Pharmacokinetic/pharmacodynamic evaluation of gamithromycin against rabbit pasteurellosis.

BACKGROUND: Gamithromycin is an effective therapy for bovine and swine respiratory diseases but not utilized for rabbits. Given its potent activity against respiratory pathogens, we sought to determine the pharmacokinetic profiles, antimicrobial activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with therapeutic effect of gamithromycin against Pasteurella multocida in rabbits. RESULTS: Gamithromycin showed favorable PK properties in rabbits, including high subcutaneous bioavailability (86.7 ± 10.7%) and low plasma protein binding (18.5-31.9%). PK analysis identified a mean plasma peak concentration (Cmax) of 1.64 ± 0.86 mg/L and terminal half-life (T1/2) of 31.5 ± 5.74 h after subcutaneous injection. For P. multocida, short post-antibiotic effects (PAE) (1.1-5.3 h) and post-antibiotic sub-inhibitory concentration effects (PA-SME) (6.6-9.1 h) were observed after exposure to gamithromycin at 1 to 4× minimal inhibitory concentration (MIC). Gamithromycin demonstrated concentration-dependent bactericidal activity and the PK/PD index area under the concentration-time curve over 24 h (AUC24h)/MIC correlated well with efficacy (R2 > 0.99). The plasma AUC24h/MIC ratios of gamithromycin associated with the bacteriostatic, bactericidal and bacterial eradication against P. multocida were 15.4, 24.9 and 27.8 h in rabbits, respectively. CONCLUSIONS: Subcutaneous administration of 6 mg/kg gamithromycin reached therapeutic concentrations in rabbit plasma against P. multocida. The PK/PD ratios determined herein in combination with ex vivo activity and favorable rabbit PK indicate that gamithromycin may be used for the treatment of rabbit pasteurellosis.

Reliability and validity of the Chinese version of chronic liver disease questionnaire-nonalcoholic fatty liver disease in patients with nonalcoholic fatty liver disease: a multicenter cross-sectional survey in China.

PURPOSE: The Chronic Liver Disease Questionnaire (CLDQ)-Nonalcoholic Fatty Liver Disease (NAFLD) is a disease-specific instrument to assess the health-related quality of life (HRQL) of patients with NAFLD. In order to provide further evidence for the cross-cultural utility of this instrument in the Chinese population, we translated the CLDQ-NAFLD into Chinese and examined its reliability and validity. METHODS: Patients with NAFLD in 90 hospitals across China were enrolled in this multicenter cross-sectional survey. Eligible patients completed the Chinese version of CLDQ-NAFLD at enrollment to assess HRQL. Internal consistency of the questionnaire was assessed using Cronbach's alpha coefficient and split-half reliability. Convergent and discriminant validity were assessed using Spearman correlation coefficient. Factor analysis was used to test the construct validity. RESULTS: Between March and August 2019, 5181 patients with a mean age of 43.8 ± 13.3 years were enrolled. All domains exhibited good internal consistency, with Cronbach's alpha and split-half reliability greater than 0.70. The scaling success rate of all domains was 100% for convergent validity and 99.4% (179/180) for discriminant validity. The inter-scale correlations indicated a significant correlation between all CLDQ-NAFLD domains (r = 0.608 to 0.832, all p < 0.001). Factor analysis of 36 items extracted 6 factors, which explained 69.14% of the total variance. CONCLUSION: The Chinese version of CLDQ-NAFLD is a reliable and valid instrument for assessing the HRQL of Chinese patients with NAFLD.

Health-related quality of life in Chinese population with non-alcoholic fatty liver disease: a national multicenter survey.

