Appropriate oxygen vacancies and Mo-N bond synergistically modulate charge transfer dynamics of MoO3-x/S-CN for superior photocatalytic disinfection: Unveiling synergistic effects and disinfection mechanism.

Highly efficient charge transfer is a critical factor to modulate the photocatalytic activity. However, the conscious modulation of charge transfer efficiency is still a great challenge. Herein, a novel interfacial Mo-N bond and appropriate oxygen vacancies (OVs) modulated S-scheme MoO3-x/S-CN heterojunction was rationally fabricated for efficient photocatalytic disinfection. The results of characterizations and density functional theory (DFT) calculations suggested that the enhanced charge transfer dynamics is ascribed to the optimizing oxygen vacancies density and forming interfacial Mo-N bond. It can improve charge transfer efficiency from 36.4% (MoO3-x) to 52.5% (MoO3-x/S-CN) and produce more reactive oxygen species (ROS), achieving entirely inactivate of 7.60-log E. coli and S. aureus within 50 min and 75 min. Besides, MoO3-x/S-CN can well resist the disturbance from the coexisting substances, and can be applied in a wide pH range, and even authentic water bodies. Monitoring of bacterial antioxidant systems and membrane integrity revealed that bacterial inactivation begins with the oxidation of cell membrane and dies from leakage of intracellular substances and destruction of cell structure. This work provides an inspiration on consciously modulating S-scheme charge transfer efficiency by optimizing oxygen vacancies density and atomic-level interface control for promoting the photocatalytic antibacterial activity.

Insights into the role of reactive oxygen species in photocatalytic H2O2 generation and OTC removal over a novel BN/Zn3In2S6 heterojunction.

Developing photocatalysts with superior performance to generate hydrogen peroxide (H2O2) and degrade oxytetracycline (OTC) is an effective strategy for the treatment of energy crisis and water purification. Herein, BN nanosheets were anchored onto the Zn3In2S6 microspheres for the research. Experimental and density functional theory (DFT) results demonstrate that due to different work functions and unique 2D/2D contact, the electron is spatially separated in BN/Zn3In2S6 nanocomposite, which increases the electron transfer efficiency from 43.7% (Zn3In2S6) to 55.6% (BN/ZIS-4). As a result, BN/ZIS-4 with optimal ratio of BN and Zn3In2S6 exhibits the highest OTC degradation efficiency (84.5%) and H2O2 generation rate (115.5 µmol L-1) under visible light illumination, which is 2.2 and 2.9 times than that of pristine Zn3In2S6. H2O2 generation is dominated by two pathways: two-step single-electron process (O2 → ∙O2- → H2O2) and another way (O2 → ∙O2- → 1O2 → H2O2). In the process of degrading OTC, ∙O2-, 1O2 and ∙OH are regarded as the main active species. This work offers a new insight for designing efficient, stable and reusable photocatalysts to solve current environmental conundrums.

Integrating the Z-scheme heterojunction and hot electrons injection into a plasmonic-based Zn2In2S5/W18O49 composite induced improved molecular oxygen activation for photocatalytic degradation and antibacterial performance.

The semiconductor-based photocatalysts with local surface plasmon resonance (LSPR) effect can extend light response to near-infrared region (NIR), as well as promote charge-carriers transfer, which provide a novel insight into designing light-driven photocatalyst with excellent photocatalytic performance. Here, we designed cost-effective wide-spectrum Zn2In2S5/W18O49 composite with enhanced photocatalytic performance based on a dual-channel charge transfer pathway. Benefiting from the synergistic effect of Z-scheme heterostructure and unique LSPR effect, the interfacial charge-carriers transfer rate and light-absorbing ability of Zn2In2S5/W18O49 were enhanced significantly under visible and NIR (vis-NIR) light irradiation. More reactive oxygen species (ROS) were formed by efficient molecular oxygen activation, which were the critical factors for both Escherichia coli (E. coli) photoinactivation and tetracycline (TC) photodegradation. The enhancement of molecular oxygen activation (MOA) ability was verified via quantitative analyses, which evaluated the amount of ROS through degrading nitrotetrazolium blue chloride (NBT) and p-phthalic acid (TA). By combining theoretical calculations with diverse experimental results, we proposed a credible photocatalytic reaction mechanism for antibiotic degradation and bacteria inactivation. This study develops a new insight into constructing promising photocatalysts with efficient photocatalytic activity in practical wastewater treatment.

