Miracle-dz/UniFAR-FTUs huggingface dataset:
Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group.

BACKGROUND Sirolimus (rapamycin) is a potent immunosuppressant with a mechanism of action different from cyclosporine (CsA) or tacrolimus. METHODS In 11 European centers, first cadaveric renal allograft recipients were randomized to CsA (n=42) or sirolimus (n=41). Dosing of these agents was concentration-controlled and open-labeled. All patients received corticosteroids and azathioprine. RESULTS At 12 months, graft survival (98% sirolimus vs. 90% CsA), patient survival (100% vs. 98%), and incidence of biopsy-confirmed acute rejection (41% vs. 38%) were similar. Serum creatinine was lower with sirolimus, significantly (P< or =0.05) so at 3 and 4 months, and serum uric acid and magnesium were normal. Laboratory abnormalities reported significantly more often with sirolimus included hypertriglyceridemia (51% vs. 12%), hypercholesterolemia (44% vs. 14%), thrombocytopenia (37% vs. 0%), leukopenia (39% vs. 14%), and, of lesser importance, increased liver enzymes and hypokalemia. These abnormalities improved 2 months after transplantation when the sirolimus target trough level was lowered from 30 to 15 ng/ml. Occurrence of cytomegalovirus was comparable (14% vs. 12%); incidences of herpes simplex (24% vs. 10%, P=0.08) and pneumonia (17% vs. 2%, P=0.03) were higher with sirolimus. No gingival hyperplasia was seen with sirolimus, tremor was rare, and hypertension was less frequent (17% vs. 33%). Two malignancies were observed with CsA and none with sirolimus. CONCLUSIONS Results at 12 months suggest that sirolimus can be used as base therapy in the prophylaxis of acute renal transplant rejection, and has a safety profile that differs from CsA.
Impact of In ovo-Administered Lead and Testosterone on Developing Female Thymocytes

The developing immune system is particularly sensitive to lead-induced immunotoxicity, but in some models, genders can differ in lead-induced immunotoxicity. Using an avian in ovo model of lead-induced T-helper disruption, the ability of in ovo administered lead and testosterone to alter thymocyte maturation among female embryos was investigated. On embryonic day (E) 8, Cornell K-strain embryos were given either testosterone (12.5 μg/egg in ethanol) or 15% ethanol in 100 μl volume. The groups then received either lead acetate (200 μg/egg) or sodium acetate (control) on E 12 of incubation. On E 20, thymocytes from 4–5 female embryos per group were analyzed by flow cytometry for cell surface markers CD3, CD4, CD8, TCR1, and TCR2. Lead alone did not induce any appreciable changes among the cell populations measured in this study. However, when testosterone treatment was followed by lead (testosterone + lead), there was a significant increase in CD4+CD8+ double-positive cells compared with either control or lead treatment groups. Testosterone, either by itself or in combination with lead, significantly reduced the percentage of cells with the CD4+CD8− phenotype when compared to the lead alone group. No change was detected with respect to the CD4−CD8+, CD4−CD8−, TCR1+, and TCR2+ phenotypes following any treatment. Therefore, sex hormonal balance in early life appears to influence the manner in which the developing thymus responds to the heavy metal lead.
Identification of Components of the Intrafollicular Bradykinin-Producing System in the Porcine Ovary1

Abstract As a step in elucidating the biological role of plasma kallikrein (PK) present in the follicular fluid of mammalian ovaries, we examined pig ovary fluid to determine its constituent activators and substrates. Using the inactive precursor form of plasma kallikrein (prePK) as a substrate, we purified an enzyme capable of activating this protein. The prePK-activating enzyme was shown to be the active enzyme blood coagulation factor XIIa. We also isolated high molecular weight kininogen (HMW-K) from the same fluid. Incubation of HMW-K with the ovarian follicular fluid PK resulted in the production of the nanopeptide bradykinin (BK). Expression of prePK, blood coagulation factor XII, and HMW-K was examined by Northern blot analysis using ovary and liver poly(A)+ RNA. All these transcripts were found in the liver, but none were found in the ovary. In addition, it was found that BK levels in the fluid derived from the small follicles were approximately 6 times higher than those from medium and large follicles. These results demonstrate the presence of a BK-producing system in the ovarian follicles and suggest the physiological importance of this peptide hormone in the early stages of follicular development and at ovulation.
Prevalence of and risk factors for sexual dysfunction in young Chinese women according to the Female Sexual Function Index: an internet-based survey