BACKGROUND: Health Related Quality of Life (HRQL) is a multi-dimensional construct that can comprehensively evaluate the patient's health status, including physical, emotional, mental and social well-being. In this study, we aimed to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on HRQL in a Chinese population. METHODS: In this national multicenter cross-sectional survey, patients with NAFLD were enrolled. Chronic Liver Disease Questionnaire (CLDQ)-NAFLD was used to qualify HRQL. Univariate and multivariate analysis were used to identify independent risk factors of HRQL. RESULTS: A total of 5181 patients with NAFLD from 90 centers were enrolled in this study (mean age, 43.8 ± 13.3 years; male, 65.8%). The overall CLDQ score was 5.66 ± 0.89. Multivariate logistic regression analysis showed that body mass index (BMI: HR, 1.642; 95% CI, 1.330-2.026), alanine transaminase (ALT: HR, 1.006; 95% CI, 1.001-1.011), triglyceride (HR, 1.184; 95% CI, 1.074-1.305), disease severity (HR, 3.203; 95% CI, 1.418-7.232) and cardiovascular disease (HR, 4.305; 95% CI, 2.074-8.939) were independent risk factors for overall CLDQ score. In the logistic analyses of individual domain, BMI and triglyceride were independent risk factors of all domains. ALT, disease severity, diabetes, depression and cardiovascular disease were influencing factors for the CLDQ score of several domains. CONCLUSIONS: This national multicenter cross-sectional survey in China indicated that the HRQL in patients with NAFLD was impaired. HRQL was found to be significantly associated with sociodemographic and clinical factors. Attention should be paid to the optimally managing care of patients with NAFLD to improve their HRQL.

Persistence of Magnetism in Atomically Thin MnPS3 Crystals.

The magnetic state of atomically thin semiconducting layered antiferromagnets such as CrI3 and CrCl3 can be probed by forming tunnel barriers and measuring their resistance as a function of magnetic field (H) and temperature (T). This is possible because the spins within each individual layer are ferromagnetically aligned and the tunneling magnetoresistance depends on the relative orientation of the magnetization in adjacent layers. The situation is different for systems that are antiferromagnetic within the layers in which case it is unclear whether magnetoresistance measurements can provide information about the magnetic state. Here, we address this issue by investigating tunnel transport through atomically thin crystals of MnPS3, a van der Waals semiconductor that in the bulk exhibits easy-axis antiferromagnetic order within the layers. For thick multilayers below T ∼ 78 K, a T-dependent magnetoresistance sets in at µ0H ∼ 5 T and is found to track the boundary between the antiferromagnetic and the spin-flop phases known from bulk measurements. We show that the magnetoresistance persists as thickness is reduced with nearly unchanged characteristic temperature and magnetic field scales, albeit with a different dependence on H, indicating the persistence of magnetism in the ultimate limit of individual monolayers.

Non-optimal effectiveness of convalescent plasma transfusion and hydroxychloroquine in treating COVID-19: a case report.

BACKGROUND: Convalescent plasma (CP) transfusion was reported to be effective in treating critically ill patients with COVID-19, and hydroxychloroquine could potently inhibit SARS-CoV-2 in vitro. Herein, we reported a case receiving combination therapy with CP transfusion and hydroxychloroquine for the first time. CASE PRESENTATION: Laboratory findings showed high lactic acid level (2.1 mmol/L) and C-reactive protein (CRP, 48.8 mg/L), and low white blood cell count (1.96 × 109/L) in a 65-year-old Chinese man, who was diagnosed with severe COVID-19. CP was intravenously given twice, and hydroxychloroquine was orally administrated for a week (0.2 g, three times a day). The lactic acid and C-reactive protein levels remained high (2.1 mmol/L and 73.23 mg/L, respectively), while the arterial oxyhemoglobin saturation decreased to 86% with a low oxygenation index (OI, 76 mmHg) on day 4 after CP transfusion. His temperature returned to normal and the OI ascended above 300 on day 11. Moreover, the RNA test remained positive in throat swab, and computed tomography revealed severe pulmonary lesions on day 11 after admission. CONCLUSION: These findings suggested that the effectiveness of combination therapy with CP and hydroxychloroquine may be non-optimal, and specific therapy needs to be explored.

Determining Interaction Enhanced Valley Susceptibility in Spin-Valley-Locked MoS2.

