Discovery of orbital ordering in Bi2Sr2CaCu2O8+x.

The primordial ingredient of cuprate superconductivity is the CuO2 unit cell. Theories usually concentrate on the intra-atom Coulombic interactions dominating the 3d9 and 3d10 configurations of each copper ion. However, if Coulombic interactions also occur between electrons of the 2p6 orbitals of each planar oxygen atom, spontaneous orbital ordering may split their energy levels. This long-predicted intra-unit-cell symmetry breaking should generate an orbitally ordered phase, for which the charge transfer energy ε separating the 2p6 and 3d10 orbitals is distinct for the two oxygen atoms. Here we introduce sublattice-resolved ε(r) imaging to CuO2 studies and discover intra-unit-cell rotational symmetry breaking of ε(r). Spatially, this state is arranged in disordered Ising domains of orthogonally oriented orbital order bounded by dopant ions, and within whose domain walls low-energy electronic quadrupolar two-level systems occur. Overall, these data reveal a Q = 0 orbitally ordered state that splits the oxygen energy levels by ~50 meV, in underdoped CuO2.

Circulating Extracellular Vesicle-Propagated microRNA Signature as a Vascular Calcification Factor in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) accelerates vascular calcification via phenotypic switching of vascular smooth muscle cells (VSMCs). We investigated the roles of circulating small extracellular vesicles (sEVs) between the kidneys and VSMCs and uncovered relevant sEV-propagated microRNAs (miRNAs) and their biological signaling pathways. METHODS AND RESULTS: We established CKD models in rats and mice by adenine-induced tubulointerstitial fibrosis. Cultures of A10 embryonic rat VSMCs showed increased calcification and transcription of osterix (Sp7), osteocalcin (Bglap), and osteopontin (Spp1) when treated with rat CKD serum. sEVs, but not sEV-depleted serum, accelerated calcification in VSMCs. Intraperitoneal administration of a neutral sphingomyelinase and biogenesis/release inhibitor of sEVs, GW4869 (2.5 mg/kg per 2 days), inhibited thoracic aortic calcification in CKD mice under a high-phosphorus diet. GW4869 induced a nearly full recovery of calcification and transcription of osteogenic marker genes. In CKD, the miRNA transcriptome of sEVs revealed a depletion of 4 miRNAs, miR-16-5p, miR-17~92 cluster-originated miR-17-5p/miR-20a-5p, and miR-106b-5p. Their expression decreased in sEVs from CKD patients as kidney function deteriorated. Transfection of VSMCs with each miRNA-mimic mitigated calcification. In silico analyses revealed VEGFA (vascular endothelial growth factor A) as a convergent target of these miRNAs. We found a 16-fold increase in VEGFA transcription in the thoracic aorta of CKD mice under a high-phosphorus diet, which GW4869 reversed. Inhibition of VEGFA-VEGFR2 signaling with sorafenib, fruquintinib, sunitinib, or VEGFR2-targeted siRNA mitigated calcification in VSMCs. Orally administered fruquintinib (2.5 mg/kg per day) for 4 weeks suppressed the transcription of osteogenic marker genes in the mouse aorta. The area under the curve of miR-16-5p, miR-17-5p, 20a-5p, and miR-106b-5p for the prediction of abdominal aortic calcification was 0.7630, 0.7704, 0.7407, and 0.7704, respectively. CONCLUSIONS: The miRNA transcriptomic signature of circulating sEVs uncovered their pathologic role, devoid of the calcification-protective miRNAs that target VEGFA signaling in CKD-driven vascular calcification. These sEV-propagated miRNAs are potential biomarkers and therapeutic targets for vascular calcification.

Differentiated roles of Lifshitz transition on thermodynamics and superconductivity in La2-xSrxCuO4.