Abstract Objectives: Female sexual dysfunction (FSD) is a very common sexual health problem worldwide. The prevalence of FSD in Chinese women is, however, unknown. This is the first study to investigate a large number of young women throughout China via the internet, to determine the prevalence and types of FSD and to identify the risk factors for FSD. Methods: The primary endpoint was the Female Sexual Function Index (FSFI) score, with additional questions on contraception, sexual activity, relationship stability, pregnancy and other factors which may influence sexual function. The online questionnaire was completed by women from 31 of the 34 Chinese provinces. Results: A total of 1618 completed questionnaires were received, and 1010 were included in the analyses after screening (62.4%). The mean age of the respondents was 25.1 ± 4.5 years. The mean total FSFI score was 24.99 ± 4.60. According to FSFI definitions (cut-off score 26.55), 60.2% of women were at risk of FSD. Based on domain scores, 52 were considered at high risk of dysfunction for pain (5.1%), 35 for orgasm (3.5%), 33 for desire (3.3%), 20 for arousal (2.0%), 6 for satisfaction (0.6%) and 2 for lubrication (0.2%). Conclusions: The prevalence of FSFI scores indicating risk of sexual dysfunction was about 60% in Chinese women. An unstable relationship, pressure to become pregnant, non-use of contraception, negative self-evaluation of appearance and increasing age were significantly associated with FSD in young Chinese women.
Two Distinct Modes of PERIOD Recruitment onto dCLOCK Reveal a Novel Role for TIMELESS in Circadian Transcription

Negative transcriptional feedback loops are a core feature of eukaryotic circadian clocks and are based on rhythmic interactions between clock-specific repressors and transcription factors. In Drosophila, the repression of dCLOCK (dCLK)-CYCLE (CYC) transcriptional activity by dPERIOD (dPER) is critical for driving circadian gene expression. Although growing lines of evidence indicate that circadian repressors such as dPER function, at least partly, as molecular bridges that facilitate timely interactions between other regulatory factors and core clock transcription factors, how dPER interacts with dCLK-CYC to promote repression is not known. Here, we identified a small conserved region on dPER required for binding to dCLK, termed CBD (for dCLK binding domain). In the absence of the CBD, dPER is unable to stably associate with dCLK and inhibit the transcriptional activity of dCLK-CYC in a simplified cell culture system. CBD is situated in close proximity to a region that interacts with other regulatory factors such as the DOUBLETIME kinase, suggesting that complex architectural constraints need to be met to assemble repressor complexes. Surprisingly, when dPER missing the CBD (dPER(ΔCBD)) was evaluated in flies the clock mechanism was operational, albeit with longer periods. Intriguingly, the interaction between dPER(ΔCBD) and dCLK is TIM-dependent and modulated by light, revealing a novel and unanticipated in vivo role for TIM in circadian transcription. Finally, dPER(ΔCBD) does not provoke the daily hyperphosphorylation of dCLK, indicating that direct interactions between dPER and dCLK are necessary for the dCLK phosphorylation program but are not required for other aspects of dCLK regulation.
The transcriptomics of sympatric dwarf and normal lake whitefish (Coregonus clupeaformis spp., Salmonidae) divergence as revealed by next‐generation sequencing

Gene expression divergence is one of the mechanisms thought to be involved in the emergence of incipient species. Next‐generation sequencing has become an extremely valuable tool for the study of this process by allowing whole transcriptome sequencing, or RNA‐Seq. We have conducted a 454 GS‐FLX pyrosequencing experiment to refine our understanding of adaptive divergence between dwarf and normal lake whitefish species (Coregonus clupeaformis spp.). The objectives were to: (i) investigate transcriptomic divergence as measured by liver RNA‐Seq; (ii) test the correlation between divergence in expression and sequence polymorphism; and (iii) investigate the extent of allelic imbalance. We also compared the results of RNA‐seq with those of a previous microarray study performed on the same fish. Following de novo assembly, results showed that normal whitefish overexpressed more contigs associated with protein synthesis while dwarf fish overexpressed more contigs related to energy metabolism, immunity and DNA replication and repair. Moreover, 63 SNPs showed significant allelic imbalance, and this phenomenon prevailed in the recently diverged dwarf whitefish. Results also showed an absence of correlation between gene expression divergence as measured by RNA‐Seq and either polymorphism rate or sequence divergence between normal and dwarf whitefish. This study reiterates an important role for gene expression divergence, and provides evidence for allele‐specific expression divergence as well as evolutionary decoupling of regulatory and coding sequences in the adaptive divergence of normal and dwarf whitefish. It also demonstrates how next‐generation sequencing can lead to a more comprehensive understanding of transcriptomic divergence in a young species pair.
Optical Detection of Lead and Potassium Ions Using a Quantum-Dot-Based Aptamer Nanosensor