Two-dimensional transition metal dichalcogenides (TMDCs) are recently emerged electronic systems with various novel properties, such as spin-valley locking, circular dichroism, valley Hall effect, and superconductivity. The reduced dimensionality and large effective masses further produce unconventional many-body interaction effects. Here we reveal strong interaction effects in the conduction band of MoS2 by transport experiment. We study the massive Dirac electron Landau levels (LL) in high-quality MoS2 samples with field-effect mobilities of 24 000 cm2/(V·s) at 1.2 K. We identify the valley-resolved LLs and low-lying polarized LLs using the Lifshitz-Kosevitch formula. By further tracing the LL crossings in the Landau fan diagram, we unambiguously determine the density-dependent valley susceptibility and the interaction enhanced g-factor from 12.7 to 23.6. Near integer ratios of Zeeman-to-cyclotron energies, we discover LL anticrossings due to the formation of quantum Hall Ising ferromagnets, the valley polarizations of which appear to be reversible by tuning the density or an in-plane magnetic field. Our results provide evidence for many-body interaction effects in the conduction band of MoS2 and establish a fertile ground for exploring strongly correlated phenomena of massive Dirac electrons.

Gate-tunable strong-weak localization transition in few-layer black phosphorus.

Atomically-thin black phosphorus (BP) field-effect transistors show strong-weak localization transition, which is tunable through gate voltages. Hopping transports through charge impurity-induced localized states are observed at low carrier density regime. Variable-range hopping model is applied to simulate scattering behaviors of charge carriers. In the high carrier concentration regime, a negative magnetoresistance indicates weak localization effects. The extracted phase coherence length is power-law temperature-dependent [Formula: see text] and demonstrates inelastic electron-electron interactions and the 2D transport features in few-layer BP field-effect devices. The competition between localization and phase coherence lengths is investigated and analyzed based on observed gate-tunable strong-weak localization transition in few-layer BP.

Evolution of drug-resistant mutations in HBV genomes in patients with treatment failure during the past seven years (2010-2016).

The objective of this study was to analyze the prevalence of drug-resistant HBV mutants in patients with treatment failure during the past seven years (2010-2016). 4055 HBV-infected patients who underwent HBV polymerase gene mutation test from 2010 to 2016 were enrolled. The nucleos(t)ide analogues (NAs) resistance mutation positions, including rtL180, rtA181, rtT184, rtS202, rtM204, rtI233, rtN236, rtI169, rtV173, and rtM250 were analyzed. Genotypic resistance mutations were detected in 30.8% (1248/4055) of the patients with treatment failure. Rates of drug-resistant mutations associated with LAM, ADV, ETV, and multidrug were 27.23% (1104/4055), 9.67% (392/4055), 3.69% (150/4055), and 0.79% (32/4055). Among the primary NA-resistant mutations, rtM204I (13.44%, 545/4055) occurred more frequently, followed by rtM204V, rtN236T, rtA181T, and rtA181V. For single-base mutations, rtL180M and rtA181V increased gradually during the past seven years, while rtM204I/V and rtN236T decreased after 2015. The development of drug-resistant mutations positively correlated with the consumption of ETV (r = 0.964, P = 0.002), and weakly correlated with that of LAM (r = 0.679, P = 0.109) and ADV (r = 0.429, P = 0.354). Moreover, single-base mutation rtA181V and multi-base mutations (rtL180M + M204I and rtL180M + M204V + M204I) were more common in HBV genotype C than those in genotype B (1.94% vs. 0.66%, 1.84% vs. 0.16%, 1.02% vs. 0.16%, respectively). NA-related mutations in HBV RT region increased in the past seven years, especially for LAM. Frequencies of rtL180M and rtA181T/V increased gradually in the past seven years, to which we should pay more attention.

Odd-Integer Quantum Hall States and Giant Spin Susceptibility in p-Type Few-Layer WSe_{2}.

We fabricate high-mobility p-type few-layer WSe_{2} field-effect transistors and surprisingly observe a series of quantum Hall (QH) states following an unconventional sequence predominated by odd-integer states under a moderate strength magnetic field. By tilting the magnetic field, we discover Landau level crossing effects at ultralow coincident angles, revealing that the Zeeman energy is about 3 times as large as the cyclotron energy near the valence band top at the Γ valley. This result implies the significant roles played by the exchange interactions in p-type few-layer WSe_{2}, in which itinerant or QH ferromagnetism likely occurs. Evidently, the Γ valley of few-layer WSe_{2} offers a unique platform with unusually heavy hole carriers and a substantially enhanced g factor for exploring strongly correlated phenomena.

