Evidence for an atomic chiral superfluid with topological excitations.

Topological superfluidity is an important concept in electronic materials as well as ultracold atomic gases1. However, although progress has been made by hybridizing superconductors with topological substrates, the search for a material-natural or artificial-that intrinsically exhibits topological superfluidity has been ongoing since the discovery of the superfluid 3He-A phase2. Here we report evidence for a globally chiral atomic superfluid, induced by interaction-driven time-reversal symmetry breaking in the second Bloch band of an optical lattice with hexagonal boron nitride geometry. This realizes a long-lived Bose-Einstein condensate of 87Rb atoms beyond present limits to orbitally featureless scenarios in the lowest Bloch band. Time-of-flight and band mapping measurements reveal that the local phases and orbital rotations of atoms are spontaneously ordered into a vortex array, showing evidence of the emergence of global angular momentum across the entire lattice. A phenomenological effective model is used to capture the dynamics of Bogoliubov quasi-particle excitations above the ground state, which are shown to exhibit a topological band structure. The observed bosonic phase is expected to exhibit phenomena that are conceptually distinct from, but related to, the quantum anomalous Hall effect3-7 in electronic condensed matter.

AMPK, a hub for the microenvironmental regulation of bone homeostasis and diseases.

AMP-activated protein kinase (AMPK), a crucial regulatory kinase, monitors energy levels, conserving ATP and boosting synthesis in low-nutrition, low-energy states. Its sensitivity links microenvironmental changes to cellular responses. As the primary support structure and endocrine organ, the maintenance, and repair of bones are closely associated with the microenvironment. While a series of studies have explored the effects of specific microenvironments on bone, there is lack of angles to comprehensively evaluate the interactions between microenvironment and bone cells, especially for bone marrow mesenchymal stem cells (BMMSCs) which mediate the differentiation of osteogenic lineage. It is noteworthy that accumulating evidence has indicated that AMPK may serve as a hub between BMMSCs and microenvironment factors, thus providing a new perspective for us to understand the biology and pathophysiology of stem cells and bone. In this review, we emphasize AMPK's pivotal role in bone microenvironment modulation via ATP, inflammation, reactive oxygen species (ROS), calcium, and glucose, particularly in BMMSCs. We further explore the use of AMPK-activating drugs in the context of osteoarthritis and osteoporosis. Moreover, building upon the foundation of AMPK, we elucidate a viewpoint that facilitates a comprehensive understanding of the dynamic relationship between the microenvironment and bone homeostasis, offering valuable insights for prospective investigations into stem cell biology and the treatment of bone diseases.

Involvement of BRD4 in Alcoholic Liver Injury: Autophagy Modulation via Regulation of the SIRT1/Beclin1 Axis.

Alcoholic liver disease (ALD) caused by chronic alcohol abuse involves complex processes from steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma, posing a global health issue. Bromodomain protein 4 (BRD4) typically serves as a "reader" modulating the functions of transcription factors involved in various biological processes and disease progression. However, the specific mechanisms underlying alcoholic liver injury remain unclear. In this study, we detected aberrant BRD4 expression in the alcohol-induced ALD mouse model of chronic and binge ethanol feeding developed by the National Institute on Alcohol Abuse and Alcoholism, consistent with the in vitro results in Aml-12 mouse hepatocytes. Blocking and inhibiting BRD4 restored the impaired autophagic flux and lysosomal functions in alcohol-treated Aml-12 cells, whereas BRD4 overexpression reduced the expression levels of autophagy marker and lysosomal genes. Furthermore, mouse BRD4 knockdown, mediated by a short hairpin RNA carried by the adeno-associated virus serotype 8, significantly attenuated the alcohol-induced hepatocyte damage, including lipid deposition and inflammatory cell infiltration. Mechanistically, BRD4 overexpression in alcoholic liver injury inhibited the expression of sirtuin (SIRT)1 in Aml-12 cells. Chromatin immunoprecipitation and dual-luciferase reporter assays revealed that BRD4 functions as a transcription factor and suppressor, actively binding to the SIRT1 promoter region and inhibiting its transcription. SIRT1 activated autophagy, which was suppressed in alcoholic liver injury via Beclin1 deacetylation. In conclusion, our study revealed that BRD4 negatively regulated the SIRT1/Beclin1 axis and that its deficiency alleviated alcohol-induced liver injury in mice, thus providing a new strategy for ALD treatment.