The effect of Lifshitz transition on thermodynamics and superconductivity in hole-doped cuprates has been heavily debated but remains an open question. In particular, an observed peak of electronic specific heat is proposed to originate from fluctuations of a putative quantum critical point p* (e.g., the termination of pseudogap at zero temperature), which is close to but distinguishable from the Lifshitz transition in overdoped La-based cuprates where the Fermi surface transforms from hole-like to electron-like. Here we report an in situ angle-resolved photoemission spectroscopy study of three-dimensional Fermi surfaces in La2-xSrxCuO4 thin films (x = 0.06 to 0.35). With accurate kz dispersion quantification, the said Lifshitz transition is determined to happen within a finite range around x = 0.21. Normal state electronic specific heat, calculated from spectroscopy-derived band parameters, reveals a doping-dependent profile with a maximum at x = 0.21 that agrees with previous thermodynamic microcalorimetry measurements. The account of the specific heat maximum by underlying band structures excludes the need for additionally dominant contribution from the quantum fluctuations at p*. A d-wave superconducting gap smoothly across the Lifshitz transition demonstrates the insensitivity of superconductivity to the dramatic density of states enhancement.

LRBA is essential for urinary concentration and body water homeostasis.

Protein kinase A (PKA) directly phosphorylates aquaporin-2 (AQP2) water channels in renal collecting ducts to reabsorb water from urine for the maintenance of systemic water homeostasis. More than 50 functionally distinct PKA-anchoring proteins (AKAPs) respectively create compartmentalized PKA signaling to determine the substrate specificity of PKA. Identification of an AKAP responsible for AQP2 phosphorylation is an essential step toward elucidating the molecular mechanisms of urinary concentration. PKA activation by several compounds is a novel screening strategy to uncover PKA substrates whose phosphorylation levels were nearly perfectly correlated with that of AQP2. The leading candidate in this assay proved to be an AKAP termed lipopolysaccharide-responsive and beige-like anchor protein (LRBA). We found that LRBA colocalized with AQP2 in vivo, and Lrba knockout mice displayed a polyuric phenotype with severely impaired AQP2 phosphorylation. Most of the PKA substrates other than AQP2 were adequately phosphorylated by PKA in the absence of LRBA, demonstrating that LRBA-anchored PKA preferentially phosphorylated AQP2 in renal collecting ducts. Furthermore, the LRBA-PKA interaction, rather than other AKAP-PKA interactions, was robustly dissociated by PKA activation. AKAP-PKA interaction inhibitors have attracted attention for their ability to directly phosphorylate AQP2. Therefore, the LRBA-PKA interaction is a promising drug target for the development of anti-aquaretics.

ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease.

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a central kinase involved in energy homeostasis. Increased intracellular AMP levels result in AMPK activation through the binding of AMP to the γ-subunit of AMPK. Recently, we reported that AMP-induced AMPK activation is impaired in the kidneys in chronic kidney disease (CKD) despite an increase in the AMP/ATP ratio. However, the mechanisms by which AMP sensing is disrupted in CKD are unclear. Here, we identified mechanisms of energy homeostasis in which Unc-51-like kinase 1 (ULK1)-dependent phosphorylation of AMPKγ1 at Ser260/Thr262 promoting AMP sensitivity of AMPK. AMPK activation by AMP was impaired in Ulk1 knockout mice despite an increased AMP/ATP ratio. ULK1 expression is markedly downregulated in CKD kidneys, leading to AMP sensing failure. Additionally, MK8722, an allosteric AMPK activator, stimulated AMPK in the kidneys of a CKD mouse model (5/6th nephrectomy) via a pathway that is independent of AMP sensing. Thus, our study shows that MK8722 treatment significantly attenuates the deterioration of kidney function in CKD and may be a potential therapeutic option in CKD therapeutics.

Absence of ULK1 decreases AMPK activity in the kidney, leading to chronic kidney disease progression.

AMP-activated protein kinase (AMPK) inactivation in chronic kidney disease (CKD) leads to energy status deterioration in the kidney, constituting the vicious cycle of CKD exacerbation. Unc-51-like kinase 1 (ULK1) is considered a downstream molecule of AMPK; however, it was recently reported that the activity of AMPK could be regulated by ULK1 conversely. We demonstrated that AMPK and ULK1 activities were decreased in the kidneys of CKD mice. However, whether and how ULK1 is involved in the underlying mechanism of CKD exacerbation remains unknown. In this study, we investigated the ULK1 involvement in CKD, using ULK1 knockout mice. The CKD model of Ulk1-/- mice exhibited significantly exacerbated renal function and worsening renal fibrosis. In the kidneys of the CKD model of Ulk1-/- mice, reduced AMPK and its downstream ß-oxidation could be observed, leading to an energy deficit of increased AMP/ATP ratio. In addition, AMPK signaling in the kidney was reduced in control Ulk1-/- mice with normal renal function compared to control wild-type mice, suggesting that ULK1 deficiency suppressed AMPK activity in the kidney. This study is the first to present ULK1 as a novel therapeutic target for CKD treatment, which regulates AMPK activity in the kidney.

