Discovery of Self-Assembled 2D Ru/Si Superlattices Boosting Hydrogen Evolution.

2D heterostructuring is a versatile methodology for designing nanoarchitecture catalytic systems that allow for reconstruction and modulation of interfaces and electronic structures. However, catalysts with such structures are extremely scarce due to limited synthetic strategies. Here, a highly ordered 2D Ru/Si/Ru/Si… nano-heterostructures (RSHS) is reported by acid etching of the LaRuSi electride. RSHS shows a superior electrocatalytic activity for hydrogen evolution with an overpotential of 14 mV at 10 mA cm-2 in alkaline media. Both experimental analysis and first-principles calculations demonstrate that the electronic states of Ru can be tuned by strong interactions of the interfacial Ru-Si, leading to an optimized hydrogen adsorption energy. Moreover, due to the synergistic effect of Ru and Si, the energy barrier of water dissociation is significantly reduced. The well-organized superlattice structure will provide a paradigm for construction of efficient catalysts with tunable electronic states and dual active sites.

Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.

Dipole Coupling Accelerated H2 O Dissociation by Magnesium-Based Intermetallic Catalysts.

The water (H2 O) dissociation is critical for various H2 O-associated reactions, including water gas shift, hydrogen evolution reaction and hydrolysis corrosion. While the d-band center concept offers a catalyst design guideline for H2 O activation, it cannot be applied to intermetallic or main group elements-based systems because Coulomb interaction was not considered. Herein, using hydrolysis corrosion of Mg as an example, we illustrate the critical role of the dipole of the intermetallic catalysts for H2 O dissociation. The H2 O dissociation kinetics can be enhanced using Mgx Mey (Me=Co, Ni, Cu, Si and Al) as catalysts, and the hydrogen generation rate of Mg2 Ni-loaded Mg reached 80 times as high as Ni-loaded Mg. The adsorbed H2 O molecules strongly couple with the Mg-Me dipole of Mgx Mey , lowering the H2 O dissociation barrier. The dipole-based H2 O dissociation mechanism is applicable to non-transition metal-based systems, such as Mg2 Si and Mg17 Al12 , offering a flexible catalyst design strategy for controllable H2 O dissociation.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

Unique Catalytic Mechanism for Ru-Loaded Ternary Intermetallic Electrides for Ammonia Synthesis.

Intermetallic electrides have recently shown their priority as catalyst components in ammonia synthesis and CO2 activation. However, their function mechanism has been elusive since its inception, which hinders the further development of such catalysts. In this work, ternary intermetallic electrides La-TM-Si (TM = Co, Fe, and Mn) were synthesized as hosts of ruthenium (Ru) particles for ammonia synthesis catalysis. Although they have the same crystal structure and possess low work functions commonly, the promotion effects on Ru particles rather differ from each other. The catalytic activity follows the sequence of Ru/LaCoSi > Ru/LaFeSi > Ru/LaMnSi. Furthermore, Ru/LaCoSi exhibits much better catalytic durability than the other two. A combination of experiments and first-principles calculations shows that apparent N2 activation energy on each catalyst is much lower than that over conventional Ru-based catalysts, which suggests that N2 dissociation can be conspicuously promoted by the concerted actions of the specific electronic structure and atomic configuration of intermetallic electride-supported catalysts. The NHx formations proceeded on La are energetically favored, which makes it possible to bypass the scaling relations based on only Ru as the active site. The rate-determining step of Ru/La-TM-Si was identified to be NH2 formation. The transition metal (TM) in La-TM-Si electrides has a significant influence on the metal-support interaction of Ru and La-TM-Si. These findings provide a guide for the development of new and effective catalyst hosts for ammonia synthesis and other hydrogenation reactions.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

Dissociative and Associative Concerted Mechanism for Ammonia Synthesis over Co-Based Catalyst.

The current catalytic reaction mechanism for ammonia synthesis relies on either dissociative or associative routes, in which adsorbed N2 dissociates directly or is hydrogenated step-by-step until it is broken upon the release of NH3 through associative adsorption. Here, we propose a concerted mechanism of associative and dissociative routes for ammonia synthesis over a cobalt-loaded nitride catalyst. Isotope exchange experiments reveal that the adsorbed N2 can be activated on both Co metal and the nitride support, which leads to superior low-temperature catalytic performance. The cooperation of the surface low work function (2.6 eV) feature and the formation of surface nitrogen vacancies on the CeN support gives rise to a dual pathway for N2 activation with much reduced activation energy (45 kJ·mol-1) over that of Co-based catalysts reported so far, which results in efficient ammonia synthesis under mild conditions.

