Structure Responsible for the Superconducting State in La3Ni2O7 at High-Pressure and Low-Temperature Conditions.

Very recently, a new superconductor with Tc = 80 K has been reported in nickelate (La3Ni2O7) at around 15-40 GPa conditions (Nature, 621, 493, 2023), which is the second type of unconventional superconductor, besides cuprates, with Tc above liquid nitrogen temperature. However, the phase diagram plotted in this report was mostly based on the transport measurement under low-temperature and high-pressure conditions, and the assumed corresponding X-ray diffraction (XRD) results were carried out at room temperature. This encouraged us to carry out in situ high-pressure and low-temperature synchrotron XRD experiments to determine which phase is responsible for the high Tc state. In addition to the phase transition from the orthorhombic Amam structure to the orthorhombic Fmmm structure, a tetragonal phase with the space group of I4/mmm was discovered when the sample was compressed to around 19 GPa at 40 K where the superconductivity takes place in La3Ni2O7. The calculations based on this tetragonal structure reveal that the electronic states that approached the Fermi energy were mainly dominated by the eg orbitals (3dz2 and 3dx2-y2) of Ni atoms, which are located in the oxygen octahedral crystal field. The correlation between Tc and this structural evolution, especially Ni-O octahedra regularity and the in-plane Ni-O-Ni bonding angles, is analyzed. This work sheds new light to identify what is the most likely phase responsible for superconductivity in double-layered nickelate.

Negative linear compressibility and strong enhancement of emission in Eu[Ag(CN)2]3·3H2O under pressure.

The framework material Eu[Ag(CN)2]3·3H2O exhibits a negative linear compressibility (NLC) of -4.2(1) TPa-1 over the largest pressure range yet observed (0-8.2 GPa). High-pressure single-crystal X-ray diffraction data show that the rapid contraction of the Kagome silver layers under compression causes the wine-rack lattice to expand along the c-axis. The hydrogen bonds between the water molecules and the main frameworks constrain the structural deformation under pressure and eventually a weak NLC effect generated. Furthermore, we found that the pressure-induced emission intensity increases almost 800-fold at 4.0 GPa, followed by a gradual decrease and disappearance at 8.1 GPa. Under compression, high pressure significantly tunes the triplet level positions near the Eu3+ ions, and horizontal displacement between a quenching excited state and the excited levels of Eu3+ facilitates the energy transfer process to the 5D0 excited state and limits the nonradiative corssover at elevated pressures, thus increasing the emission intensity. In addition, we observe a gradual band gap reduction with increasing pressure, and the sample could not be returned to the initial state after the pressure was completely released. By controlling the structural flexibility, we observe a coupled NLC and pressure-induced strong enhancement of the emission properties of Eu[Ag(CN)2]3·3H2O, which provides a new route for the design of new optical devices with intriguing luminescence properties under extreme environments.

Control of lipolysis by a population of oxytocinergic sympathetic neurons.

Oxytocin (OXT), a nine-amino-acid peptide produced in the hypothalamus and released by the posterior pituitary, has well-known actions in parturition, lactation and social behaviour1, and has become an intriguing therapeutic target for conditions such as autism and schizophrenia2. Exogenous OXT has also been shown to have effects on body weight, lipid levels and glucose homeostasis1,3, suggesting that it may also have therapeutic potential for metabolic disease1,4. It is unclear, however, whether endogenous OXT participates in metabolic homeostasis. Here we show that OXT is a critical regulator of adipose tissue lipolysis in both mice and humans. In addition, OXT serves to facilitate the ability of ß-adrenergic agonists to fully promote lipolysis. Most surprisingly, the relevant source of OXT in these metabolic actions is a previously unidentified subpopulation of tyrosine hydroxylase-positive sympathetic neurons. Our data reveal that OXT from the peripheral nervous system is an endogenous regulator of adipose and systemic metabolism.