A case of unexpected diagnosis of fibronectin glomerulopathy with histological features of membranoproliferative glomerulonephritis.

Fibronectin (FN) glomerulopathy (FNG), a rare autosomal hereditary renal disease, is characterized by proteinuria resulting from the massive accumulation of FN in the glomeruli. It typically affects individuals aged 10-50 years. In this report, we describe the case of a 57-year-old man who was diagnosed with FNG through genetic analysis and histological examination that revealed membranoproliferative glomerulonephritis. Despite treatment with prednisolone, the therapeutic response was unsatisfactory. Prednisolone was subsequently tapered and discontinued because the patient had pulmonary thromboembolism. Subsequent comprehensive genetic testing, which was initially not conducted because the patient's parents did not have a history of kidney disease, identified a known disease-causing variant in the FN1 gene, indicating a de novo variant. FNG was further confirmed by positive staining of glomeruli with FN using an IST-4 antibody. Although corticosteroid therapy is commonly employed as the initial treatment for MPGN, its appropriateness depends on the underlying etiology. Thus, clinicians must be aware of potential rare genetic causes underlying MPGN.

Associations Between Dietary Potassium Intake From Different Food Sources and Hyperkalemia in Patients With Chronic Kidney Disease.

OBJECTIVE: Previous studies reported mixed results on associations between dietary potassium intake and hyperkalemia in patients with chronic kidney disease (CKD). This study investigated the association between potassium intake from different food sources and hyperkalemia in patients with non-dialysis-dependent CKD. METHODS: A total of 285 patients were recruited at a university hospital and 2 city hospitals in Tokyo. Dietary potassium intake was estimated by a validated diet history questionnaire. Associations of potassium intake from all foods and individual food groups with serum potassium were examined by multivariable linear regression among potassium binder nonusers. An association between tertile groups of potassium intake and hyperkalemia, defined as serum potassium ≥5.0 mEq/L, was evaluated by multivariable logistic regression. RESULTS: Among 245 potassium binder nonusers, total potassium intake was weakly associated with serum potassium (regression coefficient = 0.147, 95% confidence interval (CI): 0.018-0.277), while an association with hyperkalemia was not observed (first vs third tertile: adjusted odds ratio = 0.98, 95% CI: 0.29-3.26). As for food groups, potassium intakes from potatoes, pulses, and green/yellow vegetables were positively associated with serum potassium. Patients in the highest tertile of potassium intake from potatoes had higher odds of hyperkalemia as compared to those in the lowest tertile (adjusted odds ratio = 4.12, 95% CI: 1.19-14.34). CONCLUSION: Total potassium intake was weakly associated with serum potassium, but not with hyperkalemia. Potassium intake from potatoes was associated with hyperkalemia. These findings highlight the importance of considering food sources of potassium in the management of hyperkalemia in CKD.

In Vitro Pharmacological Profile of KW-6356, a Novel Adenosine A2A Receptor Antagonist/Inverse Agonist.