Upconversion nanoparticle and gold nanocage satellite assemblies for sensitive ctDNA detection in serum.

A rapid molecular diagnostic technique targeting circulating tumor DNA (ctDNA) has become one of the most clinically significant liquid biopsy methods for non-invasive and timely diagnosis of cancer. Herein, a sensitive detection system of ctDNA based on a fluorescence resonance energy transfer (FRET) system using upconversion nanoparticles (UCNPs) and gold nanocages (AuNCs) was constructed. Through the doping of Yb and Tm ions, the excitation and emission wavelengths of UCNPs were adjusted to 980 nm and 806 nm, respectively. Subsequently, UCNPs and AuNCs with the corresponding wavelength absorption were linked by complementary pairing of surface-modified DNA to form near-infrared fluorescent nanoprobes (NIR probes). Targeting DNA mutation recognition and signal transduction were realized by using NIR probes through the toehold-mediated strand displacement reaction. This method could detect a single point mutation of the KRAS gene with a wide detection range from 5 pM to 1000 pM and the limit of detection reached 6.30 pM. More importantly, the stable and highly specific NIR probes could be directly used in the serum environment without complicated pretreatment and amplification processes in advance. It could be envisioned that this specific and sensitive ctDNA detection strategy has great potential in clinical diagnosis and monitoring of diverse malignant tumors.

Patchouli Oil Attenuates High Fat Diet-induced Non-alcoholic Hepatic Steatosis.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Nevertheless, no first-line therapy exists. Hepatic steatosis is the earliest stage of NAFLD, which is characterized by an accumulation of hepatic lipids. Patchouli oil (PO), which is isolated from the well-known Chinese herb named Pogostemon cablin (Blanco) Benth. (Lamiaceae), inhibits hepatic lipid accumulation effectively. However, its potential ability for the treatment of NAFLD had not been reported before. Thus, the objective of this study was to investigate the effectiveness of PO against hepatic steatosis and its underlying mechanisms. We used a high fat diet (HFD)-induced hepatic steatosis model of rats to estimate the effect of PO against NAFLD. Hematoxylin-eosin and oil red O staining were used to analyze the hepatic histopathological changes. ELISA, RT-qPCR, and Western blotting analysis were applied to evaluate the parameters for hepatic steatosis. Our results showed that PO significantly attenuated the lipid profiles and the serum enzymes, evidenced by quantitative and histopathological analyses. It also markedly down-regulated the expression of sterol regulatory element-binding protein 1 (SREPB-1c) with its downstream factors in de novo lipogenesis. And, likewise, in lipid export by very low-density lipoproteins (VLDL), related molecules were dramatically improved. Furthermore, PO observably normalized the aberrant peroxisome proliferator-activated receptor α (PPAR-α) signal in fatty acids oxidation. In conclusion, PO exerted a preventing effect against HFD-induced steatosis and might be due to decrease de novo lipogenesis, promote export of lipids, as well as owing to improve fatty acids oxidation.

Pseudogap Control of Physical and Chemical Properties in CeFeSi-Type Intermetallics.

We describe the synthesis of the new ternary compound CaRuSi whose chemical and physical properties help draw a clear picture of how electronic structure controls the behavior of an isostructural series of intermetallics. DFT calculations reveal that an electronic pseudogap arises near the Fermi level ( EF), corresponding to 14 valence electrons per RuSi unit. The closed-shell-like character is further investigated by comparisons with the electronic structures of CaCoSi (15 electrons), where the EF lies above the corresponding pseudogap, and its hydride CaCoSiH, where formation of H anions restores the 14-electron count on the metal sublattice, returning the EF to the pseudogap. The chemical origin of the 14-electron pseudogap is interpreted with a reversed approximation Molecular Orbital analysis. Here, the pseudogap is shown to coincide with the filling of Ru 16 electron configurations isolobal to the d8 square planar complexes of coordination chemistry (but where 4 electron pairs are shared covalently between Ru atoms such that only 12 electrons are required), and the occupation of Si lone pairs (2 electrons). Experimentally, the pseudogap is confirmed with heat capacity measurements, which indicate that the 14-electron systems CaRuSi and CaCoSiH each exhibit  a smaller electronic density of states at the EF than the 15-electron system CaCoSi. Importantly, the 14-electron pseudogap also significantly affects the chemical properties of the compounds, as evidenced by the difference in the stabilities of CaCoSiH and CaRuSiH observed in hydrogen desorption measurements. These results may support the design of functional materials for superconductivity, hydrogen storage, and catalysis involving hydrogenation.