A Mechanism Study on the (+)-ESI-TOF/HRMS Fragmentation of Some PPI Prazoles and Their Related Substances.

Fragmentation mechanisms of some prazoles and their related substances were newly investigated in this paper via positive mode ESI-TOF HRMS1 and HRMS2. Some novel fragmentation rules or ions were found or detected in the research. The pyridine and the benzoimidazole ring remained in most cases during the ionization, and heterolytic fragmentations often occurred near the -S(O)nCH2- linker to give the [1,3]-H migration ion or [1,7]-H migration ion rearranging across the benzoimdazole ring. Smiles rearrangement ionizations also frequently occurred, initiated by the attack of the lone pair electrons from the pyridine ring, and the sulfones gave special N-(2-benzoimdazolyl) pyridine ions (11b and 12c) by a direct extraction from SO2, and the thioethers gave similar framework ions (8c, 9c and 10c) via the rearrangement and a further homolytic cleavage of SH radicals. However, the sulfoxides were seldom detected in the corresponding Smiles rearrangement ions during our measurement, and the N'-oxides of the pyridines did not undergo the Smiles rearrangement ionization due to the absence of the lone pair electrons. The 5/6-membered chelating ions with Na+ or K+ were frequently detected as the molecular and further fragment ions. Some novel and interesting fragment ions containing bivalent (8b and 9b), tetravalent (4b, 5c and 6c) or hexavalent (15b and 16b) sulfurs were first reported here.

Photosensitive small extracellular vesicles regulate the immune microenvironment of triple negative breast cancer.

Currently, the treatment of triple-negative breast cancer (TNBC) is limited by the special pathological characteristics of this disease. In recent years, photodynamic therapy (PDT) has created new hope for the treatment of TNBC. Moreover, PDT can induce immunogenic cell death (ICD) and improve tumor immunogenicity. However, even though PDT can improve the immunogenicity of TNBC, the inhibitory immune microenvironment of TNBC still weakens the antitumor immune response. Therefore, we used the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by TNBC cells to improve the tumor immune microenvironment and enhance antitumor immunity. In addition, bone mesenchymal stem cell (BMSC)-derived sEVs have good biological safety and a strong drug loading capacity, which can effectively improve the efficiency of drug delivery. In this study, we first obtained primary BMSCs and sEVs, and then the photosensitizers Ce6 and GW4869 were loaded into the sEVs by electroporation to produce immunomodulatory photosensitive nanovesicles (Ce6-GW4869/sEVs). When administered to TNBC cells or orthotopic TNBC models, these photosensitive sEVs could specifically target TNBC and improve the tumor immune microenvironment. Moreover, PDT combined with GW4869-based therapy showed a potent synergistic antitumor effect mediated by direct killing of TNBC and activation of antitumor immunity. Here, we designed photosensitive sEVs that could target TNBC and regulate the tumor immune microenvironment, providing a potential approach for improving the effectiveness of TNBC treatment. STATEMENT OF SIGNIFICANCE: We designed an immunomodulatory photosensitive nanovesicle (Ce6-GW4869/sEVs) with the photosensitizer Ce6 to achieve photodynamic therapy and the neutral sphingomyelinase inhibitor GW4869 to inhibit the secretion of small extracellular vesicles (sEVs) by triple-negative breast cancer (TNBC) cells to improve the tumor immune microenvironment and enhance antitumor immunity. In this study, the immunomodulatory photosensitive nanovesicle could target TNBC cells and regulate the tumor immune microenvironment, thus providing a potential approach for improving the treatment effect in TNBC. We found that the reduction in tumor sEVs secretion induced by GW4869 improved the tumor-suppressive immune microenvironment. Moreover, similar therapeutic strategies can also be applied in other kinds of tumors, especially immunosuppressive tumors, which is of great value for the clinical translation of tumor immunotherapy.

Computational Investigations of Reaction Mechanisms and Transformation Products of Olefins with Hypochlorous Acid.