KW-6356 is a novel adenosine A2A (A2A) receptor antagonist/inverse agonist, and its efficacy as monotherapy in Parkinson's disease (PD) patients has been reported. Istradefylline is a first-generation A2A receptor antagonist approved for use as adjunct treatment to levodopa/decarboxylase inhibitor in adult PD patients experiencing "OFF" episodes. In this study, we investigated the in vitro pharmacological profile of KW-6356 as an A2A receptor antagonist/inverse agonist and the mode of antagonism and compared them with istradefylline. In addition, we determined cocrystal structures of A2A receptor in complex with KW-6356 and istradefylline to explore the structural basis of the antagonistic properties of KW-6356. Pharmacological studies have shown that KW-6356 is a potent and selective ligand for the A2A receptor (the -log of inhibition constant = 9.93 ± 0.01 for human receptor) with a very low dissociation rate from the receptor (the dissociation kinetic rate constant = 0.016 ± 0.006 minute-1 for human receptor). In particular, in vitro functional studies indicated that KW-6356 exhibits insurmountable antagonism and inverse agonism, whereas istradefylline exhibits surmountable antagonism. Crystallography of KW-6356- and istradefylline-bound A2A receptor have indicated that interactions with His2506.52 and Trp2466.48 are essential for the inverse agonism, whereas the interactions at both deep inside the orthosteric pocket and the pocket lid stabilizing the extracellular loop conformation may contribute to the insurmountable antagonism of KW-6356. These profiles may reflect important differences in vivo and help predict better clinical performance. SIGNIFICANCE STATEMENT: KW-6356 is a potent and selective adenosine A2A receptor antagonist/inverse agonist and exhibits insurmountable antagonism, whereas istradefylline, a first-generation adenosine A2A receptor antagonist, exhibits surmountable antagonism. Structural studies of adenosine A2A receptor in complex with KW-6356 and istradefylline explain the characteristic differences in the pharmacological properties of KW-6356 and istradefylline.

Identification of protein kinase A signalling molecules in renal collecting ducts.

Body water homeostasis is maintained by the correct balance between water intake and water loss through urine, faeces, sweat and breath. It is known that elevated circulating levels of the antidiuretic hormone vasopressin decrease urine volume to prevent excessive water loss from the body. Vasopressin/cAMP/protein kinase A (PKA) signalling is the canonical pathway in renal collecting ducts for phosphorylating aquaporin-2 (AQP2) water channels, which leads to the reabsorption of water from urine via AQP2. Although recent omics data have verified various downstream targets of PKA, crucial regulators that mediate PKA-induced AQP2 phosphorylation remain unknown, mainly because vasopressin is usually used to activate PKA as a positive control. Vasopressin is extremely potent and phosphorylates various PKA substrates non-specifically, making it difficult to narrow down the candidate mediators responsible for AQP2 phosphorylation. The intracellular localization of PKA is tightly regulated by its scaffold proteins, also known as A-kinase anchoring proteins (AKAPs). Furthermore, each AKAP has a target domain that determines its intracellular localization, enabling the creation of a local PKA signalling network. Although vasopressin activates most PKAs independently of their intracellular localization, some chemical compounds preferentially act on PKAs localized on AQP2-containing vesicles while simultaneously phosphorylating AQP2 and its surrounding PKA substrates. Immunoprecipitation with antibodies against phosphorylated PKA substrates followed by mass spectrometry analysis revealed that the PKA substrate in proximity to AQP2 was lipopolysaccharide-responsive and beige-like anchor (LRBA). Furthermore, Lrba knockout studies revealed that LRBA was required for vasopressin-induced AQP2 phosphorylation.

LRBA signalosomes activate vasopressin-induced AQP2 trafficking at recycling endosomes.

Aquaporin-2 (AQP2) water channels are proteins that are recycled between intracellular vesicles and the apical plasma membrane in renal collecting ducts. Lipopolysaccharide-responsive beige-like anchor protein (LRBA) is a protein kinase A (PKA) anchoring protein that creates compartmentalized PKA signalling responsible for AQP2 phosphorylation. In response to increased plasma osmolality, vasopressin/cyclic adenosine monophosphate (cAMP)/PKA signalling phosphorylates AQP2, promoting AQP2 trafficking into the apical plasma membrane and increasing water reabsorption from urine. However, the molecular mechanisms by which LRBA mediates vasopressin-induced AQP2 phosphorylation remain unknown. To investigate AQP2 intracellular localization and phosphorylation status in vivo, a density gradient ultracentrifugation technique was combined with an in situ proximity ligation assay, super-resolution structured illumination microscopy and immunoelectron microscopy. Most of the AQP2 was localized on the recycling endosome in the presence of tolvaptan, a vasopressin type 2 receptor (V2R) antagonist. Desmopressin, a V2R agonist, phosphorylated AQP2, translocating it from the recycling endosome to the apical plasma membrane. In contrast, LRBA was constitutively localized at the recycling endosome. Therefore, LRBA and AQP2 were well colocalized in the absence of vasopressin stimulation. The loss of LRBA/PKA signalling by Lrba knockout impaired vasopressin-induced AQP2 phosphorylation, resulting in AQP2 retention at the recycling endosome. Defective AQP2 trafficking caused low urinary concentrating ability in Lrba-/- mice. The LRBA-PKA complex created compartmentalized PKA signalling at the recycling endosome, which facilitated AQP2 phosphorylation in response to vasopressin. KEY POINTS: Membrane proteins are continuously internalized into the endosomal system via endocytosis, after which they are either recycled back to the plasma membrane or degraded at the lysosome. In T cells, lipopolysaccharide-responsive beige-like anchor protein (LRBA) binds directly to the cytotoxic T lymphocyte antigen 4 (CTLA-4), a checkpoint immune molecule, to prevent CTLA-4 lysosomal degradation and promote its vesicle recycling. LRBA has different physiological functions in renal collecting ducts. LRBA and aquaporin-2 (AQP2) water channels were colocalized on the recycling endosome in vivo in the absence of the anti-diuretic hormone vasopressin. LRBA promoted vasopressin-induced AQP2 trafficking, increasing water reabsorption from urine via AQP2. LRBA determined renal responsiveness to vasopressin at recycling endosomes. LRBA is a ubiquitously expressed anchor protein. LRBA signalosomes might regulate membrane trafficking of several constitutively recycled proteins at recycling endosomes.