Intermetallic Electride Catalyst as a Platform for Ammonia Synthesis.

Electrides loaded with transition-metal (TM) nanoparticles have recently attracted attention as emerging materials for catalytic NH3 synthesis. However, they suffer from disadvantages associated with the growth and aggregation of nanoparticles. TM-containing intermetallic electrides appear to be promising catalysts with the advantages of both electrides and transition metals in a single phase. LaRuSi is reported here to be an intermetallic electride with superior activity for NH3 synthesis, and direct evidence is provided supporting its electride-character-induced catalytic performance. The discussion is made mainly based on the contrasting synthesis rates over the isostructural compounds LaRuSi, CaRuSi, and LaRu2 Si2 , and the N2 isotope-exchange reactions over these compounds. Lattice hydride ions, which can reversibly exchange with anionic electrons, are shown to be indispensable in the promotion of NHx formation. The mechanism derived from the present findings provides new guidelines for NH3 synthesis.

Palmatine ameliorated murine colitis by suppressing tryptophan metabolism and regulating gut microbiota.

Inflammatory bowel disease (IBD), majorly include Crohn's disease (CD) and ulcerative colitis (UC), is chronic and relapsing inflammatory disorders of the gastrointestinal tract, which treatment options remain limited. Here we examined the therapeutic effects of an isoquinoline alkaloid, Palmatine (Pal), on mice experimental colitis induced by dextran sulfate sodium (DSS) and explored underlying mechanisms. Colitis was induced in BALB/c mice by administering 3% DSS in drinking water for 7 days. Pal (50 and 100 mg kg-1) and the positive drug Sulfasalazine (SASP, 200 mg kg-1) were orally administered for 7 days. Disease activity index (DAI) was evaluated on day 8, and colonic tissues were collected for biochemistry analysis. The fecal microbiota was characterized by high-throughput Illumina MiSeq sequencing. And plasma metabolic changes were detected by UPLC-MS. Our results showed that Pal treatment significantly reduced DAI scores and ameliorated colonic injury in mice with DSS-induced colitis. Mucosal integrity was improved and cell apoptosis was inhibited. Moreover, gut microbiota analysis showed that mice received Pal-treatment have higher relative abundance of Bacteroidetes and Firmicutes, but reduced amount of Proteobacteria. Moreover, Pal not only suppressed tryptophan catabolism in plasma, but also decreased the protein expression of indoleamine 2,3-dioxygenase 1 (IDO-1, the rate-limiting enzyme of tryptophan catabolism) in colon tissue. This is consolidated by molecular docking, which suggested that Pal is a potent IDO-1 inhibitor. Taken together, our findings demonstrate that Pal ameliorated DSS-induced colitis by mitigating colonic injury, preventing gut microbiota dysbiosis, and regulating tryptophan catabolism, which indicated that Pal has great therapeutic potential for colitis.

Patchoulene Epoxide Isolated from Patchouli Oil Suppresses Acute Inflammation through Inhibition of NF-κB and Downregulation of COX-2/iNOS.

According to the GC-MS analysis, compositional variation was observed between samples of patchouli oil, of which an unknown compound identified as patchoulene epoxide (PAO) was found only in the long-stored oil, whose biological activity still remains unknown. Therefore, the present study aimed to evaluate the potential anti-inflammatory activity with three in vivo inflammatory models: xylene-induced ear edema, acetic acid-induced vascular permeability, and carrageenan-induced paw edema. Further investigation into its underlying mechanism on carrageenan-induced paw edema was conducted. Results demonstrated that PAO significantly inhibited the ear edema induced by xylene, lowered vascular permeability induced by acetic acid and decreased the paw edema induced by carrageenan. Moreover, PAO markedly decreased levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), prostaglandin E2 (PGE2), and nitric oxide (NO), but increased levels of interleukin-4 (IL-4) and interleukin-10 (IL-10). PAO was also shown to significantly downregulate the protein and mRNA expressions of cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS). Western blot analysis revealed that PAO remarkably inhibited p50 and p65 translocation from the cytosol to the nucleus by suppressing IKKß and IκBα phosphorylation. In conclusion, PAO exhibited potent anti-inflammatory activity probably by suppressing the activation of iNOS, COX-2 and NF-κB signaling pathways.

