Unravelling biological roles and mechanisms of GABABR on addiction and depression through mood and memory disorders.

The metabotropic γ-aminobutyric acid type B receptor (GABABR) remains a hotspot in the recent research area. Being an idiosyncratic G-protein coupled receptor family member, the GABABR manifests adaptively tailored functionality under multifarious modulations by a constellation of agents, pointing to cross-talk between receptors and effectors that converge on the domains of mood and memory. This review systematically summarizes the latest achievements in signal transduction mechanisms of the GABABR-effector-regulator complex and probes how the up-and down-regulation of membrane-delimited GABABRs are associated with manifold intrinsic and extrinsic agents in synaptic strength and plasticity. Neuropsychiatric conditions depression and addiction share the similar pathophysiology of synapse inadaptability underlying negative mood-related processes, memory formations, and impairments. In the attempt to emphasize all convergent discoveries, we hope the insights gained on the GABABR system mechanisms of action are conducive to designing more therapeutic candidates so as to refine the prognosis rate of diseases and minimize side effects.

Time-reversal symmetry-breaking charge order in a kagome superconductor.

The kagome lattice1, which is the most prominent structural motif in quantum physics, benefits from inherent non-trivial geometry so that it can host diverse quantum phases, ranging from spin-liquid phases, to topological matter, to intertwined orders2-8 and, most rarely, to unconventional superconductivity6,9. Recently, charge sensitive probes have indicated that the kagome superconductors AV3Sb5 (A = K, Rb, Cs)9-11 exhibit unconventional chiral charge order12-19, which is analogous to the long-sought-after quantum order in the Haldane model20 or Varma model21. However, direct evidence for the time-reversal symmetry breaking of the charge order remains elusive. Here we use muon spin relaxation to probe the kagome charge order and superconductivity in KV3Sb5. We observe a noticeable enhancement of the internal field width sensed by the muon ensemble, which takes place just below the charge ordering temperature and persists into the superconducting state. Notably, the muon spin relaxation rate below the charge ordering temperature is substantially enhanced by applying an external magnetic field. We further show the multigap nature of superconductivity in KV3Sb5 and that the [Formula: see text] ratio (where Tc is the superconducting transition temperature and λab is the magnetic penetration depth in the kagome plane) is comparable to those of unconventional high-temperature superconductors. Our results point to time-reversal symmetry-breaking charge order intertwining with unconventional superconductivity in the correlated kagome lattice.

Singular charge fluctuations at a magnetic quantum critical point.

Strange metal behavior is ubiquitous in correlated materials, ranging from cuprate superconductors to bilayer graphene, and may arise from physics beyond the quantum fluctuations of a Landau order parameter. In quantum-critical heavy-fermion antiferromagnets, such physics may be realized as critical Kondo entanglement of spin and charge and probed with optical conductivity. We present terahertz time-domain transmission spectroscopy on molecular beam epitaxy-grown thin films of YbRh2Si2, a model strange-metal compound. We observed frequency over temperature scaling of the optical conductivity as a hallmark of beyond-Landau quantum criticality. Our discovery suggests that critical charge fluctuations play a central role in the strange metal behavior, elucidating one of the long-standing mysteries of correlated quantum matter.

Orbital-Selective Kondo Entanglement and Antiferromagnetic Order in USb_{2}.

In heavy-fermion compounds, the dual character of f electrons underlies their rich and often exotic properties like fragile heavy quasiparticles, a variety of magnetic orders and unconventional superconductivity. 5f-electron actinide materials provide a rich setting to elucidate the larger and outstanding issue of the competition between magnetic order and Kondo entanglement and, more generally, the interplay among different channels of interactions in correlated electron systems. Here, by using angle-resolved photoemission spectroscopy, we present the detailed electronic structure of USb_{2} and observe two different kinds of nearly flat bands in the antiferromagnetic state of USb_{2}. Polarization-dependent measurements show that these electronic states are derived from 5f orbitals with different characters; in addition, further temperature-dependent measurements reveal that one of them is driven by the Kondo correlations between the 5f electrons and conduction electrons, while the other reflects the dominant role of the magnetic order. Our results on the low-energy electronic excitations of USb_{2} implicate orbital selectivity as an important new ingredient for the competition between Kondo correlations and magnetic order and, by extension, in the rich landscape of quantum phases for strongly correlated f electron systems.