Fasting influences aquaporin expression, water transport and adipocyte metabolism in the peritoneal membrane.

BACKGROUND: The water channels aquaporin-1 (AQP1) and AQP7 are abundantly expressed in the peritoneal membrane. While AQP1 facilitates water transport during peritoneal dialysis (PD), the role of AQP7, which mediates glycerol transport during fasting, remains unknown. METHODS: We investigated the distribution of AQP7 and AQP1 and used a mouse model of PD to investigate the role of AQP7 in the peritoneal membrane at baseline and after fasting. RESULTS: Single nucleus RNA-sequencing revealed that AQP7 was mostly detected in mature adipocytes, whereas AQP1 was essentially expressed in endothelial cells. Fasting induced significant decreases in whole body fat, plasma glucose, insulin and triglycerides, as well as higher plasma glycerol and corticosterone levels in mice, paralleled by major decreases in adipocyte size and levels of fatty acid synthase and leptin, and increased levels of hormone-sensitive lipase mRNAs in the peritoneum. Mechanistically, fasting upregulated the expression of AQP1 and AQP7 in the peritoneum, with increased ultrafiltration but no change in small solute transport. Studies based on Aqp1 and Aqp7 knockout mice and RU-486 inhibition demonstrated that the glucocorticoid induction of AQP1 mediates the increase in ultrafiltration whereas AQP7 regulates the size of adipocytes in the peritoneum. CONCLUSIONS: Fasting induces a coordinated regulation of lipolytic and lipogenic factors and aqua(glycero)porins in the peritoneum, driving structural and functional changes. These data yield novel information on the specific roles of aquaporins in the peritoneal membrane and indicate that fasting improves fluid removal in a mouse model of PD.

The adenosine A2A receptor antagonist/inverse agonist, KW-6356 enhances the anti-parkinsonian activity of L-DOPA with a low risk of dyskinesia in MPTP-treated common marmosets.

The adenosine A2A receptor antagonist/inverse agonist, KW-6356 has been shown to be effective in Parkinson's disease (PD) patients as monotherapy and as an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor. However, the effects of KW-6356 combined with L-DOPA on anti-parkinsonian activity and established dyskinesia has not been investigated in preclinical experiments. We examined the effects of combination of KW-6356 with L-DOPA in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets. Oral administration of KW-6356 (1 mg/kg) enhanced the anti-parkinsonian activities of various doses of L-DOPA (2.5-10 mg/kg). In MPTP-treated common marmosets primed with L-DOPA to show dyskinesia, KW-6356 (1 mg/kg) also enhanced the anti-parkinsonian activities of various doses of L-DOPA (1.25-10 mg/kg) but not dyskinesia. Chronic co-administration of KW-6356 (1 mg/kg) with a low dose of L-DOPA (2.5 mg/kg) for 21 days increased the degree of dyskinesia induced by the low dose of L-DOPA, but the amplitude of dyskinesia induced by combined administration of KW-6356 (1 mg/kg) with L-DOPA (2.5 mg/kg) was lower than that induced by an optimal dose of L-DOPA (10 mg/kg). These results suggest that KW-6356 can be used to potentiate the effects of a wide range of L-DOPA doses with a low risk of dyskinesia for the treatment of PD.