Antisite-Defects Control of Magnetic Properties in MnSb2Te4.

The intrinsic magnetic topological materials Mn(Sb/Bi)2n+2Te3n+4 have attracted extensive attention due to their topological quantum properties. Although, the Mn-Sb/Bi antisite defects have been frequently reported to exert significant influences on both magnetism and band topology, their formation mechanism and the methods to manipulate their distribution and concentration remain elusive. Here, we present MnSb2Te4 as a typical example and demonstrate that Mn-Sb antisite defects and magnetism can be tuned by controlling the crystal growth conditions. The cooling rate is identified as the primary key parameter. Magnetization and chemical analysis demonstrate that a slower cooling rate would lead to a higher Mn concentration, a higher magnetic transition temperature, and a higher saturation moment. Further analysis indicates that the Mn content at the original Mn site (MnMn, 3a site) varies more significantly with the cooling rate than the Mn content at the Sb site (MnSb, 6c site). Based on experimental observations, magnetic phase diagrams regarding MnMn and MnSb concentrations are constructed. With the assistance of first-principles calculations, it is demonstrated that the Mn-Sb mixing states primarily result from the mixing entropy and the growth kinetics. The present findings offer valuable insights into defects engineering for preparation of two-dimensional quantum materials.

Tetrahydrocurcumin ameliorates hepatic steatosis by restoring hepatocytes lipophagy through mTORC1-TFEB pathway in nonalcoholic steatohepatitis.

PURPOSE: To investigate the therapeutic effect and underlying mechanism of tetrahydrocurcumin (THC) on nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD). METHODS: NASH rat model was established through long-term feeding HFD, and the steatosis cell model was stimulated via palmitate acid (PA). The therapeutic effect of THC was evaluated in terms of liver function, lipid metabolism, liver pathophysiology, inflammation and oxidative stress in vivo, and lipid accumulation in vitro. The alteration in lipophagy was identified by using western blot and immunofluorescence. mTORC1-TFEB signaling pathway was measured by qRT-PCR, western blot and protein-ligand docking. In addition, chloroquine and MHY1485 were further introduced to validate the effect of THC on lipophagy and mTORC1-TFEB signaling pathway, respectively. RESULTS: THC effectively improved hepatic steatosis, inflammation and oxidative stress in NASH rats, and reduced lipid accumulation in steatosis L02 cells and Hep G2 cells. THC promoted lipophagy with increasing LC3B-II as well as decreasing P62 expression via lysosomal biogenesis upregulation, which was greatly weakened after chloroquine intervention. mTORC1-TFEB is a critical pathway for regulating lysosome in autophagy, THC treatment induced TFEB nucleus translocation via inhibiting mTORC1 to upregulate lysosomal biogenesis. However, these effects were partly eliminated by mTORC1 activator MHY1485. CONCLUSION: THC restored lipophagy to reduce lipid accumulation by regulating mTORC1-TFEB pathway in NASH rats and steatosis hepatocytes. These findings suggested that THC represents a therapeutic candidate for NASH treatment.

Interpretable machine learning models for the prediction of all-cause mortality and time to death in hemodialysis patients.

INTRODUCTION: The elevated mortality and hospitalization rates among hemodialysis (HD) patients underscore the necessity for the development of accurate predictive tools. This study developed two models for predicting all-cause mortality and time to death-one using a comprehensive database and another simpler model based on demographic and clinical data without laboratory tests. METHOD: A retrospective cohort study was conducted from January 2017 to June 2023. Two models were created: Model A with 85 variables and Model B with 22 variables. We assessed the models using random forest (RF), support vector machine, and logistic regression, comparing their performance via the AU-ROC. The RF regression model was used to predict time to death. To identify the most relevant factors for prediction, the Shapley value method was used. RESULTS: Among 359 HD patients, the RF model provided the most reliable prediction. The optimized Model A showed an AU-ROC of 0.86 ± 0.07, a sensitivity of 0.86, and a specificity of 0.75 for predicting all-cause mortality. It also had an R2 of 0.59 for predicting time to death. The optimized Model B had an AU-ROC of 0.80 ± 0.06, a sensitivity of 0.81, and a specificity of 0.70 for predicting all-cause mortality. In addition, it had an R2 of 0.81 for predicting time to death. CONCLUSION: Two new interpretable clinical tools have been proposed to predict all-cause mortality and time to death in HD patients using machine learning models. The minimal and readily accessible data on which Model B is based makes it a valuable tool for integrating into clinical decision-making processes.