Hypochlorous acid (HOCl) as the main component in chlorination and also as the innate immune factor relevant to immune defense has attracted considerable attention. Electrophilic addition reaction of olefins with HOCl, one of the most important prototype of chemical reactions, has been intensively studied for a long time; however, it has not been fully understood yet. In this study, addition reaction mechanisms and transformation products of model olefins with HOCl were systematically investigated by the density functional theory method. The results indicate that the traditionally believed stepwise mechanism with a chloronium-ion intermediate is only suitable for olefins substituted with electron-donating groups (EDGs) and weak electron-withdrawing groups (EWGs) but it is a carbon-cation intermediate that is favorable for EDGs featuring p-π or π-π conjugation with the C═C moiety. Moreover, olefins substituted with moderate or/and strong EWGs prefer the concerted and nucleophilic addition mechanisms, respectively. Epoxide and truncated aldehyde as the main transformation products can be generated from chlorohydrin through a series of reactions involving hypochlorite; however, their generation is kinetically not as feasible as the formation of chlorohydrin. The reactivity of three chlorinating agents (HOCl, Cl2O, and Cl2) and the case study of chlorination and degradation of cinnamic acid were also explored. Additionally, APT charge on the double-bond moiety in olefin and energy gap (ΔE) between the highest occupied molecular orbital (HOMO) energy of olefin and the lowest unoccupied molecular orbital (LUMO) energy of HOCl were found to be good parameters to distinguish the regioselectivity of chlorohydrin and reactivity of olefin, respectively. The findings of this work are helpful in further understanding the chlorination reactions of unsaturated compounds and identifying complicated transformation products.

Pressure-Induced Ferroelastic Transition Drives a Large Shape Change in a Ni(II) Complex Single Crystal.

Crystals with significant length reduction at an accessible low pressure are highly desirable for piezo-responsive devices. Here, we show a molecular crystal [Ni(en)3](ox) (en = ethylenediamine and ox = oxalate anion) that exhibits an abrupt shape change with a contraction rate of ∼4.7% along its c axis near the phase transition pressure of ∼0.2 GPa. High-pressure single-crystal X-ray diffraction and Raman spectroscopy measurements reveal that this material undergoes a first-order ferroelastic transition from high-symmetry trigonal P3̅1c to low-symmetry monoclinic P21/n at ∼0.2 GPa. The oxalate anions serve as unique components, and their disorder-order transformation and rotation of 90° through cooperative intermolecular hydrogen bonding triggered unconventional anisotropic microsize contraction under compression, which can be appreciated visually. Such a prominent directional deformation at a low pressure driven by molecular motors of oxalate anions provides insights for the design of novel molecular crystal-based piezo-responsive switches and actuators in deep-sea environments.

Early crystallization of amorphous selenium under high pressure studied by synchrotron XRD method.

The amorphous selenium (a-Se) was studied via x-ray diffraction (XRD) under pressures ranging from ambient pressure up to 30 GPa at room temperature to study its high-pressure behavior. Two compressional experiments on a-Se samples, with and without heat treatment, respectively, were conducted. Contrary to the previous reports that a-Se crystallized abruptly at around 12 GPa, in this work we report an early partially crystallized state at 4.9 GPa before completing the crystallization at around 9.5 GPa based onin-situhigh pressure XRD measurements on the a-Se with 70 °C heat treatment. In comparison, crystallization pressure on another a-Se sample without thermal treatment history was observed to be 12.7 GPa, consistent with the previously reported crystallization pressure. Thus, it is proposed in this work that prior heat treatment of a-Se can result in an earlier crystallization under high pressure, which helps to understand the possible mechanism caused by the previous controversial reports on pressure induced crystallization behavior in a-Se.

Design, synthesis, and biological evaluation of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines as potent EGFRT790M/L858R inhibitors to treat non-small cell lung cancer.