Direct visualization of coexisting channels of interaction in CeSb.

Our understanding of correlated electron systems is vexed by the complexity of their interactions. Heavy fermion compounds are archetypal examples of this physics, leading to exotic properties that weave magnetism, superconductivity and strange metal behavior together. The Kondo semimetal CeSb is an unusual example where different channels of interaction not only coexist, but have coincident physical signatures, leading to decades of debate about the microscopic picture describing the interactions between the f moments and the itinerant electron sea. Using angle-resolved photoemission spectroscopy, we resonantly enhance the response of the Ce f electrons across the magnetic transitions of CeSb and find there are two distinct modes of interaction that are simultaneously active, but on different kinds of carriers. This study reveals how correlated systems can reconcile the coexistence of different modes on interaction-by separating their action in momentum space, they allow their coexistence in real space.

Low-carrier density and fragile magnetism in a Kondo lattice system.

Kondo-based semimetals and semiconductors are of extensive current interest as a viable platform for strongly correlated states in the dilute carrier limit. It is thus important to explore the routes to understand such systems. One established pathway is through the Kondo effect in metallic nonmagnetic analogs, in the so called half-filling case of one conduction electron and one 4f electron per site. Here, we demonstrate that Kondo-based semimetals develop out of conduction electrons with a low-carrier density in the presence of an even number of rare-earth sites. We do so by studying the Kondo material Yb3Ir4Ge13 along with its closed-4f -shell counterpart, Lu3Ir4Ge13. Through magnetotransport, optical conductivity, and thermodynamic measurements, we establish that the correlated semimetallic state of Yb3Ir4Ge13 below its Kondo temperature originates from the Kondo effect of a low-carrier conduction-electron background. In addition, it displays fragile magnetism at very low temperatures, which in turn, can be tuned to a Griffiths-phase-like regime through Lu-for-Yb substitution. These findings are connected with recent theoretical studies in simplified models. Our results can pave the way to exploring strong correlation physics in a semimetallic environment.

Spectral Evidence for Emergent Order in Ba_{1-x}Na_{x}Fe_{2}As_{2}.

We report an angle-resolved photoemission spectroscopy study of the iron-based superconductor family, Ba_{1-x}Na_{x}Fe_{2}As_{2}. This system harbors the recently discovered double-Q magnetic order appearing in a reentrant C_{4} phase deep within the underdoped regime of the phase diagram that is otherwise dominated by the coupled nematic phase and collinear antiferromagnetic order. From a detailed temperature-dependence study, we identify the electronic response to the nematic phase in an orbital-dependent band shift that strictly follows the rotational symmetry of the lattice and disappears when the system restores C_{4} symmetry in the low temperature phase. In addition, we report the observation of a distinct electronic reconstruction that cannot be explained by the known electronic orders in the system.

Evolution of the Kondo lattice and non-Fermi liquid excitations in a heavy-fermion metal.

Strong electron correlations can give rise to extraordinary properties of metals with renormalized Landau quasiparticles. Near a quantum critical point, these quasiparticles can be destroyed and non-Fermi liquid behavior ensues. YbRh2Si2 is a prototypical correlated metal exhibiting the formation of quasiparticle and Kondo lattice coherence, as well as quasiparticle destruction at a field-induced quantum critical point. Here we show how, upon lowering the temperature, Kondo lattice coherence develops at zero field and finally gives way to non-Fermi liquid electronic excitations. By measuring the single-particle excitations through scanning tunneling spectroscopy, we find the Kondo lattice peak displays a non-trivial temperature dependence with a strong increase around 3.3 K. At 0.3 K and with applied magnetic field, the width of this peak is minimized in the quantum critical regime. Our results demonstrate that the lattice Kondo correlations have to be sufficiently developed before quantum criticality can set in.