Achieving Ultrahigh Carrier Mobility in Two-Dimensional Hole Gas of Black Phosphorus.

We demonstrate that a field-effect transistor (FET) made of few-layer black phosphorus (BP) encapsulated in hexagonal boron nitride (h-BN) in vacuum exhibits a room-temperature hole mobility of 5200 cm2/(Vs), being limited just by the phonon scattering. At cryogenic temperatures, the FET mobility increases up to 45 000 cm2/(Vs), which is five times higher compared to the mobility obtained in earlier reports. The unprecedentedly clean h-BN-BP-h-BN heterostructure exhibits Shubnikov-de Haas oscillations and a quantum Hall effect with Landau level (LL) filling factors down to v = 2 in conventional laboratory magnetic fields. Moreover, carrier density independent effective mass of m* = 0.26 m0 is measured, and a Landé g-factor of g = 2.47 is reported. Furthermore, an indication for a distinct hole transport behavior with up- and down-spin orientations is found.

van der Waals epitaxial growth of atomically thin Bi2Se3 and thickness-dependent topological phase transition.

Two-dimensional (2D) atomic-layered heterostructures stacked by van der Waals interactions recently introduced new research fields, which revealed novel phenomena and provided promising applications for electronic, optical, and optoelectronic devices. In this study, we report the van der Waals epitaxial growth of high-quality atomically thin Bi2Se3 on single crystalline hexagonal boron nitride (h-BN) by chemical vapor deposition. Although the in-plane lattice mismatch between Bi2Se3 and h-BN is approximately 65%, our transmission electron microscopy analysis revealed that Bi2Se3 single crystals epitaxially grew on h-BN with two commensurate states; that is, the (1̅21̅0) plane of Bi2Se3 was preferably parallel to the (1̅100) or (1̅21̅0) plane of h-BN. In the case of the Bi2Se3 (2̅110) ∥ h-BN (11̅00) state, the Moiré pattern wavelength in the Bi2Se3/h-BN superlattice can reach 5.47 nm. These naturally formed thin crystals facilitated the direct assembly of h-BN/Bi2Se3/h-BN sandwiched heterostructures without introducing any impurity at the interfaces for electronic property characterization. Our quantum capacitance (QC) measurements showed a compelling phenomenon of thickness-dependent topological phase transition, which was attributed to the coupling effects of two surface states from Dirac Fermions at/or above six quintuple layers (QLs) to gapped Dirac Fermions below six QLs. Moreover, in ultrathin Bi2Se3 (e.g., 3 QLs), we observed the midgap states induced by intrinsic defects at cryogenic temperatures. Our results demonstrated that QC measurements based on h-BN/Bi2Se3/h-BN sandwiched structures provided rich information regarding the density of states of Bi2Se3, such as quantum well states and Landau quantization. Our approach in fabricating h-BN/Bi2Se3/h-BN sandwiched device structures through the combination of bottom-up growth and top-down dry transferring techniques can be extended to other two-dimensional layered heterostructures.

Intermediate metallic phase in VO2 observed with scanning tunneling spectroscopy.

This investigation focuses on the formation of nanoscale puddles of an intermediate metallic phase (IMP) in the metal-insulator transition (MIT) temperature regime of single-crystalline vanadium dioxide (VO2) nanowires. The electronic structure of VO2 nanowires was examined with scanning tunneling spectroscopy. The evolution of the local density of states of individual nanowires throughout the MIT regime is presented with differential tunneling conductance spectra and images measured as the temperature was increased. Our results show that the formation of an IMP plays an important role in the MIT of intrinsic VO2.

Infrared optoelectronics in twisted black phosphorus.