Mineralocorticoids induce polyuria by reducing apical aquaporin-2 expression of the kidney in partial vasopressin deficiency.

The symptoms of diabetes insipidus may be masked by the concurrence of adrenal insufficiency and emerge after the administration of hydrocortisone, occasionally at high doses. To elucidate the mechanism underlying polyuria induced by the administration of high-dose corticosteroids in the deficiency of arginine vasopressin (AVP), we first examined the secretion of AVP in three patients in whom polyuria was observed only after the administration of high-dose corticosteroids. Next, we examined the effects of dexamethasone or aldosterone on water balance in wild-type and familial neurohypophyseal diabetes insipidus (FNDI) model mice. A hypertonic saline test showed that AVP secretion was partially impaired in all patients. In one patient, there were no apparent changes in AVP secretion before and after the administration of high-dose corticosteroids. In FNDI mice, unlike dexamethasone, the administration of aldosterone increased urine volumes and decreased urine osmolality. Immunohistochemical analyses showed that, after the administration of aldosterone in FNDI mice, aquaporin-2 expression was decreased in the apical membrane and increased in the basolateral membrane in the collecting duct. These changes were not observed in wild-type mice. The present data suggest that treatment with mineralocorticoids induces polyuria by reducing aquaporin-2 expression in the apical membrane of the kidney in partial AVP deficiency.

Rapidly progressive IgA nephropathy with membranoproliferative glomerulonephritis-like lesions in an elderly man following the third dose of an mRNA COVID-19 vaccine: a case report.

BACKGROUND: As messenger RNA (mRNA)-based vaccines for coronavirus disease 2019 (COVID-19) have been administered to millions of individuals worldwide, cases of de novo and relapsing glomerulonephritis after mRNA COVID-19 vaccination are increasing in the literature. While most previous publications reported glomerulonephritis after the first or second dose of an mRNA vaccine, few reports of glomerulonephritis occurring after the third dose of an mRNA vaccine currently exist. CASE PRESENTATION: We report a case of rapidly progressive glomerulonephritis in a patient following the third dose of an mRNA COVID-19 vaccine. A 77-year-old Japanese man with a history of hypertension and atrial fibrillation was referred to our hospital for evaluation of anorexia, pruritus, and lower extremity edema. One year before referral, he received two mRNA vaccines (BNT162b2) for COVID-19. Three months before the visit, he received a third mRNA vaccine (mRNA-1273) for COVID-19. On admission, the patient presented severe renal failure with a serum creatinine level of 16.29 mg/dL, which had increased from 1.67 mg/dL one month earlier, prompting us to initiate hemodialysis. Urinalysis showed nephrotic-range proteinuria and hematuria. Renal biopsy revealed mild mesangial proliferation and expansion, a lobular appearance, and double contours of the glomerular basement membrane. Renal tubules had severe atrophy. Immunofluorescence microscopy showed strong mesangial staining for IgA, IgM, and C3c. Electron microscopy exhibited mesangial and subendothelial electron-dense deposits, leading to a diagnosis of IgA nephropathy with membranoproliferative glomerulonephritis-like changes. The kidney function remained unchanged after steroid therapy. CONCLUSIONS: Although the link between renal lesions and mRNA vaccines remains unclear, a robust immune response induced by mRNA vaccines may play a role in the pathogenesis of glomerulonephritis. Further studies of the immunological effects of mRNA vaccines on the kidney are warranted.

The Effect of Antihypertensive Therapy on Skeletal Muscle Mass and Bone Mineral Density in Patients With End-Stage Kidney Disease.