Hesperetin derivative 2a inhibits lipopolysaccharide-induced acute liver injury in mice via downregulation of circDcbld2.

Acute liver injury (ALI) is a complex, life-threatening inflammatory liver disease, and persistent liver damage leads to rapid decline and even failure of liver function. However, the pathogenesis of ALI is still not fully understood, and no effective treatment has been discovered. Recent evidence shows that many circular RNAs (circRNAs) are associated with the occurrence of liver diseases. In this study we investigated the mechanisms of occurrence and development of ALI in lipopolysaccharide (LPS)-induced ALI mice. We found that expression of the circular RNA circDcbld2 was significantly elevated in the liver tissues of ALI mice and LPS-treated RAW264.7 cells. Knockdown of circDcbld2 markedly alleviates LPS-induced inflammatory responses in ALI mice and RAW264.7 cells. We designed and synthesized a series of hesperidin derivatives for circDcbld2, and found that hesperetin derivative 2a (HD-2a) at the concentrations of 2, 4, 8 µM effectively inhibited circDcbld2 expression in RAW264.7 cells. Administration of HD-2a (50, 100, 200 mg/kg. i.g., once 24 h in advance) effectively relieved LPS-induced liver dysfunction and inflammatory responses. RNA sequencing analysis revealed that the anti-inflammatory and hepatoprotective effects of HD-2a were mediated through downregulating circDcbld2 and suppressing the JAK2/STAT3 pathway. We conclude that HD-2a downregulates circDcbld2 to inhibit the JAK2/STAT3 pathway, thereby inhibiting the inflammatory responses in ALI. The results suggest that circDcbld2 may be a potential target for the prevention and treatment of ALI, and HD-2a may have potential as a drug for the treatment of ALI.

Hydroxyl ion absorption in on-chip high-Q resonators.

Thermal silica is a common dielectric used in all-silicon photonic circuits. Additionally, bound hydroxyl ions (Si-OH) can provide a significant component of optical loss in this material on account of the wet nature of the thermal oxidation process. A convenient way to quantify this loss relative to other mechanisms is through OH absorption at 1380 nm. Here, using ultra-high-quality factor (Q-factor) thermal-silica wedge microresonators, the OH absorption loss peak is measured and distinguished from the scattering loss baseline over a wavelength range from 680 nm to 1550 nm. Record-high on-chip resonator Q-factors are observed for near-visible and visible wavelengths, and the absorption limited Q-factor is as high as 8 billion in the telecom band. Hydroxyl ion content level around 2.4 ppm (weight) is inferred from both Q measurements and by secondary ion mass spectroscopy (SIMS) depth profiling.

AlGaAs soliton microcombs at room temperature.

Soliton mode locking in high-Q microcavities provides a way to integrate frequency comb systems. Among material platforms, AlGaAs has one of the largest optical nonlinearity coefficients, and is advantageous for low-pump-threshold comb generation. However, AlGaAs also has a very large thermo-optic effect that destabilizes soliton formation, and femtosecond soliton pulse generation has only been possible at cryogenic temperatures. Here, soliton generation in AlGaAs microresonators at room temperature is reported for the first time, to the best of our knowledge. The destabilizing thermo-optic effect is shown to instead provide stability in the high-repetition-rate soliton regime (corresponding to a large, normalized second-order dispersion parameter D2/κ). Single soliton and soliton crystal generation with sub-milliwatt optical pump power are demonstrated. The generality of this approach is verified in a high-Q silica microtoroid where manual tuning into the soliton regime is demonstrated. Besides the advantages of large optical nonlinearity, these AlGaAs devices are natural candidates for integration with semiconductor pump lasers. Furthermore, the approach should generalize to any high-Q resonator material platform.

Evidence for Quantum Stripe Ordering in a Triangular Optical Lattice.