Three types of 2-arylamino-4-(piperidin-4-yloxy)pyrimidines (I-III) were designed and synthesized as covalent EGFR(epidermal growth factor receptor)T790M/L858R inhibitors by replacement of the common reported 4-(3-amino)phenoxyl moiety with 4-(4-hydroxy)piperidine-4-oxyl, and the introduction of fused-thiophene or -pyrrole on the pyrimidine core to strategically achieve conformational restriction. According to our biological evaluation, it was found that compound 9i could potently suppress EGFRT790M/L858R kinase and H1975 cell proliferation, with IC50 values of 4.902 nM and 0.6210 µM, respectively. Further study showed that 9i not only demonstrated highly selective inhibitory effects toward EGFRT790M/L858R over wild-type EGFR (EGFRWT), but it also had low cytotoxicity against normal HBE(human bronchial epithelial) and L-02 cells. Action mechanism studies showed that 9i effectively hindered cell migration and promoted apoptosis by AO(Acridine Orange)/EB(Ethidium Bromide) staining. These data would provide important clues for the screening of novel covalent EGFRT790M/L858R inhibitors for non-small cell lung cancer (NSCLC) treatment.

Record high Tc element superconductivity achieved in titanium.

It is challenging to search for high Tc superconductivity (SC) in transition metal elements wherein d electrons are usually not favored by conventional BCS theory. Here we report experimental discovery of surprising SC up to 310 GPa with Tc above 20 K in wide pressure range from 108 GPa to 240 GPa in titanium. The maximum Tconset above 26.2 K and zero resistance Tczero of 21 K are record high values hitherto achieved among element superconductors. The Hc2(0) is estimated to be ∼32 Tesla with coherence length 32 Å. The results show strong s-d transfer and d band dominance, indicating correlation driven contributions to high Tc SC in dense titanium. This finding is in sharp contrast to the theoretical predications based on pristine electron-phonon coupling scenario. The study opens a fresh promising avenue for rational design and discovery of high Tc superconductors among simple materials via pressure tuned unconventional mechanism.

Target and drug predictions for SARS-CoV-2 infection in hepatocellular carcinoma patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the coronavirus disease (COVID-19), which poses a major threat to humans worldwide. With the continuous progress of the pandemic, a growing number of people are infected with SARS-CoV-2, including hepatocellular carcinoma (HCC) patients. However, the relationship between COVID-19 and HCC has not been fully elucidated. In order to provide better treatment for HCC patients infected with SARS-CoV-2, it's urgently needed to identify common targets and find effective drugs for both. In our study, transcriptomic analysis was performed on both selected lung epithelial cell datasets of COVID-19 patients and the datasets of HCC patients to identify the synergistic effect of COVID-19 in HCC patients. What's more, common differentially expressed genes were identified, and a protein-protein interactions network was designed. Then, hub genes and basic modules were detected based on the protein-protein interactions network. Next, functional analysis was performed using gene ontology terminology and the Kyoto Encyclopedia of Genes and Genomes pathway. Finally, protein-protein interactions revealed COVID-19 interaction with key proteins associated with HCC and further identified transcription factor (TF) genes and microRNAs (miRNA) with differentially expressed gene interactions and transcription factor activity. This study reveals that COVID-19 and HCC are closely linked at the molecular level and proposes drugs that may play an important role in HCC patients with COVID-19. More importantly, according to the results of our research, two critical drugs, Ilomastat and Palmatine, may be effective for HCC patients with COVID-19, which provides clinicians with a novel therapeutic idea when facing possible complications in HCC patients with COVID-19.

Application of lipid nanovesicle drug delivery system in cancer immunotherapy.

