Discovering cancer immunotherapy targets in vivo

A key challenge facing the cancer immunology field is the discovery of the most suitable targets for therapeutic intervention. We recently reported a novel RNA-interference (RNAi)-based approach for systematic discovery of such targets in the tumor microenvironment in vivo utilizing pooled shRNA libraries as a screening tool. Here, we discuss applying this unbiased method to develop innovative cancer therapeutics

Robust Audio Anti-Spoofing with Fusion-Reconstruction Learning on Multi-Order Spectrograms

Robust audio anti-spoofing has been increasingly challenging due to the recent advancements on deepfake techniques. While spectrograms have demonstrated their capability for anti-spoofing, complementary information presented in multi-order spectral patterns have not been well explored, which limits their effectiveness for varying spoofing attacks. Therefore, we propose a novel deep learning method with a spectral fusion-reconstruction strategy, namely S2pecNet, to utilise multi-order spectral patterns for robust audio anti-spoofing representations. Specifically, spectral patterns up to second-order are fused in a coarse-to-fine manner and two branches are designed for the fine-level fusion from the spectral and temporal contexts. A reconstruction from the fused representation to the input spectrograms further reduces the potential fused information loss. Our method achieved the state-of-the-art performance with an EER of 0.77% on a widely used dataset: ASVspoof2019 LA Challenge

Blocking interaction between SHP2 and PD‐1 denotes a novel opportunity for developing PD‐1 inhibitors

Small molecular PD‐1 inhibitors are lacking in current immuno‐oncology clinic. PD‐1/PD‐L1 antibody inhibitors currently approved for clinical usage block interaction between PD‐L1 and PD‐1 to enhance cytotoxicity of CD8+ cytotoxic T lymphocyte (CTL). Whether other steps along the PD‐1 signaling pathway can be targeted remains to be determined. Here, we report that methylene blue (MB), an FDA‐approved chemical for treating methemoglobinemia, potently inhibits PD‐1 signaling. MB enhances the cytotoxicity, activation, cell proliferation, and cytokine‐secreting activity of CTL inhibited by PD‐1. Mechanistically, MB blocks interaction between Y248‐phosphorylated immunoreceptor tyrosine‐based switch motif (ITSM) of human PD‐1 and SHP2. MB enables activated CTL to shrink PD‐L1 expressing tumor allografts and autochthonous lung cancers in a transgenic mouse model. MB also effectively counteracts the PD‐1 signaling on human T cells isolated from peripheral blood of healthy donors. Thus, we identify an FDA‐approved chemical capable of potently inhibiting the function of PD‐1. Equally important, our work sheds light on a novel strategy to develop inhibitors targeting PD‐1 signaling axis

Contributions of Flexible-Arch Configurations in Shimenzi Arch Dam: New Evidence from Field Measurements

This paper presents a retrospective investigation into the performance of a new type of flexible-arch configurations in Shimenzi arch dam based on the past ten-year-long field measurements. The flexible-arch configurations are mainly comprised of artificial short joints at the middle downstream surface and a middle contraction joint with hinged well and enlarged arch ends with bending joints. Fundamental design considerations of these components are provided, and their contributions to the performance of Shimenzi arch dam are discussed in detail using the monitoring data from joint meters, strain gauges, and thermometers. Some elementary numerical studies have been conducted on a typical arch structure with different arrangements of artificial joints. Both the field data and numerical results prove well the effectiveness of the purposely built short joints and the middle contraction joint on the relaxation of tensile stress mobilization. Field survey data also clearly demonstrate the significance of the hinged well at the upstream side of the middle joint for a continuous arch force transfer

Depositing boron on Cu(111): Borophene or boride?

Large-area single-crystal surface structures were successfully prepared on Cu(111) substrate with boron deposition, which is critical for prospective applications. However, the proposed borophene structures do not match the scanning tunneling microscopy (STM) results very well, while the proposed copper boride is at odds with the traditional knowledge that ordered copper-rich borides normally do not exist due to small difference in electronegativity and large difference in atomic size. To clarify the controversy and elucidate the formation mechanism of the unexpected copper boride, we conducted systematic STM, X-ray photoelectron spectroscopy and angle-resolved photoemission spectroscopy investigations, confirming the synthesis of two-dimensional copper boride rather than borophene on Cu(111) after boron deposition under ultrahigh vacuum. First-principles calculations with defective surface models further indicate that boron atoms tend to react with Cu atoms near terrace edges or defects, which in turn shapes the intermediate structures of copper boride and leads to the formation of stable Cu-B monolayer via large-scale surface reconstruction eventually.Comment: 15 pages, 4 figure

New early oligocene zircon U-Pb dates for the ‘Miocene’ Wenshan Basin, Yunnan, China: Biodiversity and paleoenvironment