2D/2D Heterojunction systems for the removal of organic pollutants: A review.

Photocatalysis is considered to be an effective way to remove organic pollutants, but the key to photocatalysis is finding a high-efficiency and stable photocatalyst. 2D materials-based heterojunction has aroused widespread concerns in photocatalysis because of its merits in more active sites, adjustable band gaps and shorter charge transfer distance. Among various 2D heterojunction systems, 2D/2D heterojunction with a face-to-face contact interface is regarded as a highly promising photocatalyst. Due to the strong coupling interface in 2D/2D heterojunction, the separation and migration of photoexcited electron-hole pairs are facilitated, which enhances the photocatalytic performance. Thus, the design of 2D/2D heterojunction can become a potential model for expanding the application of photocatalysis in the removal of organic pollutants. Herein, in this review, we first summarize the fundamental principles, classification, and strategies for elevating photocatalytic performance. Then, the synthesis and application of the 2D/2D heterojunction system for the removal of organic pollutants are discussed. Finally, the challenges and perspectives in 2D/2D heterojunction photocatalysts and their application for removing organic pollutants are presented.

GLS1 depletion inhibited colorectal cancer proliferation and migration via redox/Nrf2/autophagy-dependent pathway.

Cancer cells can metabolize glutamine to replenish TCA cycle intermediates for cell survival. Glutaminase (GLS1) is over-expressed in multiple cancers, including colorectal cancer (CRC). However, the role of GLS1 in colorectal cancer development has not yet fully elucidated. In this study, we found that GLS1 levels were significantly increased in CRC cells. Knockdown of GLS1 by shRNAs as well as GLS1 inhibitor BPTES decreased DLD1 and SW480 cell proliferation, colony formation and migration. Knockdown of GLS1 as well as BPTES induced reactive oxygen species (ROS) production, down-regulation of GSH/GSSG ratio, an decrease in Nrf2 protein expression and an increase in cytoplasmic Nrf2 protein expression in DLD1 and SW480 cells. Furthermore, Knockdown of GLS1 as well as BPTES inhibited autophagy pathway, antioxidant NAC and Nrf2 activator could reversed inhibition of GLS1-mediated an decrease in autophagic flux in DLD1 and SW480 cells. Depletion of GLS1-induced inhibition of DLD1 and SW480 CRC cell proliferation, colony formation and migration was reversed by autophagy inducer rapamycin. These results suggest that targeting GLS1 might be a new potential therapeutic target for the treatment of CRC.

Development and innovation of haploid induction technologies in plants.

Haploid induction is one of the main techniques for breeding new varieties of major crops, and its key steps are improving the haploid induction rate and simplifying the induction procedure. With the development and innovation of plant haploid induction technologies, haploid breeding has been widely used in varietal improvement of important crops, showing the advantages of rapid homozygosity of heterozygous genes, shortening breeding period, and improving breeding efficiency. The combination of haploid breeding with crossing breeding, mutation breeding, reverse breeding, and molecular marker-assisted selection will greatly improve the effectiveness of crop breeding. Haploids and doubled haploids have demonstrated their usefulness in production of genetic populations, characterization of gene functions, and transgenic and cytological studies in plants. In this review, we summarize the progress of haploid induction technologies in view of various haploid induction techniques and applications of haploids and double haploids. In particular, the advances on the haploid induction in several major crops by genome editing were briefly described. Finally, we discuss current issues and future perspectives in this field, so as to promote the application of the haploid induction techniques, especially the techniques of creating haploid inducer lines by genome editing in crop breeding.

In suit constructing 2D/1D MgIn2S4/CdS heterojunction system with enhanced photocatalytic activity towards treatment of wastewater and H2 production.