Electrons and holes, fundamental charge carriers in semiconductors, dominate optical transitions and detection processes. Twisted van der Waals (vdW) heterostructures offer an effective approach to manipulate radiation, separation, and collection processes of electron-hole pairs by creating an atomically sharp interface. Here, we demonstrate that twisted interfaces in vdW layered black phosphorus (BP), an infrared semiconductor with highly anisotropic crystalline structure and properties, can significantly alter both recombination and separation processes of electron-hole pairs. On the one hand, the twisted interface breaks the symmetry of optical transition states resulting in infrared light emission of originally symmetry-forbidden optical states along the zigzag direction. On the other hand, spontaneous electronic polarization/bulk photovoltaic effect is generated at the twisted interface enabling effective separation of electron-hole pairs without external voltage bias. This is supported by first-principles calculations and repeated experiments at various twisted angles from 0 to 90°. Importantly, these phenomena can be observed in twisted heterostructures with thickness beyond two-dimensional. Our results suggest that the engineering of vdW twisted interfaces is an effective strategy for manipulating the optoelectronic properties of materials and constructing functional devices.

Tobramycin-resistant small colony variant mutant of Salmonella enterica serovar Typhimurium shows collateral sensitivity to nitrofurantoin.

The increasing antibiotic resistance poses a significant global health challenge, threatening our ability to combat infectious diseases. The phenomenon of collateral sensitivity, whereby resistance to one antibiotic is accompanied by increased sensitivity to another, offers potential avenues for novel therapeutic interventions against infections unresponsive to classical treatments. In this study, we elucidate the emergence of tobramycin (TOB)-resistant small colony variants (SCVs) due to mutations in the hemL gene, which render S. Typhimurium more susceptible to nitrofurantoin (NIT). Mechanistic studies demonstrate that the collateral sensitivity in TOB-resistant S. Typhimurium SCVs primarily stems from disruptions in haem biosynthesis. This leads to dysfunction in the electron transport chain (ETC) and redox imbalance, ultimately inducing lethal accumulation of reactive oxygen species (ROS). Additionally, the upregulation of nfsA/B expressions facilitates the conversion of NIT prodrug into its active form, promoting ROS-mediated bacterial killing and contributing to this collateral sensitivity pattern. Importantly, alternative NIT therapy demonstrates a significant reduction of bacterial load by more than 2.24-log10 cfu/g in the murine thigh infection and colitis models. Our findings corroborate the collateral sensitivity of S. Typhimurium to nitrofurans as a consequence of evolving resistance to aminoglycosides. This provides a promising approach for treating infections due to aminoglycoside-resistant strains.

Quantum oscillations in field-induced correlated insulators of a moiré superlattice.

We report an observation of quantum oscillations (QOs) in the correlated insulators with valley anisotropy of twisted double bilayer graphene (TDBG). The anomalous QOs are best captured in the magneto resistivity oscillations of the insulators at v = -2, with a period of 1/B and an oscillation amplitude as high as 150 kΩ. The QOs can survive up to ∼10 K, and above 12 K, the insulating behaviors are dominant. The QOs of the insulator are strongly D dependent: the carrier density extracted from the 1/B periodicity decreases almost linearly with D from -0.7 to -1.1 V/nm, suggesting a reduced Fermi surface; the effective mass from Lifshitz-Kosevich analysis depends nonlinearly on D, reaching a minimal value of 0.1 me at D = ∼ -1.0 V/nm. Similar observations of QOs are also found at v = 2, as well as in other devices without graphite gate. We interpret the D sensitive QOs of the correlated insulators in the picture of band inversion. By reconstructing an inverted band model with the measured effective mass and Fermi surface, the density of state at the gap, calculated from thermal broadened Landau levels, agrees qualitatively with the observed QOs in the insulators. While more theoretical understandings are needed in the future to fully account for the anomalous QOs in this moiré system, our study suggests that TDBG is an excellent platform to discover exotic phases where correlation and topology are at play.

Exogenous abscisic acid prolongs the dormancy of recalcitrant seed of Panax notoginseng.