The Paris System for urine cytology in upper tract urothelial specimens: A comparative analysis with biopsy and surgical resection.

INTRODUCTION: The Paris System (TPS) has recently been used in classification of urinary tract cytological specimens. Upper urinary tract (UUT) specimens are cytologically challenging. The utility of TPS was investigated in evaluating UUT specimens and its correlation with subsequent histological follow-up. METHOD: From 2014 to 2017, 324 cytology cases of UUT from 179 patients were retrieved. Concurrent or subsequent biopsy or resection within a 2-month period was available in 125 cases from 74 patients. RESULT: None of the cases with a cytology of low-grade urothelial neoplasm was found to have a high-grade urothelial carcinoma (HGUC) on biopsy. Among the 19 atypical urothelial cells (AUC) cytology cases, the histology is heterogeneous (seven benign, one atypia, five low-grade lesion, and six HGUC). The risk of HGUC for each cytological diagnostic category are 0% for non-diagnostic/unsatisfactory, 6% for negative for HGUC, 27.3% for AUC, 0% for low-grade urothelial neoplasm, 48% for suspicious for HGUC and 95% for positive HGUC. When we considered cytology cases with suspicious or positive for HGUC interpretations as positive, the performance of TPS in predicting high grade urothelial carcinoma on histology had values of: 78.6% sensitivity, 86% specificity, 80.5% positive predictive value and 84.5% negative predictive value. CONCLUSION: More than one-third of the UUT cytological cases were classified as AUC and approximately 1/15 as suspicious or positive for HGUC. Based on UUT cytology specimens, the risk of malignancy of each cytological diagnostic category of TPS was comparable to those reported in the literature. The use of TPS in evaluating UUT cytology specimens was specific and sensitive in identifying patients with HGUC by histology.

Regulation of miRNAs on c-met protein expression in ovarian cancer and its implication.

OBJECTIVE: HGF/c-met signal pathway exerts important roles in tumor pathogenesis. The study of c-met related regulatory mechanism provides the basis for finding anti-tumor molecular drugs. MiRNAs can effectively regulate gene expression and work as gene therapy. The identification of miRNAs for c-met regulation and study of related mechanism are of critical importance. MATERIALS AND METHODS: Bioinformatics approach was used to search for possible miRNAs with regulatory functions on c-met gene. Using pcDNA3.1-EGFP as the scaffold, miRNAs over-expression and inhibitor plasmids were constructed for electroporation-transfection in ovarian cell line ES-2, and pcDNA3.1-EGFP empty plasmid was used as the control group. qRT-PCR and Western blot were applied to measure c-met mRNA and protein expression, followed by transwell chamber in vitro assay for the evaluation of invasion potency. RESULTS: Bioinformatics prediction showed favorable regulatory function on c-met gene by miR-204. The differential expressions of EGFP were observed between pcDNA3.1-EGFP-204-up and inhibitor plasmid pcDNA3.1-EGFP-204-down. After transfection for 24 h and 48 h, c-met expression in miR-204 over-expression group gradually decreased (p<0.05 compared to control group), accompanied with reducing cell migration or invasion potency in a time dependent manner (p<0.05). In contrast, no significant difference in the level of c-met was found in the inhibitor group and control group (p>0.05). CONCLUSIONS: The up-regulation of miR-204 suppressed the expression of c-met in ovarian cancer cells and inhibited cell infiltration. The suppression of miR-204 expression, however, presented no significant impact on cell infiltration potency.

Kondo Insulator to Semimetal Transformation Tuned by Spin-Orbit Coupling.