Aberrant concordance among dynamics of spontaneous brain activity in patients with migraine without aura: A multivariate pattern analysis study.

Background: Alterations in the static and dynamic characteristics of spontaneous brain activity have been extensively studied to investigate functional brain changes in migraine without aura (MwoA). However, alterations in concordance among the dynamics of spontaneous brain activity in MwoA remain largely unknown. This study aimed to determine the possibilities of diagnosis based on the concordance indices. Methods: Resting-state functional MRI scans were performed on 32 patients with MwoA and 33 matched healthy controls (HCs) in the first cohort, as well as 36 patients with MwoA and 32 HCs in the validation cohort. The dynamic indices including fractional amplitude of low-frequency fluctuation, regional homogeneity, voxel-mirrored homotopic connectivity, degree centrality and global signal connectivity were analyzed. We calculated the concordance of grey matter volume-wise (across voxels) and voxel-wise (across time windows) to quantify the degree of integration among different functional levels represented by these dynamic indices. Subsequently, the voxel-wise concordance alterations were analyzed as features for multi-voxel pattern analysis (MVPA) utilizing the support vector machine. Results: Compared with that of HCs, patients with MwoA had lower whole-grey matter volume-wise concordance, and the mean value of volume-wise concordance was negatively correlated with the frequency of migraine attacks. The MVPA results revealed that the most discriminative brain regions were the right thalamus, right cerebellar Crus II, left insula, left precentral gyrus, right cuneus, and left inferior occipital gyrus. Conclusions: Concordance alterations in the dynamics of spontaneous brain activity in brain regions could be an important feature in the identification of patients with MwoA.

Phage therapy combats pan drug-resistant Acinetobacter baumannii infection safely and efficiently.

Phage therapy offers a promising approach to combat the growing threat of antimicrobial resistance. Yet, key questions remain regarding dosage, administration routes, combination therapy, and the causes of therapeutic failure. In this study, we focused on a novel lytic phage, ФAb4B, which specifically targeted the Acinetobacter baumannii strains with KL160 capsular polysaccharide, including the pan-drug resistant A. baumannii YQ4. ФAb4B exhibited the ability to effectively inhibit biofilm formation and eradicate mature biofilms independently of dosage. Additionally, it demonstrated a wide spectrum of antibiotic-phage synergy and did not show any cytotoxic or haemolytic effects. Continuous phage injections, both intraperitoneally and intravenously over 7 d, showed no acute toxicity in vivo. Importantly, phage therapy significantly improved neutrophil counts, outperforming ciprofloxacin. However, excessive phage injections suppressed neutrophil levels. The combinatorial treatment of phage-ciprofloxacin rescued 91% of the mice, a superior outcome compared to phage alone (67%). The efficacy of the combinatorial treatment was independent of phage dosage. Notably, prophylactic administration of the combinatorial regimen provided no protection, but even when combined with a delayed therapeutic regimen, it saved all the mice. Bacterial resistance to the phage was not a contributing factor to treatment failure. Our preclinical study systematically describes the lytic phage's effectiveness in both in vitro and in vivo settings, filling in crucial details about phage treatment against bacteriemia caused by A. baumannii, which will provide a robust foundation for the future of phage therapy.

Unraveling the Promise of RET Inhibitors in Precision Cancer Therapy by Targeting RET Mutations.

Over the past decades, the role of rearranged during transfection (RET) alterations in tumorigenesis has been firmly established. RET kinase inhibition is an essential therapeutic target in patients with RET-altered cancers. In clinical practice, initial efficacy can be achieved in patients through the utilization of multikinase inhibitors (MKIs) with RET inhibitory activity. However, the effectiveness of these MKIs is impeded by the adverse events associated with off-target effects. Recently, many RET-selective inhibitors, characterized by heightened specificity and potency, have been developed, representing a substantial breakthrough in the field of RET precision oncology. This Perspective focuses on the contemporary understanding of RET mutations, recent advancements in next-generation RET inhibitors, and the challenges associated with resistance to RET inhibitors. It provides valuable insights for the development of next-generation MKIs and selective RET inhibitors.

Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging.

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.