A novel visible-light-driven 2D/1D MgIn2S4/CdS catalyst with heterostructure was fabricated for sewage treatment and energy conversion. In this study, MIS/CdS-0.3 heterostructure catalyst displayed the remarkable photocatalytic performance, which could reduce about 100% of Cr(VI) within 30 min and decompose approximately 95.98% of oxytetracycline (OTC) after 60 min. Meanwhile, the degradation details and possible decomposition pathways for OTC solution were further verified by 3D EEM and LC-MS. Moreover, the as-obtained 2D/1D MgIn2S4/CdS hybrid composites signally promoted the hydrogen evolved in the light illumination at 420 nm. Meanwhile, some consequences based on various characterization technologies confirmed that the significant photo-induced charge separation rate is a crucial factor in the enhancement of photocatalytic capacity. The intimate contact and the formation of heterostructure between 2D MgIn2S4 nanosheets and 1D CdS nanorods with matched band gaps were beneficial for charge migration. Moreover, the band structures and the density of states (DOS) of MgIn2S4 and CdS were obtained based on density functional theory (DFT). In addition, the results of cycling experiments, XRD spectra and PL showed that the composition and performance of the composite are well-maintained, suggesting the great recyclability and stability. This work indicated that developing a 2D/1D heterostructure photocatalyst offers a cracking approach to enhance the photocatalytic property of semiconductor-based catalysts for pollutant removal and the generation of clean energy.

FOXM1 facilitates breast cancer cell stemness and migration in YAP1-dependent manner.

Breast cancer has the highest incidence and mortality in the female population. Forkhead box M1 (FOXM1) known as a transcription factor is upregulated and associated with poor prognosis in a variety of cancers. However, the molecular mechanisms of FOXM1 on breast cancer progression are poorly understood. In this study, we found that FOXM1 was up-regulated in breast cancer. FOXM1 promoted cell proliferation, clonal formation, and migration capacity in triple negative breast cancer by increasing transcriptional activity of YAP1. FOXM1 also maintained cell stemness via the Hippo pathway. The YAP1-TEAD binding inhibitor Verteporfin reduced the transcription level of OCT4 and NANOG but the Hippo pathway activator XMU-MP-1 could increase the transcription level of OCT4 and NANOG. In summary, our findings indicated that FOXM1 promoted breast cancer progression through the Hippo pathway, and it was suggested a new strategy to treat breast cancer.

Regulation of the Ysh1 endonuclease of the mRNA cleavage/polyadenylation complex by ubiquitin-mediated degradation.

Mutation of the essential yeast protein Ipa1 has previously been demonstrated to cause defects in pre-mRNA 3' end processing and growth, but the mechanism underlying these defects was not clear. In this study, we show that the ipa1-1 mutation causes a striking depletion of Ysh1, the evolutionarily conserved endonuclease subunit of the 19-subunit mRNA Cleavage/Polyadenylation (C/P) complex, but does not decrease other C/P subunits. YSH1 overexpression rescues both the growth and 3' end processing defects of the ipa1-1 mutant. YSH1 mRNA level is unchanged in ipa1-1 cells, and proteasome inactivation prevents Ysh1 loss and causes accumulation of ubiquitinated Ysh1. Ysh1 ubiquitination is mediated by the Ubc4 ubiquitin-conjugating enzyme and Mpe1, which in addition to its function in C/P, is also a RING ubiquitin ligase. In summary, Ipa1 affects mRNA processing by controlling the availability of the C/P endonuclease and may represent a regulatory mechanism that could be rapidly deployed to facilitate reprogramming of cellular responses.

TSPAN8 promotes colorectal cancer cell growth and migration in LSD1-dependent manner.