Understanding strongly correlated quantum materials, such as high-T_{c} superconductors, iron-based superconductors, and twisted bilayer graphene systems, remains as one of the outstanding challenges in condensed matter physics. Quantum simulation with ultracold atoms in particular optical lattices, which provide orbital degrees of freedom, is a powerful tool to contribute new insights to this endeavor. Here, we report the experimental realization of an unconventional Bose-Einstein condensate of ^{87}Rb atoms populating degenerate p orbitals in a triangular optical lattice, exhibiting remarkably long coherence times. Using time-of-flight spectroscopy, we observe that this state spontaneously breaks the rotational symmetry and its momentum spectrum agrees with the theoretically predicted coexistence of exotic stripe and loop-current orders. Like certain strongly correlated electronic systems with intertwined orders, such as high-T_{c} cuprate superconductors, twisted bilayer graphene, and the recently discovered chiral density-wave state in kagome superconductors AV_{3}Sb_{5} (A=K, Rb, Cs), the newly demonstrated quantum state, in spite of its markedly different energy scale and the bosonic quantum statistics, exhibits multiple symmetry breakings at ultralow temperatures. These findings hold the potential to enhance our comprehension of the fundamental physics governing these intricate quantum materials.

Mitochondrial micropeptide STMP1 promotes G1/S transition by enhancing mitochondrial complex IV activity.

The roles of micropeptides in cell cycle regulation and cancer development remain largely unknown. Here we found that a micropeptide STMP1 (small transmembrane protein 1) was up-regulated in multiple malignancies including hepatocellular carcinoma (HCC), and its high level was associated with short recurrence-free survival of HCC patients. Gain- and loss-of-function analyses revealed that STMP1 accelerated cell proliferation and clonogenicity in vitro and tumor growth in vivo, and silencing STMP1 blocked G1/S transition. Mechanistically, STMP1 promoted the mRNA and protein levels of CCNE2, CDK2, and E2F1. STMP1 was localized in the inner membrane of mitochondria and interacted with mitochondrial complex IV and then enhanced its activity. Moreover, treatment with the mitochondrial complex IV inhibitor tetrathiomolybdate dramatically abrogated the promoting effect of STMP1 on cell proliferation and the expression of cyclin E2, CDK2, and E2F1. These results suggest that STMP1 may promote G1/S transition and cell proliferation by enhancing mitochondrial complex IV activity, which highlights STMP1 as a new regulator of the cell cycle and a potential target for anti-cancer therapy.

Neuroinflammation in the anterior cingulate cortex: the potential supraspinal mechanism underlying the mirror-image pain following motor fiber injury.

BACKGROUND: Peripheral nerve inflammation or lesion can affect contralateral healthy structures, and thus result in mirror-image pain. Supraspinal structures play important roles in the occurrence of mirror pain. The anterior cingulate cortex (ACC) is a first-order cortical region that responds to painful stimuli. In the present study, we systematically investigate and compare the neuroimmune changes in the bilateral ACC region using unilateral- (spared nerve injury, SNI) and mirror-(L5 ventral root transection, L5-VRT) pain models, aiming to explore the potential supraspinal neuroimmune mechanism underlying the mirror-image pain. METHODS: The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Viral injections for the designer receptors exclusively activated by designer drugs (DREADD) were used to modulate ACC glutamatergic neurons. Immunohistochemistry, immunofluorescence, western blotting, protein microarray were used to detect the regulation of inflammatory signaling. RESULTS: Increased expressions of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokine CX3CL1 in ACC induced by unilateral nerve injury were observed on the contralateral side in the SNI group but on the bilateral side in the L5-VRT group, representing a stronger immune response to L5-VRT surgery. In remote ACC, both SNI and L5-VRT induced robust bilateral increase in the protein level of Nav1.6 (SCN8A), a major voltage-gated sodium channel (VGSC) that regulates neuronal activity in the mammalian nervous system. However, the L5-VRT-induced Nav1.6 response occurred at PO 3d, earlier than the SNI-induced one, 7 days after surgery. Modulating ACC glutamatergic neurons via DREADD-Gq or DREADD-Gi greatly changed the ACC CX3CL1 levels and the mechanical paw withdrawal threshold. Neutralization of endogenous ACC CX3CL1 by contralateral anti-CX3CL1 antibody attenuated the induction and the maintenance of mechanical allodynia and eliminated the upregulation of CX3CL1, TNF-α and Nav1.6 protein levels in ACC induced by SNI. Furthermore, contralateral ACC anti-CX3CL1 also inhibited the expression of ipsilateral spinal c-Fos, Iba1, CD11b, TNF-α and IL-6. CONCLUSIONS: The descending facilitation function mediated by CX3CL1 and its downstream cascade may play a pivotal role, leading to enhanced pain sensitization and even mirror-image pain. Strategies that target chemokine-mediated ACC hyperexcitability may lead to novel therapies for the treatment of neuropathic pain.