Recent theoretical studies of topologically nontrivial electronic states in Kondo insulators have pointed to the importance of spin-orbit coupling (SOC) for stabilizing these states. However, systematic experimental studies that tune the SOC parameter λ_{SOC} in Kondo insulators remain elusive. The main reason is that variations of (chemical) pressure or doping strongly influence the Kondo coupling J_{K} and the chemical potential µ-both essential parameters determining the ground state of the material-and thus possible λ_{SOC} tuning effects have remained unnoticed. Here, we present the successful growth of the substitution series Ce_{3}Bi_{4}(Pt_{1-x}Pd_{x})_{3} (0≤x≤1) of the archetypal (noncentrosymmetric) Kondo insulator Ce_{3}Bi_{4}Pt_{3}. The Pt-Pd substitution is isostructural, isoelectronic, and isosize, and it therefore is likely to leave J_{K} and µ essentially unchanged. By contrast, the large mass difference between the 5d element Pt and the 4d element Pd leads to a large difference in λ_{SOC}, which thus is the dominating tuning parameter in the series. Surprisingly, with increasing x (decreasing λ_{SOC}), we observe a Kondo insulator to semimetal transition, demonstrating an unprecedented drastic influence of the SOC. The fully substituted end compound Ce_{3}Bi_{4}Pd_{3} shows thermodynamic signatures of a recently predicted Weyl-Kondo semimetal.

Observation of universal strong orbital-dependent correlation effects in iron chalcogenides.

Establishing the appropriate theoretical framework for unconventional superconductivity in the iron-based materials requires correct understanding of both the electron correlation strength and the role of Fermi surfaces. This fundamental issue becomes especially relevant with the discovery of the iron chalcogenide superconductors. Here, we use angle-resolved photoemission spectroscopy to measure three representative iron chalcogenides, FeTe0.56Se0.44, monolayer FeSe grown on SrTiO3 and K0.76Fe1.72Se2. We show that these superconductors are all strongly correlated, with an orbital-selective strong renormalization in the dxy bands despite having drastically different Fermi surface topologies. Furthermore, raising temperature brings all three compounds from a metallic state to a phase where the dxy orbital loses all spectral weight while other orbitals remain itinerant. These observations establish that iron chalcogenides display universal orbital-selective strong correlations that are insensitive to the Fermi surface topology, and are close to an orbital-selective Mott phase, hence placing strong constraints for theoretical understanding of iron-based superconductors.

Leptin receptor signaling inhibits ovarian follicle development and egg laying in chicken hens.

BACKGROUND: Nutrition intake during growth strongly influences ovarian follicle development and egg laying in chicken hens, yet the underlying endocrine regulatory mechanism is still poorly understood. The relevant research progress is hindered by difficulties in detection of leptin gene and its expression in the chicken. However, a functional leptin receptor (LEPR) is present in the chicken which has been implicated to play a regulatory role in ovarian follicle development and egg laying. The present study targeted LEPR by immunizing against its extracellular domain (ECD), and examined the resultant ovarian follicle development and egg-laying rate in chicken hens. METHODS: Hens that have been immunized four times with chicken LEPR ECD were assessed for their egg laying rate and feed intake, numbers of ovarian follicles, gene expression profiles, serum lipid parameters, as well as STAT3 signaling pathway. RESULTS: Administrations of cLEPR ECD antigen resulted in marked reductions in laying rate that over time eventually recovered to the levels exhibited by the Control hens. Together with the decrease in egg laying rate, cLEPR-immunized hens also exhibited significant reductions in feed intake, plasma concentrations of glucose, triglyceride, high-density lipoprotein, and low-density lipoprotein. Parallelled by reductions in feed intake, mRNA gene expression levels of AgRP, orexin, and NPY were down regulated, but of POMC, MC4R and lepR up-regulated in Immunized hen hypothalamus. cLEPR-immunization also promoted expressions of apoptotic genes such as caspase3 in theca and fas in granulosa layer, but severely depressed IGF-I expression in both theca and granulosa layers. CONCLUSIONS: Immunization against cLEPR ECD in egg-laying hens generated antibodies that mimic leptin bioactivity by enhancing leptin receptor transduction. This up-regulated apoptotic gene expression in ovarian follicles, negatively regulated the expression of genes that promote follicular development and hormone secretion, leading to follicle atresia and interruption of egg laying. The inhibition of progesterone secretion due to failure of follicle development also lowered feed intake. These results also demonstrate that immunization against cLEPR ECD may be utilized as a tool for studying bio-functions of cLEPR.

