis may serve as a novel target for TNBC patients.

Illumina Sequencing of 18S/16S rRNA Reveals Microbial Community Composition, Diversity, and Potential Pathogens in 17 Turfgrass Seeds.

The increasing need for turfgrass seeds is coupled with the high risk of dangerous microbial pathogens being transmitted through the domestic and international trade of seeds. Concerns continue to be raised about seed safety and quality. Here, we show that next-generation sequencing (NGS) of DNA represents an effective and reliable tactic to monitor the microbial communities within turfgrass seeds. A comparison of DNA sequence data with reference databases revealed the presence of 26 different fungal orders. Among them, serious plant disease pathogens such as Bipolaris sorokiniana, Boeremia exigua, Claviceps purpurea, and Rhizoctonia zeae were detected. Seedborne bacteria, including Erwinia persicina and Acidovorax avenae, were identified from different bacterial orders. Our study indicated that the traditional culturing method and the NGS approach for pathogen identification complement each other. The reliability of culturing and NGS methods was further validated by PCR with specific primers. The combination of these different techniques ensures maximum sensitivity and specificity for turfgrass seed pathogen testing assay.