Experimental realization of a high precision tunable hexagonal optical lattice.

Hexagonal optical lattices offer a tunable platform to study exotic orbital physics in solid state materials. Here, we present a versatile high-precision scheme to implement a hexagonal optical lattice potential, which is engineered by overlapping two independent triangular optical sublattices generated by laser beams with slightly different wavelengths around 1064 nm. This enables us to precisely control the detailed structure of the hexagonal lattice by adjusting the relative position and the relative lattice depth of the two triangular optical sublattices. Taking advantage of the sensitive dependence of the second Bloch band on small lattice deformations, we propose a strategy to optimize the optical lattice geometry with an extremely high precision. This method can also be extended to other lattice configurations involving more than two sublattices. Our work provides the experimental requirements in the search for novel orbital physics of ultracold atoms, for example, in the flat p-band of the hexagonal optical lattice.

Flexible Cuprous Triazolate Frameworks as Highly Stable and Efficient Electrocatalysts for CO2 Reduction with Tunable C2 H4 /CH4 Selectivity.

Cu-based metal-organic frameworks have attracted much attention for electrocatalytic CO2 reduction, but they are generally instable and difficult to control the product selectivity. We report flexible Cu(I) triazolate frameworks as efficient, stable, and tunable electrocatalysts for CO2 reduction to C2 H4 /CH4 . By changing the size of ligand side groups, the C2 H4 /CH4 selectivity ratio can be gradually tuned and inversed from 11.8 : 1 to 1 : 2.6, giving C2 H4 , CH4 , and hydrocarbon selectivities up to 51 %, 56 %, and 77 %, respectively. After long-term electrocatalysis, they can retain the structures/morphologies without formation of Cu-based inorganic species. Computational simulations showed that the coordination geometry of Cu(I) changed from triangular to tetrahedral to bind the reaction intermediates, and two adjacent Cu(I) cooperated for C-C coupling to form C2 H4 . Importantly, the ligand side groups controlled the catalyst flexibility by the steric hindrance mechanism, and the C2 H4 pathway is more sensitive than the CH4 one.

An unnatural tripeptide structure containing intramolecular double H-bonds mimics a turn hairpin conformation.

A series of unnatural tripeptides, each consisting of two aromatic γ-amino acid residues and an ϖ-amino acid residue, are designed to probe their folding into hairpin conformations. The ϖ-amino acid residues, with aliphatic or aromatic spacers of different sizes, serve as the loop of the hairpins. Studies based on one-dimensional (1D) 1H NMR performed at different concentrations, solvent polarity, and temperature, along with 2D-NMR studies, demonstrated that the doubly H-bonded aromatic γ-amino acid residues play important roles in driving these tripeptides into the hairpin conformation. The loop based on 5-aminovaleric acid, which offers a four-carbon (CH2)4 spacer, enhanced the stability of the corresponding hairpin, while loops having a shorter, a longer and a more rigid spacer disfavored the formation of the hairpins. Results from computational studies are in good agreement with the experimental observations. Furthermore, the crystal structure of peptide 1b revealed the expected hairpin conformation in the solid state. This turn motif, which contains H-bonded aromatic γ-amino acid residues as the core unit and an ϖ-amino acid residue serving as the loop, provides a new platform that can be used to obtain a variety of turn conformations by incorporating diverse amino acids into the loops.