The seeds of Panax notoginseng (Burk.) F. H. Chen are typically characterized by their recalcitrance and after-ripening process and exhibit a high water content at harvest as well as a high susceptibility to dehydration. Storage difficulty and the low germination of recalcitrant seeds of P. notoginseng are known to cause an obstacle to agricultural production. In this study, the ratio of embryo to endosperm (Em/En) in abscisic acid (ABA) treatments (1 mg·l-1 and 10 mg·l-1, LA and HA) was 53.64% and 52.34%, respectively, which were lower than those in control check (CK) (61.98%) at 30 days of the after-ripening process (DAR). A total of 83.67% of seeds germinated in the CK, 49% of seeds germinated in the LA treatment, and 37.33% of seeds germinated in the HA treatment at 60 DAR. The ABA, gibberellin (GA), and auxin (IAA) levels were increased in the HA treatment at 0 DAR, while the jasmonic acid (JA) levels were decreased. ABA, IAA, and JA were increased, but GA was decreased with HA treatment at 30 DAR. A total of 4,742, 16,531, and 890 differentially expressed genes (DEGs) were identified between the HA-treated and CK groups, respectively, along with obvious enrichment in the ABA-regulated plant hormone pathway and the mitogen-activated protein kinase (MAPK) signaling pathway. The expression of pyracbactin resistance-like (PYL) and SNF1-related protein kinase subfamily 2 (SnRK2s) increased in the ABA-treated groups, whereas the expression of type 2C protein phosphatase (PP2C) decreased, both of which are related to the ABA signaling pathway. As a result of the changes in expression of these genes, increased ABA signaling and suppressed GA signaling could inhibit the growth of the embryo and the expansion of developmental space. Furthermore, our results demonstrated that MAPK signaling cascades might be involved in the amplification of hormone signaling. Meanwhile, our study uncovered that the exogenous hormone ABA could inhibit embryonic development, promote dormancy, and delay germination in recalcitrant seeds. These findings reveal the critical role of ABA in regulating the dormancy of recalcitrant seeds, and thereby provide a new insight into recalcitrant seeds in agricultural production and storage.

Estimated glomerular filtration rate partially recovered in patients without Hypertriglyceridemia during Tenofovir disoproxil fumarate treatment.

BACKGROUND: Decrease in estimated glomerular filtration rate (eGFR) during Tenofovir disoproxil fumarate (TDF) treatment remains a concern, and few patients experience partial recovery of eGFR. This study aimed to investigate the risk factors for eGFR recovery in patients with and without hypertriglyceridemia. METHODS: A total of 203 patients with chronic HBV infection were prospectively recruited and followed up for three years. Data were collected at baseline, first, second, and third years during TDF treatment. RESULTS: Most patients achieved normal ALT (80.0% vs. 82.5%) and undetectable HBV DNA (95.0% vs. 95.6%) in both groups (p > 0.05). For patients with hypertriglyceridemia, eGFR and cholesterol did not change significantly during the 3-year follow-up, while triglyceride (TG) decreased significantly in the first year and persisted at a lower level in the subsequent two years. For patients without hypertriglyceridemia, eGFR declined significantly in the first year of treatment, then gradually recovered during the subsequent two years, and eGFR was negatively correlated with TG at the four time points. Fifteen (15/183, 8.2%) patients without hypertriglyceridemia experienced eGFR partial recovery in the third year. Univariate and multivariate analyses showed that baseline eGFR <90 mL/(min·1.73 m2) (p < 0.01; 95% CI: 0.019-0.284) and age (p < 0.01; 95% CI: 0.817-0.960) were independent risk factors for eGFR recovery. CONCLUSION: eGFR partially recovered in patients without hypertriglyceridemia during TDF treatment, and TG regulation might be a useful strategy to hinder renal function decline, although larger, confirmatory studies are necessary to validate our findings.Key messagesFor patients with normal triglyceride, eGFR declined significantly at the first year of TDF treatment, then gradually recovered during the subsequent two years, and eGFR was negatively correlated with TG. Baseline eGFR <90 mL/(min·1.73 m2) and age were independent risk factors for eGFR recovery.

The decline of fertility in male uremic patients is correlated with low expression of the cystic fibrosis transmembrane conductance regulator protein (CFTR) in human sperm.