MicroRNA-19a-3p inhibits breast cancer progression and metastasis by inducing macrophage polarization through downregulated expression of Fra-1 proto-oncogene.

One of the hallmarks of malignancy is the polarization of tumor-associated macrophages (TAMs) from a pro-immune (M1-like) phenotype to an immune-suppressive (M2-like) phenotype. However, the molecular basis of the process is still unclear. MicroRNA (miRNA) comprises a group of small, non-coding RNAs that are broadly expressed by a variety of organisms and are involved in cell behaviors such as suppression or promotion of tumorigenesis. Here, we demonstrate that miR-19a-3p, broadly conserved among vertebrates, was downregulated in RAW264.7 macrophage cells of the M2 phenotype in conditoned medium of 4T1 mouse breast tumor cells. This downregulation correlated with an increased expression of the Fra-1 gene, which was reported to act as a pro-oncogene by supporting the invasion and progression of breast tumors. We found significant upregulation of miR-19a-3p in RAW264.7 macrophages after transfection with a miR-19a-3p mimic that resulted in a significant suppression of the expression of this gene. In addition, we could measure the activity of binding between miR-19a-3p and Fra-1 with a psiCHECK luciferase reporter system. Further, transfection of RAW264.7 macrophage cells with the miR-19a-3p mimic decreased the expression of the Fra-1 downstream genes VEGF, STAT3 and pSTAT3. Most importantly, the capacity of 4T1 breast tumor cells to migrate and invade was impaired in vivo by the intratumoral injection of miR-19a-3p. Taken together, these findings indicate that miR-19a-3p is capable of downregulating the M2 phenotype in M2 macrophages and that the low expression of this miRNA has an important role in the upregulation of Fra-1 expression and induction of M2 macrophage polarization.

Observation of temperature-induced crossover to an orbital-selective Mott phase in A(x)Fe(2-y)Se2 (A=K, Rb) superconductors.

Using angle-resolved photoemission spectroscopy, we observe the low-temperature state of the A(x)Fe(2-y)Se(2) (A=K, Rb) superconductors to exhibit an orbital-dependent renormalization of the bands near the Fermi level-the d(xy) bands heavily renormalized compared to the d(xz)/d(yz) bands. Upon raising the temperature to above 150 K, the system evolves into a state in which the d(xy) bands have depleted spectral weight while the d(xz)/d(yz) bands remain metallic. Combined with theoretical calculations, our observations can be consistently understood as a temperature-induced crossover from a metallic state at low temperatures to an orbital-selective Mott phase at high temperatures. Moreover, the fact that the superconducting state of A(x)Fe(2-y)Se(2) is near the boundary of such an orbital-selective Mott phase constrains the system to have sufficiently strong on-site Coulomb interactions and Hund's coupling, highlighting the nontrivial role of electron correlation in this family of iron-based superconductors.

Magnetism, f-electron localization and superconductivity in 122-type heavy-fermion metals.

Both CeCu2Si2 and YbRh2Si2 crystallize in the tetragonal ThCr2Si2 crystal structure. Recent neutron-scattering results on normal-state CeCu2Si2 reveal a slowing down of the quasielastic response which complies with the scaling expected for a quantum critical point (QCP) of itinerant, i.e., three-dimensional spin-density-wave (SDW), type. This interpretation is in full agreement with the non-Fermi-liquid behavior observed in transport and thermodynamic measurements. The momentum dependence of the magnetic excitation spectrum reveals two branches of an overdamped dispersive mode whose coupling to the heavy charge carriers is strongly retarded. These overdamped spin fluctuations are considered to be the driving force for superconductivity in CeCu2Si2 (Tc = 600 mK). The weak antiferromagnet YbRh2Si2 (TN = 70 mK) exhibits a magnetic-field-induced QCP at BN = 0.06 T (B⊥c). There is no indication of superconductivity down to T = 10 mK. The magnetic QCP appears to concur with a breakdown of the Kondo effect. Doping-induced variations of the average unit-cell volume result in a detachment of the magnetic and electronic instabilities. A comparison of the properties of these isostructural compounds suggests that 3D SDW QCPs are favorable for unconventional superconductivity. The question whether a Kondo-breakdown QCP may also give rise to superconductivity, however, remains to be clarified.