Immunotherapy has gradually emerged as the most promising anticancer therapy. In addition to conventional anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy, CAR-T therapy, etc., immunotherapy can also be induced by stimulating the maturation of immune cells or inhibiting negative immune cells, regulating the tumor immune microenvironment and cancer vaccines. Lipid nanovesicle drug delivery system includes liposomes, cell membrane vesicles, bacterial outer membrane vesicles, extracellular vesicles and hybrid vesicles. Lipid nanovesicles can be used as functional vesicles for cancer immunotherapy, and can also be used as drug carriers to deliver immunotherapy drugs to the tumor site for cancer immunotherapy. Here, we review recent advances in five kinds of lipid nanovesicles in cancer immunotherapy and assess the clinical application prospects of various lipid nanovesicles, hoping to provide valuable information for clinical translation in the future.

Superconductivity above 200 K discovered in superhydrides of calcium.

Searching for superconductivity with Tc near room temperature is of great interest both for fundamental science & many potential applications. Here we report the experimental discovery of superconductivity with maximum critical temperature (Tc) above 210 K in calcium superhydrides, the new alkali earth hydrides experimentally showing superconductivity above 200 K in addition to sulfur hydride & rare-earth hydride system. The materials are synthesized at the synergetic conditions of 160~190 GPa and ~2000 K using diamond anvil cell combined with in-situ laser heating technique. The superconductivity was studied through in-situ high pressure electric conductance measurements in an applied magnetic field for the sample quenched from high temperature while maintained at high pressures. The upper critical field Hc(0) was estimated to be ~268 T while the GL coherent length is ~11 Å. The in-situ synchrotron X-ray diffraction measurements suggest that the synthesized calcium hydrides are primarily composed of CaH6 while there may also exist other calcium hydrides with different hydrogen contents.

Negative linear compressibility in Se at ultra-high pressure above 120 GPa.

A series of in situ synchrotron X-ray diffraction (XRD) measurements were carried out, combined with first-principles calculations, to study structural phase transitions of selenium at high pressures and room temperature. Several phase transitions were observed, among which an isostructural phase transition was found at around 120 GPa for the first time. Evolved from the rhombohedral (space group R 3 m) structure (Se-V), the new phase (Se-V') exhibited an interesting increase of lattice parameter a at pressures from 120 to 148 GPa, known as negative linear compressibility (NLC). The discovery of NLC behavior observed in this work is mainly attributed to the accuracy and fine steps controlled by the membrane system for in situ XRD data collected with an exposure time of 0.5 s. After 140 GPa, a body-centered cubic (b.c.c.) structure Se-VI (space group Im 3 m) was formed, which remains stable up to 210 GPa, the highest pressure achieved in this study. The bulk moduli of phases Se-V, Se-V' and Se-VI were estimated to be 83 ± 2, 321 ± 2 and 266 ± 7 GPa, respectively, according to the P-V curve fit by the third-order Birch-Murnaghan equation of state. The Se-V' phase shows a bulk modulus almost 4 times larger than that of the Se-V phase, which is mainly due to the effect of its NLC. NLC in a higher pressure range is always more significant in terms of fundamental mechanism and new materials discovery, yet it has barely been reported at pressures above 100 GPa. This will hopefully inspire future studies on potential NLC behaviors in other materials at ultra-high pressure.

Neurotensin is an anti-thermogenic peptide produced by lymphatic endothelial cells.

The lymphatic vasculature plays important roles in the physiology of the organs in which it resides, though a clear mechanistic understanding of how this crosstalk is mediated is lacking. Here, we performed single-cell transcriptional profiling of human and mouse adipose tissue and found that lymphatic endothelial cells highly express neurotensin (NTS/Nts). Nts expression is reduced by cold and norepinephrine in an α-adrenergic-dependent manner, suggesting a role in adipose thermogenesis. Indeed, NTS treatment of brown adipose tissue explants reduced expression of thermogenic genes. Furthermore, adenoviral-mediated overexpression and knockdown or knockout of NTS in vivo reduced and enhanced cold tolerance, respectively, an effect that is mediated by NTSR2 and ERK signaling. Inhibition of NTSR2 promoted energy expenditure and improved metabolic function in obese mice. These data establish a link between adipose tissue lymphatics and adipocytes with potential therapeutic implications.