BACKGROUND: The present study was designed to investigate the possible association between infertility of male uremic patients and expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in their sperm. METHODS: Semen was collected and analyzed. Serum levels of FSH, LH and testosterone were measured by radioimmunoassay. The sperm CFTR expressions of 21 uremic patients and 15 renal transplant patients were measured and compared with those of 32 healthy and 33 infertile men. RESULTS: Only 9 ± 5.9% of sperm from uremic patients expressed CFTR, significantly less than those of the renal transplant patients (29 ± 14.3%, P< 0.001), the infertile men (42 ± 20.7%, P< 0.001) and the healthy men (51 ± 20.5%, P< 0.001). Furthermore, significantly fewer sperm from renal transplant patients expressed CFTR than those of the infertile men (P< 0.05) and the healthy men (P< 0.01). LH levels in uremic patients were significantly higher than in all other groups, whereas FSH levels in uremic patients were only significantly higher than in infertile and healthy men. There was no significant difference in testosterone level among the four categories. CONCLUSIONS: Sperm CFTR expression is depressed in uremic patients but recovers to some degree after renal transplant along with some improvement in fertility, indicating a 'reversible' change. These results suggest that the CFTR expression rate in sperm is correlated with the decline of uremic patients' fertility, and may be considered as a potential marker to assess the fertility of male uremic patients.

Tris(5-methylpyrazolyl)methane: synthesis and properties of its iron(II) complex.

The new ligand, tris(5-methylpyrazolyl)methane (1), has been prepared by the reaction of n-butyl lithium with tris(pyrazolyl)methane followed by trimethylation of the tetralithiated species with methyl iodide. The BF(4)(-), ClO(4)(-), and BPh(3)CN(-) salts of the Fe(II) complex of this ligand were also synthesized. The X-ray crystal structure of the BF(4)(-) complex (2) at 100 K had Fe-N bond lengths of 1.976 Å, indicative of a low spin Fe(II) complex, while at room temperature, the structure of this complex had a Fe-N bond distance close to 2.07 Å, indicative of an admixture of approximately 50% low-spin and 50% high-spin. The solid-state structure of the complex with a ClO(4)(-) counterion was determined at 5 different temperatures between 173 and 293 K, which allowed the thermodynamic parameters for the spin-crossover to be estimated. Mössbauer spectra of the BF(4)(-) complex further support spin-state crossover in the solid state with a transition temperature near 300 K. UV-visible spectroscopy and (1)H NMR studies of 2 show that the transition temperature in solution is closer to 400 K. No spin-crossover was observed for [Fe(1)(2)](2+)·2BPh(3)CN(-). The results allow the separation of effects of groups in the 3-position from those in the 5-position on tpm ligands, and also point toward a small cooperative effect in the spin-crossover for the Fe(II) complex.

UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for puerarin metabolism in human liver microsomes.

Puerarin has multiple pharmacological effects and is widely prescribed for patients with cardiovascular diseases, including hypertension, cerebral ischemia, myocardial ischemia, diabetes mellitus, and arteriosclerosis. While puerarin is a useful therapeutic agent, its mechanisms of action have not been well defined. Understanding puerarin metabolism, in particular its interactions with metabolizing enzymes, will contribute to our understanding of its toxic and therapeutic effects and may help to elucidate potential negative drug-drug interactions. In this study, the major metabolite of puerarin was obtained from the urine of rats administered puerarin, by a semi-preparative high-performance liquid chromatography method. The major metabolite was identified as puerarin-7-O-glucuronide. In vitro, we used a UDP-glucuronosyltransferase (UGT) reaction screening method with 12 recombinant human UGTs to demonstrate that formation of puerarin-7-O-glucuronide was catalyzed by UGT1A1, 1A9, 1A10, 1A3, 1A6, 1A7, and 1A8. UGT1A1, 1A9, and 1A10 significantly catalyzed puerarin-7-O-glucuronide formation, and the activity of UGT1A1 was significantly higher than those of 1A9 and 1A10. The V (max) of UGT1A1 was two- to threefold higher than the levels of UGT1A9 or 1A10, with a lower K ( m ) value and a higher V (max)/K ( m ) value. The kinetics of puerarin-7-O-glucuronide formation catalyzed by UGT1A1 were similar to those of the pooled human liver microsomes (HLMs), with V (max) values of 186.3 and 149.2 pmol/min/mg protein, and K ( m ) values of 811.3 and 838.9 µM, respectively. Furthermore, bilirubin and ß-estradiol, probe substrates for UGT1A1, significantly inhibited the formation of puerarin-7-O-glucuronide in HLMs.