Destruction of the Kondo effect in the cubic heavy-fermion compound Ce3Pd20Si6.

How ground states of quantum matter transform between one another reveals deep insights into the mechanisms stabilizing them. Correspondingly, quantum phase transitions are explored in numerous materials classes, with heavy-fermion compounds being among the most prominent ones. Recent studies in an anisotropic heavy-fermion compound have shown that different types of transitions are induced by variations of chemical or external pressure, raising the question of the extent to which heavy-fermion quantum criticality is universal. To make progress, it is essential to broaden both the materials basis and the microscopic parameter variety. Here, we identify a cubic heavy-fermion material as exhibiting a field-induced quantum phase transition, and show how the material can be used to explore one extreme of the dimensionality axis. The transition between two different ordered phases is accompanied by an abrupt change of Fermi surface, reminiscent of what happens across the field-induced antiferromagnetic to paramagnetic transition in the anisotropic YbRh2Si2. This finding leads to a materials-based global phase diagram--a precondition for a unified theoretical description.

Interaction of Rab31 and OCRL-1 in oligodendrocytes: its role in transport of mannose 6-phosphate receptors.

Rab31, a protein that we cloned from an oligodendrocyte cDNA library, is required for transport of mannose 6-phosphate receptors (MPRs) from the trans-Golgi network (TGN) to endosomes and for Golgi/TGN organization. Here we extend the knowledge of the mechanism of action of Rab31 by demonstrating its interaction with OCRL-1, a phosphatidylinositol 4,5-diphosphate 5-phosphatase (PI(4,5)P(2) 5-phosphatase) that regulates the levels of PI(4,5)P(2) and PI(4)P, molecules involved in transport and Golgi/TGN organization. We show that Rab31 interacts with OCRL-1 in a yeast two-hybrid system, GST-Rab31 pull-down experiments, and coimmunoprecipitation of OCRL-1 using oligodendrocyte culture lysates. Rab31 and OCRL-1 colocalize in the TGN, post-TGN carriers, and endosomes. Cation-dependent MPR (CD-MPR) is sorted to OCRL-1-containing carriers, but CD63 and vesicular stomatitis virus G (VSVG) are not. siRNA-mediated depletion of endogenous Rab31 causes collapse of the TGN apparatus and markedly decreases the levels of OCRL-1 in the TGN and endosomes. Our observations indicate that the role of Rab31 in the Golgi/TGN structure and transport of MPRs depends on its capability to recruit OCRL-1 to domains of the TGN where the formation of carriers occurs. The importance of our observations is highlighted by the fact that mutation of OCRL-1 causes demyelination in humans.

Transport of mannose-6-phosphate receptors from the trans-Golgi network to endosomes requires Rab31.

Rab31, a protein that we originally cloned from a rat oligodendrocyte cDNA library, localizes in the trans-Golgi network (TGN) and endosomes. However, its function has not yet been established. Here we show the involvement of Rab31 in the transport of mannose 6-phosphate receptors (MPRs) from TGN to endosomes. We demonstrate the specific sorting of cation-dependent-MPR (CD-MPR), but not CD63 and vesicular stomatitis virus G (VSVG) protein, to Rab31-containing trans-Golgi network carriers. CD-MPR and Rab31 containing carriers originate from extending TGN tubules that also contain clathrin and GGA1 coats. Expression of constitutively active Rab31 reduced the content of CD-MPR in the TGN relative to that of endosomes, while expression of dominant negative Rab31 triggered reciprocal changes in CD-MPR distribution. Expression of dominant negative Rab31 also inhibited the formation of carriers containing CD-MPR in the TGN, without affecting the exit of VSVG from this compartment. Importantly, siRNA-mediated depletion of endogenous Rab31 caused the collapse of the Golgi apparatus. Our observations demonstrate that Rab31 is required for transport of MPRs from TGN to endosomes and for the Golgi/TGN organization.