Central aspects of systemic oestradiol negative- and positive-feedback on the reproductive neuroendocrine system.

The central nervous system regulates fertility via the release of gonadotrophin-releasing hormone (GnRH). This control revolves around the hypothalamic-pituitary-gonadal axis, which operates under traditional homeostatic feedback by sex steroids from the gonads in males and most of the time in females. An exception is the late follicular phase in females, when homeostatic feedback is suspended and a positive-feedback response to oestradiol initiates the preovulatory surges of GnRH and luteinising hormone. Here, we briefly review the history of how mechanisms underlying central control of ovulation by circulating steroids have been studied, discuss the relative merit of different model systems and integrate some of the more recent findings in this area into an overall picture of how this phenomenon occurs.

Differential Roles of Hypothalamic AVPV and Arcuate Kisspeptin Neurons in Estradiol Feedback Regulation of Female Reproduction.

Mammalian reproductive function includes puberty onset and completion, reproductive cyclicity, steroidogenesis, gametogenesis, fertilization, pregnancy, and lactation; all are indispensable to perpetuate species. Reproductive cycles are critical for providing the hormonal milieu needed for follicular development and maturation of eggs, but cycles, in and of themselves, do not guarantee ovulation will occur. Here, we review the roles in female reproductive neuroendocrine function of two hypothalamic populations that produce the neuropeptide kisspeptin, demonstrating distinct roles in maintaining cycles and ovulation.

Identification of 2(1H)-pyrimidinones as potential EGFR T790M inhibitors for the treatment of gefitinib-resistant non-small cell lung cancer.

A new class of 2(1H)-pyrimidinone derivatives was identified as potential EGFR T790M inhibitors against TKI-resistant NSCLC. These novel compounds inhibited the EGFR T790M kinase activity at concentrations in the range of 85.3 to 519.9 nM. In particular, compound 7e exhibited the strongest activity against both EGFRWT (IC50 = 96.9 nM) and EGFRT790M (IC50 = 85.3 nM) kinases in the cells. Compared with inhibitor 7e, compound 7b displayed enhanced antiproliferative activity against gefitinib-resistant H1975 cells harboring the EGFR T790M mutation. In addition, compound 7b also has low toxicity against the normal human liver cells LO2, with an IC50 of 11.1 µM. Moreover, both the AO/EB and DAPI staining assays also demonstrated the inhibitory efficacy of 7b against the resistant H1975 cells. This contribution provides a new scaffold 2(1H)-pyrimidinone as potential EGFR T790M inhibitor against drug-resistant NSCLC.

Structure-based modification of carbonyl-diphenylpyrimidines (Car-DPPYs) as a novel focal adhesion kinase (FAK) inhibitor against various stubborn cancer cells.

A family of carbonyl-substituted diphenylpyrimidine derivatives (Car-DPPYs) with strong activity against focal adhesion kinase (FAK), were described in this manuscript. Among them, compounds 7a (IC50 = 5.17 nM) and 7f (IC50 = 2.58 nM) displayed equal anti-FAK enzymatic activity to the lead compound TAE226 (6.79 nM). In particular, compound 7a also exhibited strong antiproliferative activity against several stubborn cancer cells, including AsPC-1 cells (IC50 = 0.105 µM), BxPC-3 cells (IC50 = 0.090 µM), and MCF-7/ADR cells (IC50 = 0.59 µM). Additionally, compound 7a also showed great antitumor efficacy in vivo via aAsPC-1 cancer Xenograft mouse model. The preliminary mechanism study by Western blot analysis revealed that 7a repressed FAK phosphorylation in AsPC cancer cells. Taken together, the results indicate that compound 7a may serve as a promising preclinical candidate for treatment of stubborn cancers.

Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction.

The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedbacks are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest that activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.