Integration of [12]aneN3 and Acenaphtho[1,2-b]quinoxaline as non-viral gene vectors with two-photon property for enhanced DNA/siRNA delivery and bioimaging.

Two-photon fluorescent Acenaphtho[1,2-b]quinoxaline (ANQ) and the hydrophilic di-(triazole-[12]aneN3) moieties were combined through an alkyl chain (ANQ-A-M) or a ß-hairpin motif with two aromatic γ-amino acid residues (ANQ-H-M) to explore their capabilities for in vitro and in vivo gene delivery and tracing. ANQ-A-M and ANQ-H-M showed the same maximum absorption at 420 nm, and their fluorescent intensities around 650 nm were varied in different solvents and became poor in the protic solvents. Gel electrophoresis assays indicated that both compounds completely retarded the migration of pDNA at 20 µM in the presence of DOPE. However, the DNA condensation with ANQ-H-M was not reversible, and the particle size of the corresponding complexes were larger indicated from the SEM and DLS measurements. In vitro transfections indicated ANQ-A-M/DOPE achieved Luciferase and GFP expressions were to be 7.9- and 5.7-fold of those by Lipo2000 in A549 cells respectively. However, ANQ-H-M showed very poor transfection efficiency in Luciferase expression. With the help of single/two-photon fluorescence imaging it clearly demonstrated that the successful transfection of ANQ-A-M was attributed to its cellular uptake, apparent lysosomal escape, and reversible release of DNA; and the poor transfection of ANQ-H-M was resulted from the aggregation of the DNA complexes which prevented them from the cellular uptake, and also the strong binding ability which is not easy to release DNA. ANQ-A-M/DOPE also exhibited robust gene silencing (83% knockdown of Luciferase) and GFP expression (2.47-fold higher) efficiency compared with Lipo2000 in A549 and zebrafish, respectively. The work demonstrated that the linkage structure between fluorescent and di(triazole-[12]aneN3) played the important role for their gene delivery performance, and that ANQ-A-M represents a vector with the strong transfection efficiency in vitro and in vivo as well as the efficient real time bioimaging properties, which is potential for the development in biomedical research.

Lnc-UCID Promotes G1/S Transition and Hepatoma Growth by Preventing DHX9-Mediated CDK6 Down-regulation.

Although thousands of long noncoding RNAs (lncRNAs) have been annotated, only a limited number of them have been functionally characterized. Here, we identified an oncogenic lncRNA, named lnc-UCID (lncRNA up-regulating CDK6 by interacting with DHX9). Lnc-UCID was up-regulated in hepatocellular carcinoma (HCC), and a higher lnc-UCID level was correlated with shorter recurrence-free survival of HCC patients. Both gain-of-function and loss-of function studies revealed that lnc-UCID enhanced cyclin-dependent kinase 6 (CDK6) expression and thereby promoted G1/S transition and cell proliferation. Studies from mouse xenograft models revealed that tumors derived from lnc-UCID-silenced HCC cells had a much smaller size than those from control cells, and intratumoral injection of lnc-UCID small interfering RNA suppressed xenograft growth. Mechanistically, the 850-1030-nt domain of lnc-UCID interacted physically with DEAH (Asp-Glu-Ala-His) box helicase 9 (DHX9), an RNA helicase. On the other hand, DHX9 post-transcriptionally suppressed CDK6 expression by binding to the 3'-untranslated region (3'UTR) of CDK6 mRNA. Further investigation disclosed that lnc-UCID enhanced CDK6 expression by competitively binding to DHX9 and sequestering DHX9 from CDK6-3'UTR. In an attempt to explore the mechanisms responsible for lnc-UCID up-regulation in HCC, we found that the lnc-UCID gene was frequently amplified in HCC. Furthermore, miR-148a, whose down-regulation was associated with an increase of lnc-UCID in HCC, could bind lnc-UCID and inhibit its expression. Conclusion: Up-regulation of lnc-UCID, which may result from amplification of its gene locus and down-regulation of miR-148a, can promote HCC growth by preventing the interaction of DHX9 with CDK6 and subsequently enhancing CDK6 expression. These findings provide insights into the biological functions of lncRNAs, the regulatory network of cell cycle control, and the mechanisms of HCC development, which may be exploited for anticancer therapy.