Quantum-dot (QD) based nanosensors can be used to detect a wide range of molecules. This study examined a nanosensor comprised of thrombin binding aptamer (TBA) with 700NC InGaP QD on the 5 <sup>'</sup> terminus and an Au nanoparticle quencher on the 3 <sup>'</sup> terminus. Both K<sup>+</sup> and Pb<sup>2+</sup> bind to TBA, resulting in a conformational change that brings the Au quencher closer to the QD. Photoluminescence measurements indicated a decrease in fluorescence corresponding to an increase in either K<sup>+</sup> or Pb<sup>2+</sup> concentration. For healthy blood serum K<sup>+</sup> concentrations (3.5-5 mM), the beacon exhibited 15-17% quenching efficiency. Pb<sup>2+</sup> concentration of 0.48 μM, the threshold for toxicity in serum, yielded 14% quenching. The beacon's ability to detect changes in ion levels in a critical range of concentrations can make it an effective diagnostic tool.
Discordant Effects of Dietary L-Arginine on Vascular Structure and Reactivity in Hypercholesterolemic Rabbits

We investigated the effect of dietary supplementation of L-arginine (L-Arg), the precursor of endothelial nitric oxide (NO), on endothelium-dependent and endothelium-independent vascular responses, as well as vascular structure, in the abdominal aorta of hypercholesterolemic rabbits. Rabbits were fed (a) normal rabbit chow, (b) 1% cholesterol diet, or (c) 1% cholesterol diet supplemented with 2.25% L-Arg HCl in drinking water. After 10 weeks, the abdominal aorta was harvested for study of vascular reactivity and histomorphometry. L-Arg did not affect serum cholesterol levels. Histomorphometric analysis demonstrated an eightfold reduction in intimal thickening in the abdominal aorta of the arginine-supplemented hypercholesterolemic rabbits. By contrast, the effects on vascular reactivity were subtle. Contraction to norepinephrine (NE) was not altered by hypercholesterolemia or L-Arg. Contraction to acetylcholine (ACh) was increased in hypercholesterolemic animals; this was normalized by dietary arginine supplementation. Relaxation to nitroglycerin (NTG) was not altered by hypercholesterolemia but was attenuated in the arginine-supplemented rabbits. Endothelium-dependent relaxation to ACh was impaired in both hypercholesterolemic groups. Dietary L-Arg has a dramatic antiatherogenic effect in hypercholesterolemic rabbits. This effect is associated with rather slight changes in vascular reactivity that are suggestive of a slight increase in NO elaboration by the endothelium. The discordance between the effects of dietary arginine on vascular structure and reactivity suggests that the antiatherogenic effects of the NO precursor may not be mediated entirely by its effect on the endothelium.
Spinal Microglial Expression and Mechanical Hypersensitivity in a Postoperative Pain Model: Comparison with a Neuropathic Pain Model

Background:Postoperative pain control contributes to quality of life. Activation of spinal cord microglia after peripheral nerve injury contributes to mechanical hypersensitivity. The contribution of spinal cord microglia to hypersensitivity after surgery, however, is not well understood. Here, the authors evaluated whether inhibition of spinal microglia reduced postoperative mechanical hypersensitivity, and if so, whether the effect differed from that in a rat neuropathic pain model. Methods:Male Sprague-Dawley rats underwent either unilateral plantar hind paw incision (postoperative pain model) or L5 spinal nerve transection (neuropathic pain model), and the development of mechanical hypersensitivity was assessed using von Frey filaments. The microglial inhibitor minocycline was intraperitoneally administered daily for either 3 or 7 days. Spinal microglial activation was evaluated by OX42 immunohistochemistry. We also tested the effect of intrathecal administration of a p38 mitogen-activated protein kinase inhibitor, SB203580. Results:In the postoperative pain model, minocycline did not suppress mechanical hypersensitivity, but did inhibit an increase in spinal OX42 expression. In contrast, in the neuropathic pain model, minocycline reduced mechanical hypersensitivity in a dose-related manner and inhibited spinal OX42 expression. SB203580 attenuated hypersensitivity in the neuropathic pain model, but not in the postoperative pain model. Conclusions:The results of the present study suggest that spinal OX42 expression has a more important role in the development of neuropathic pain than in postoperative pain, and that an increase in spinal OX42 expression does not contribute to postoperative mechanical hypersensitivity.
Global optimization of Lipschitz functions

The goal of the paper is to design sequential strategies which lead to efficient optimization of an unknown function under the only assumption that it has a finite Lipschitz constant. We first identify sufficient conditions for the consistency of generic sequential algorithms and formulate the expected minimax rate for their performance. We introduce and analyze a first algorithm called LIPO which assumes the Lipschitz constant to be known. Consistency, minimax rates for LIPO are proved, as well as fast rates under an additional Holder like condition. An adaptive version of LIPO is also introduced for the more realistic setup where the Lipschitz constant is unknown and has to be estimated along with the optimization. Similar theoretical guarantees are shown to hold for the adaptive LIPO algorithm and a numerical assessment is provided at the end of the paper to illustrate the potential of this strategy with respect to state-of-the-art methods over typical benchmark problems for global optimization.
Anatomic Localization and Autonomic Modulation of Atrioventricular Junctional Rhythm in Failing Human Hearts