OBJECTIVE: Sarcopenia and osteoporosis substantially influence health and lifespan. However, the variables affecting skeletal muscle mass (SMM) or bone mineral density (BMD) remain unknown. DESIGN AND METHODS: From August 1, 2018 to July 31, 2019, we conducted a single-center, observational cohort study with 291 Japanese adult patients on maintenance hemodialysis due to end-stage kidney disease, who had their femoral neck BMD measured using dual-energy X-ray absorptiometry. After 1-year follow-up, we measured annual changes of BMD (ΔBMD) and SMM (ΔSMM), which were calculated through a modified creatinine index (mg/kg/day) using age, sex, serum creatinine, and single-pooled Kt/V for urea. The factors associated with ΔSMM/ΔBMD or progressive loss of SMM/BMD, defined as ΔSMM/ΔBMD < 0 per year, respectively, were analyzed with multivariable, linear regression or logistic regression models. RESULTS: The median age of the patients was 66 years and 33% were female. Dialysis vintage and ß-blocker-use were inversely correlated to ΔSMM. In comparison to nonusers, ß-blockers users had 2.5-fold higher SMM loss odd ratios [95% confidence interval, 1.3-4.8]. The risk for SMM loss caused by ß-blockers was not increased in users of renin-angiotensin system inhibitors. The ΔBMD was negatively correlated to the usage of calcium channel blockers. The risk of developing osteosarcopenia, which was defined as annual loss of both SMM and BMD, increased in calcium channel blockers users. CONCLUSIONS: The use of ß-blockers is associated with an elevated risk of developing sarcopenia, whereas renin-angiotensin system inhibitors may minimize this effect in patients with end-stage kidney disease. Use of calcium channel blocker therapy was associated with a faster decline of BMD.

Evidence for a vestigial nematic state in the cuprate pseudogap phase.

The CuO2 antiferromagnetic insulator is transformed by hole-doping into an exotic quantum fluid usually referred to as the pseudogap (PG) phase. Its defining characteristic is a strong suppression of the electronic density-of-states D(E) for energies |E| < [Formula: see text], where [Formula: see text] is the PG energy. Unanticipated broken-symmetry phases have been detected by a wide variety of techniques in the PG regime, most significantly a finite-Q density-wave (DW) state and a Q = 0 nematic (NE) state. Sublattice-phase-resolved imaging of electronic structure allows the doping and energy dependence of these distinct broken-symmetry states to be visualized simultaneously. Using this approach, we show that even though their reported ordering temperatures T DW and T NE are unrelated to each other, both the DW and NE states always exhibit their maximum spectral intensity at the same energy, and using independent measurements that this is the PG energy [Formula: see text] Moreover, no new energy-gap opening coincides with the appearance of the DW state (which should theoretically open an energy gap on the Fermi surface), while the observed PG opening coincides with the appearance of the NE state (which should theoretically be incapable of opening a Fermi-surface gap). We demonstrate how this perplexing phenomenology of thermal transitions and energy-gap opening at the breaking of two highly distinct symmetries may be understood as the natural consequence of a vestigial nematic state within the pseudogap phase of Bi2Sr2CaCu2O8.

The Pharmacological Potential of Adenosine A2A Receptor Antagonists for Treating Parkinson's Disease.

The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson's disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.

Phenotypic differences of mutation-negative cases in Gitelman syndrome clinically diagnosed in adulthood.

Gitelman syndrome (GS), an autosomal recessive kidney disorder, is characterized by hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. Generally, diagnosis is made in school-aged children but multiple cases have been diagnosed in adulthood. This study examines the phenotypic differences between genetically confirmed cases and mutation-negative cases in adults. A comprehensive screening of 168 genes, including GS-related genes, was performed for 84 independent individuals who were referred to our institute with a clinical diagnosis of GS. The cases of pseudo-Bartter syndrome (BS)/GS because of diuretic abuse or other causes, which was determined based on patients' medical records, were excluded during registration. Of these 70 eligible cases for analysis, 27 (38.6%) had genetic confirmation of GS, while 37 (52.8%) had no known variants associated with GS and were considered to be unsolved cases. Note that unsolved cases comprised older, mostly female, individuals with decreased kidney function and multiple basic features of GS. The phenotype of unsolved cases is similar to that of pseudo BS/GS cases, although these cases were excluded in advance. However, the genetic and autoimmune profiles of these unsolved cases have not yet been investigated to date. Therefore, these cases may be categorized into new disease groups.

Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD2 in the kidney.

BACKGROUND: Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. METHODS: To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys. RESULTS: In 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15-/- mice. Alox15-/- CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15-/- CKD mice. Mediator lipidomics revealed that Alox15-/- CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-ß1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines. CONCLUSION: Increased PGD2 in Alox15-/- CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.