The sedimentary basins of Yunnan, Southwest China, record detailed histories of Cenozoic paleoenvironmental change. They track regional tectonic and palaeobiological evolution, both of which are critically important for the development of modern floral diversity in southwestern China and throughout Asia more generally. However, to be useful, the sedimentary archives within the basins have to be placed within a well-constrained timeframe independent of biostratigraphy. Using high resolution U-Pb dating, we redefine the age of fossil-bearing strata in the Wenshan Basin. Regarded as Miocene for the last half century, these basin sediments encompass 30±2 and 32±1 Ma early Oligocene tuffaceous horizons, thus indicating a significantly greater antiquity than previously recognized. Together with other regional age revisions our result points to widespread Yunnan basin and orographic development as largely having taken place by the end Paleogene. This age revision provides an important new perspective on the preserved biotas and their evolution in Yunnan, and especially our understanding of the origin of Asian biodiversity which, regionally, had a near-modern composition by the early Oligocene. Crucially, this revised age evidences late Eocene-early Oligocene regional tectonism, pointing to the rise of eastern Tibet and the Hengduan Mountains before the growth of the Himalaya, and that Asia's high plant diversity has a Paleogene origin

New early oligocene zircon U-Pb dates for the ‘Miocene’ Wenshan Basin, Yunnan, China: Biodiversity and paleoenvironment

The sedimentary basins of Yunnan, Southwest China, record detailed histories of Cenozoic paleoenvironmental change. They track regional tectonic and palaeobiological evolution, both of which are critically important for the development of modern floral diversity in southwestern China and throughout Asia more generally. However, to be useful, the sedimentary archives within the basins have to be placed within a well-constrained timeframe independent of biostratigraphy. Using high resolution U-Pb dating, we redefine the age of fossil-bearing strata in the Wenshan Basin. Regarded as Miocene for the last half century, these basin sediments encompass 30±2 and 32±1 Ma early Oligocene tuffaceous horizons, thus indicating a significantly greater antiquity than previously recognized. Together with other regional age revisions our result points to widespread Yunnan basin and orographic development as largely having taken place by the end Paleogene. This age revision provides an important new perspective on the preserved biotas and their evolution in Yunnan, and especially our understanding of the origin of Asian biodiversity which, regionally, had a near-modern composition by the early Oligocene. Crucially, this revised age evidences late Eocene-early Oligocene regional tectonism, pointing to the rise of eastern Tibet and the Hengduan Mountains before the growth of the Himalaya, and that Asia's high plant diversity has a Paleogene origin

New early oligocene zircon U-Pb dates for the ‘Miocene’ Wenshan Basin, Yunnan, China: Biodiversity and paleoenvironment

The sedimentary basins of Yunnan, Southwest China, record detailed histories of Cenozoic paleoenvironmental change. They track regional tectonic and palaeobiological evolution, both of which are critically important for the development of modern floral diversity in southwestern China and throughout Asia more generally. However, to be useful, the sedimentary archives within the basins have to be placed within a well-constrained timeframe independent of biostratigraphy. Using high resolution U-Pb dating, we redefine the age of fossil-bearing strata in the Wenshan Basin. Regarded as Miocene for the last half century, these basin sediments encompass 30±2 and 32±1 Ma early Oligocene tuffaceous horizons, thus indicating a significantly greater antiquity than previously recognized. Together with other regional age revisions our result points to widespread Yunnan basin and orographic development as largely having taken place by the end Paleogene. This age revision provides an important new perspective on the preserved biotas and their evolution in Yunnan, and especially our understanding of the origin of Asian biodiversity which, regionally, had a near-modern composition by the early Oligocene. Crucially, this revised age evidences late Eocene-early Oligocene regional tectonism, pointing to the rise of eastern Tibet and the Hengduan Mountains before the growth of the Himalaya, and that Asia's high plant diversity has a Paleogene origin

Transcranial Magnetic Stimulation Over the Right Posterior Superior Temporal Sulcus Promotes the Feature Discrimination Processing

Attention is the dynamic process of allocating limited resources to the information that is most relevant to our goals. Accumulating studies have demonstrated the crucial role of frontal and parietal areas in attention. However, the effect of posterior superior temporal sulcus (pSTS) in attention is still unclear. To address this question, in this study, we measured transcranial magnetic stimulation (TMS)-induced event-related potentials (ERPs) to determine the extent of involvement of the right pSTS in attentional processing. We hypothesized that TMS would enhance the activation of the right pSTS during feature discrimination processing. We recruited 21 healthy subjects who performed the dual-feature delayed matching task while undergoing single-pulse sham or real TMS to the right pSTS 300 ms before the second stimulus onset. The results showed that the response time was reduced by real TMS of the pSTS as compared to sham stimulation. N270 amplitude was reduced during conflict processing, and the time-varying network analysis revealed increased connectivity between the frontal lobe and temporo-parietal and occipital regions. Thus, single-pulse TMS of the right pSTS enhances feature discrimination processing and task performance by reducing N270 amplitude and increasing connections between the frontal pole and temporo-parietal and occipital regions. These findings provide evidence that the right pSTS facilitates feature discrimination by accelerating the formation of a dynamic network