AIMS: Colorectal cancer (CRC) is the fourth leading cause of cancer-related mortality worldwide. Over-expression of tetraspanin 8 (TSPAN8) is related to the development and progression of CRC. Whether TSPAN8 plays a role in the growth of colorectal cancer and its epigenetic mechanisms regulated by Lysine Specific Demethylase 1 (LSD1) are still unknown. MAIN METHODS: In this study, RT-PCR and western blotting were used to analyze the mRNA and protein expression, respectively; cell viability was assayed with MTS analysis; cell migration was measured with Trans-well analysis. KEY FINDINGS: In the present study, the results indicated that the mRNA levels of LSD1 and TSPAN8 in CRC were significantly higher than that in corresponding adjacent non-tumor tissue. Down-regulation of LSD1 or TSPAN8 as well as LSD1 inhibitor Tranylcypromine hemisulfate inhibited the proliferation and migration of CRC cells, while over-expression of LSD1 exhibited opposite effects. LSD1 up-regulated TSPAN8 expression and reduced H3K9me2 occupancy on the TSPAN8 promoter in CRC cells. TSPAN8 promoted epithelial-mesenchymal transition (EMT) in CRC cells in LSD1-dependent manner. SIGNIFICANCE: TSPAN8 may be considered as a promising biomarker for the diagnosis and prognosis in patients with CRC. Furthermore, TSPAN8 could be a novel therapeutic target and potent LSD1 inhibitors could be designed and developed in the treatment of CRC.

KDM5B promotes breast cancer cell proliferation and migration via AMPK-mediated lipid metabolism reprogramming.

Lysine demethylase 5B (KDM5B) is up-regulated in many cancers, including breast cancer. However, the underlying metabolic mechanisms of KDM5B on breast cancer progression are poorly understood. Here, we showed that KDM5B expression positively correlates with metastasis in breast cancer. Cell functional analyses were demonstrated that KDM5B knockdown and KDM5B inhibitor AS-8351 inhibited breast cancer cell proliferation and migration. Furthermore, we reported that KDM5B knockdown and AS-8351 reversed epithelial-mesenchymal transition (EMT) and decreased the protein levels of fatty acid synthase (FASN) and ATP citrate lyase (ACLY) in MCF-7 and MDA-MB-231 cells. Interestingly, we found that activation of AMP-activated protein kinase (AMPK) signaling pathway is involved in KDM5B-mediated EMT and lipid metabolism reprogramming in breast cancer cells. As a result, silencing of KDM5B-induced activation of AMPK signaling pathway inhibited breast cancer cell proliferation and migration. Taken together, our findings indicated that KDM5B was a novel regulator of lipid metabolism reprogramming, and it was suggested a new strategy to treat breast cancer.

Nrf2 promotes breast cancer cell migration via up-regulation of G6PD/HIF-1α/Notch1 axis.

Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF-E2-related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch-like ECH-associated protein 1 (Keap1) reduced the expression of glucose-6-phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia-inducing factor 1α (HIF-1α) in MCF-7 and MDA-MB-231 cells. Overexpression of Nrf2 up-regulated the expression of Notch1 via G6PD/HIF-1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES-1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2-driven breast cancer metastasis.

Fabrication of visible-light-driven silver iodide modified iodine-deficient bismuth oxyiodides Z-scheme heterojunctions with enhanced photocatalytic activity for Escherichia coli inactivation and tetracycline degradation.

At present, various organic pollutants and pathogenic microorganisms presented in wastewater have severely threatened aquatic ecosystem and human health. Meanwhile, semiconductor photocatalysis technology for water purification has attracted increasingly significant attention. Herein, we successfully constructed a series of novel visible-light-driven (VLD) Bi4O5I2/AgI hybrid photocatalysts with different AgI amounts. Compared with pristine AgI and Bi4O5I2, Bi4O5I2/AgI with the optimal AgI contents exhibited remarkably enhanced photocatalytic performance in probe experiment for Escherichia coli (E. coli) disinfection and tetracycline (TC) degradation. The efficiency for TC degradation and E. coli inactivation reached 82% and 100% in 30 min, respectively. The enhanced electron-hole separation efficiency was responsible for improved photocatalytic activity. In addition, the destruction process of the chemical structure of TC molecules was further investigated by three-dimensional excitation-emission matrix fluorescence spectra (3D EEMs). The activity and crystal phase of the catalysts did not change significantly after four cycles, demonstrating their excellent recyclability and stability of catalysts. The Ag+ ion leaking experiments, radical trapping experiments and ESR tests demonstrated that OH, O2- and h+ were the main active species in photocatalytic disinfection processes. Furthermore, the photocatalytic mechanism of Bi4O5I2/AgI nanomaterials was discussed in detail in conjunction with the energy band structure, and a reasonable Z-scheme interfacial charge transfer mechanism was proposed. This work is expected to provide an efficient water disinfection method.

Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1.

Colorectal cancer (CRC) is the third-leading cause of cancer mortality worldwide. HACE1 function as a tumor-suppressor gene and is downregulated in several kinds of cancers. However, the distribution and clinical significance of HACE1 in CRC is still not clarified. In this study, we found that the HACE1 expression is greatly downregulated in CRC tissues and cell lines. Moreover, the HACE1 expression was significantly associated with inhibition of CRC cell proliferation, metastasis, and invasion. HACE1 inhibited epithelial-mesenchymal transition in CRC cells. Furthermore, we found that HACE1 altered the protein expression of the Hippo pathway by downregulation of YAP1. HACE1 suppresses the invasive ability of CRC cells by negatively regulating the YAP1 pathway. Our data indicates that HACE1 directly targets YAP1 and induces downregulation of YAP1, thereby increasing the activity of the Hippo pathway. In summary, these findings demonstrated that HACE1-YAP1 axis had an important part in the CRC development and progression.

Surfactant-enhanced flushing enhances colloid transport and alters macroporosity in diesel-contaminated soil.

Soil contamination by diesel has been often reported as a result of accidental spillage, leakage and inappropriate use. Surfactant-enhanced soil flushing is a common remediation technique for soils contaminated by hydrophobic organic chemicals. In this study, soil flushing with linear alkylbenzene sulfonates (LAS, an anionic surfactant) was conducted for intact columns (15cm in diameter and 12cm in length) of diesel-contaminated farmland purple soil aged for one year in the field. Dynamics of colloid concentration in column outflow during flushing, diesel removal rate and resulting soil macroporosity change by flushing were analyzed. Removal rate of n-alkanes (representing the diesel) varied with the depth of the topsoil in the range of 14%-96% while the n-alkanes present at low concentrations in the subsoil were completely removed by LAS-enhanced flushing. Much higher colloid concentrations and larger colloid sizes were observed during LAS flushing in column outflow compared to water flushing. The X-ray micro-computed tomography analysis of flushed and unflushed soil cores showed that the proportion of fine macropores (30-250µm in diameter) was reduced significantly by LAS flushing treatment. This phenomenon can be attributed to enhanced clogging of fine macropores by colloids which exhibited higher concentration due to better dispersion by LAS. It can be inferred from this study that the application of LAS-enhanced flushing technique in the purple soil region should be cautious regarding the possibility of rapid colloid-associated contaminant transport via preferential pathways in the subsurface and the clogging of water-conducting soil pores.

New Disubstituted Quindoline Derivatives Inhibiting Burkitt's Lymphoma Cell Proliferation by Impeding c-MYC Transcription.

The c-MYC oncogene is overactivated during Burkitt's lymphoma pathogenesis. Targeting c-MYC to inhibit its transcriptional activity has emerged as an effective anticancer strategy. We synthesized four series of disubstituted quindoline derivatives by introducing the second cationic amino side chain and 5-N-methyl group based on a previous study of SYUIQ-5 (1) as c-MYC promoter G-quadruplex ligands. The in vitro evaluations showed that all new compounds exhibited higher stabilities and binding affinities, and most of them had better selectivity (over duplex DNA) for the c-MYC G-quadruplex compared to 1. Moreover, the new ligands prevented NM23-H2, a transcription factor, from effectively binding to the c-MYC G-quadruplex. Further studies showed that the selected ligand, 7a4, down-regulated c-MYC transcription by targeting promoter G-quadruplex and disrupting the NM23-H2/c-MYC interaction in RAJI cells. 7a4 could inhibit Burkitt's lymphoma cell proliferation through cell cycle arrest and apoptosis and suppress tumor growth in a human Burkitt's lymphoma xenograft.

Discovery of Small Molecules for Repressing Cap-Independent Translation of Human Vascular Endothelial Growth Factor (hVEGF) as Novel Antitumor Agents.