Asymmetric Organocatalytic [4 + 1] Annulations Involving a Polarity Reversal Process: A Tandem Catalytic Approach to Highly Functionalized Spiropyrazolone Derivatives.

A tandem catalytic strategy for the asymmetric synthesis of spirocyclopentanone pyrazolones bearing three contiguous stereocenters and two quaternary carbons with good stereoselectivities has been developed. This strategy, using pyrazolones as efficient C1 synthons and involving a polarity reversal process, not only overcame the energy barrier of the dearomatization process but also avoided nucleophilic addition of the hydroxy group in the enol form tautomer. Futhermore, spirocyclopentanones could be transformed into spirocyclohexamide pyrazolone with the Lawesson reagent.

Quaternary Carbon Center Forming [3 + 2] Cyclization Reaction by Adjusting the Substituents of Substrates.

Herein, we describe a variety of chiral hybrid pyrroidine-indole polycyclic derivatives with quaternary and continuous chiral centers were synthesized in good yields with excellent stereoselectivities through an asymmetric, intermolecular, and formal [3 + 2] cyclization reaction catalyzed by a bifunctional catalyst. In addition, the selection of substituents of substrates is the key to success, and both the hydroxyl group and the trifluoromethyl group play essential roles in the reaction.

One-Pot Asymmetric Synthesis of Spiropyrazolone-Linked Cyclopropanes and Benzofurans through a General Michael Addition/Chlorination/Nucleophilic Substitution Sequence.

A sequential and general strategy has been successfully developed for the synthesis of spiropyrazolone scaffolds. This intriguing transformation of the asymmetric multicomponent catalysis process was realized with the combination of Michael addition/chlorination/nucleophilic substitution in a one-pot sequence, giving rise to a series of spiropyrazolones with fully substituted cyclopropanes and spiro-dihydrobenzofurans containing continuous stereogenic centers in good yields with excellent stereoselectivities.

Organocatalytic Regiodivergent C-C Bond Cleavage of Cyclopropenones: A Highly Efficient Cascade Approach to Enantiopure Heterocyclic Frameworks.

Here a highly efficient cascade approach is reported that combines a cycloaddition reaction with a regioselective strain-release process to afford diverse heterocyclic frameworks through bifunctional catalysis. The cooperation of hydrogen-bonding network activation and a regiodivergent strain-assisted effect is the key to promoting this complex chemical transformation, leading to the generation of two different ring systems in high yields with excellent stereoselectivities. The reaction proceeded by a mechanism involving a "spring-loaded" intermediate with switchable C-C bond cleavages achieved by controllable ring-strain release. This reaction was also amenable to gram scale synthesis with only 0.1 mol % catalyst loading.

Participation of ß-Ketothioamides in N-Heterocyclic Carbene-Catalyzed [3 + 3] Spiroannulation: Asymmetric Synthesis of Functionalized Spiro-piperidinone Derivatives.

An N-heterocyclic carbene-catalyzed asymmetric [3 + 3] spiroannulation of ß-ketothioamide was successfully developed. ß-Ketothioamides exhibit an unusual reactivity to undergo a previously challenging lactamization reaction, and the desired spiro-piperidinone derivatives containing two vicinal stereogenic centers were synthesized in good to high yields with high stereoselectivities, whose structure can be converted to the corresponding imide and δ-lactam derivatives smoothly.

Sirolimus Versus Tacrolimus as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation.

Sirolimus and tacrolimus are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of sirolimus and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane controlled trials register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection (AR), and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and QALYs gained and incremental cost-effectiveness. Altogether, 1189 patients from 8 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of AR and patient withdrawn. Nevertheless, tacrolimus increased the risk of infection. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events after renal transplant. Tacrolimus is an effective and safe immunosuppressive agent, and it may be more cost-effective than cyclosporine for the primary prevention of AR in renal transplant recipients. However, it should be noted that such superiority was reversal when the cost of sirolimus and tacrolimus changed.