Angiogenesis is important in tumorigenesis and tumor progression. Human vascular endothelial growth factor (hVEGF) is an angiogenic growth factor that plays a crucial role in tumor progression. The G-rich region within the 5'-untranslated regions (5'-UTR) of hVEGF-A mRNA can form a "switchable" RNA G-quadruplex structure that is essential for a cap-independent translation initiation. We screened our small-molecule library for binders of this G-tract. One novel quinazoline derivative, compound 1, showed a significant specific interaction with the G-tract and destabilized the G-quadruplex structure. The results of cellular experiments revealed that compound 1 down-regulated hVEGF-A translation and significantly impeded tumor cells migration. We also found that compound 1 exhibited tumor-inhibiting activity in MCF-7 xenograft tumors, which might be related to its ability to reduce hVEGF expression. These findings present a new strategy of hVEGF-A translational control in which small molecules interact with G-quadruplex structure in the 5'UTR.

Conformation Selective Antibody Enables Genome Profiling and Leads to Discovery of Parallel G-Quadruplex in Human Telomeres.

G-quadruplexes are specialized secondary structures in nucleic acids that possess significant conformational polymorphisms. The precise G-quadruplex conformations in vivo and their relevance to biological functions remain controversial and unclear, especially for telomeric G-quadruplexes. Here, we report a novel single-chain variable fragment (scFv) antibody, D1, with high binding selectivity for parallel G-quadruplexes in vitro and in vivo. Genome-wide chromatin immunoprecipitation using D1 and deep-sequencing revealed the consensus sequence for parallel G-quadruplex formation, which is characterized by G-rich sequence with a short loop size (<3 nt). By using D1, telomeric parallel G-quadruplex was identified and its formation was regulated by small molecular ligands targeting and telomere replication. Together, parallel G-quadruplex specific antibody D1 was found to be a valuable tool for determination of G-quadruplex and its conformation, which will prompt further studies on the structure of G-quadruplex and its biological implication in vivo.

A newly identified berberine derivative induces cancer cell senescence by stabilizing endogenous G-quadruplexes and sparking a DNA damage response at the telomere region.

The guanine-rich sequences are able to fold into G-quadruplexes in living cells, making these structures promising anti-cancer drug targets. In the current study, we identified a small molecule, Ber8, from a series of 9-substituted berberine derivatives and found that it could induce acute cell growth arrest and senescence in cancer cells, but not in normal fibroblasts. Further analysis revealed that the cell growth arrest was directly associated with apparent cell cycle arrest, cell senescence, and profound DNA damage at the telomere region. Significantly, our studies also provided evidence that Ber8 could stabilize endogenous telomeric G-quadruplexes structures in cells. Ber8 could then induce the delocalization of TRF1 and POT1 from the telomere accompanied by a rapid telomere uncapping. These results provide compelling insights into direct binding of telomeric G-quadruplexes and might contribute to the development of more selective, effective anticancer drugs.

Chemical intervention of the NM23-H2 transcriptional programme on c-MYC via a novel small molecule.

c-MYC is an important oncogene that is considered as an effective target for anticancer therapy. Regulation of this gene's transcription is one avenue for c-MYC-targeting drug design. Direct binding to a transcription factor and generating the intervention of a transcriptional programme appears to be an effective way to modulate gene transcription. NM23-H2 is a transcription factor for c-MYC and is proven to be related to the secondary structures in the promoter. Here, we first screened our small-molecule library for NM23-H2 binders and then sifted through the inhibitors that could target and interfere with the interaction process between NM23-H2 and the guanine-rich promoter sequence of c-MYC. As a result, a quinazolone derivative, SYSU-ID-01: , showed a significant interference effect towards NM23-H2 binding to the guanine-rich promoter DNA sequence. Further analyses of the compound-protein interaction and the protein-DNA interaction provided insight into the mode of action for SYSU-ID-01: . Cellular evaluation results showed that SYSU-ID-01: could abrogate NM23-H2 binding to the c-MYC promoter, resulting in downregulation of c-MYC transcription and dramatically suppressed HeLa cell growth. These findings provide a new way of c-MYC transcriptional control through interfering with NM23-H2 binding to guanine-rich promoter sequences by small molecules.