Background— The structure-function relationship in the atrioventricular junction (AVJ) of various animal species has been investigated in detail; however, less is known about the human AVJ. In this study, we performed high-resolution optical mapping of the human AVJ (n=6) to define its pacemaker properties and response to autonomic stimulation. Methods and Results— Isolated, coronary-perfused AVJ preparations from failing human hearts (n=6, 53±6 years) were optically mapped using the near-infrared, voltage-sensitive dye, di-4-ANBDQBS, with isoproterenol (1 &mgr;mol/L) and acetylcholine (1 &mgr;mol/L). An algorithm detecting multiple components of optical action potentials was used to reconstruct multilayered intramural AVJ activation and to identify specialized slow and fast conduction pathways (SP and FP). The anatomic origin and propagation of pacemaker activity was verified by histology. Spontaneous AVJ rhythms of 29±11 bpm (n=6) originated in the nodal-His region (n=3) and/or the proximal His bundle (n=4). Isoproterenol accelerated the AVJ rhythm to 69±12 bpm (n=5); shifted the leading pacemaker to the transitional cell regions near the FP and SP (n=4) and/or coronary sinus (n=2); and triggered reentrant arrhythmias (n=2). Acetylcholine (n=4) decreased the AVJ rhythm to 18±4 bpm; slowed FP/SP conduction leading to block between the AVJ and atrium; and shifted the pacemaker to either the transitional cell region or the nodal-His region (bifocal activation). Conclusions— We have demonstrated that the AVJ pacemaker in failing human hearts is located in the nodal-His region or His bundle regions and can be modified with autonomic stimulation. Moreover, we found that both the FP and SP are involved in anterograde and retrograde conduction.
Retroperitoneal laparoscopic partial nephrectomy for renal-cell carcinoma in a solitary kidney: report of 56 cases.

OBJECTIVE The aim of this study was to evaluate the possibility and clinical efficacy of retroperitoneal laparoscopic partial nephrectomy for T(1)- and T(2)-stage renal-cell carcinoma (RCC) of a solitary kidney. PATIENTS AND METHODS A total of 56 patients with RCC in a solitary kidney were selected in this study, including 41 men and 15 women with a mean age of 49 years. B-type ultrasonography and CT revealed T(1)N(0)M(0) tumors in 51 cases and T(2)N(0)M(0) tumors in the remaining 5 cases; 41 cases were RCC in left kidney, and 15 were RCC in right kidney. Of them, 24 cases had RCC located in the upper pole, 24 in the inferior pole, and 8 in the central region of the kidney. The mean tumor diameter was 3.0 +/- 0.8 cm (1.5-5.5 cm). Postoperative pathology report showed 46 cases of T(1)-stage tumor (T(1a): 38; T(1b): 8) and 10 cases of T(2) stage. Retroperitoneal laparoscopic nephron-sparing surgery was performed. Surgical resection was performed along a resection line 0.5 cm from the tumors. Renal function was determined using emission CT before and after operation. Preoperative three-dimensional CT image reconstruction was performed using multislice spiral CT. RESULTS All procedures were successfully performed without open conversion and serious complications. The mean warm ischemia time was 24 +/- 4.2 minutes (19-50 minutes). The mean operation time was 95 +/- 14.5 minutes. The mean blood loss volume was 105 +/- 20.4 mL. No postoperative urine leakage occurred. Both serum creatinine and nitrogen levels were normal after operation in all cases. The mean hospital stay was 9 +/- 2 days. There was no requirement for hemodialysis. No recurrence, metastasis, and implantation were observed during the 20 +/- 4 month follow-up periods, with a survival rate of 100%. CONCLUSIONS Laparoscopic partial nephrectomy can be performed safely and effectively in selected patients with tumors in a solitary kidney owing to its minimal invasion, clear dissection, less hemorrhage, and rapid recovery.
Vitamin D deficiency, inflammation, and albuminuria in chronic kidney disease: complex interactions.

OBJECTIVE Vitamin D may promote cardiovascular health in general population and in chronic kidney disease (CKD) through inhibition of the renin-angiotensin system and anti-inflammatory effects. Although proteinuria is a marker of kidney and cardiovascular disease, few studies have examined vitamin D levels, inflammation, and proteinuria simultaneously in CKD. We evaluated the relationship between calcidiol (25D), calcitriol (1,25D), inflammation, and albuminuria in Study of Early Evaluation of Kidney Disease, a multicenter CKD cohort. DESIGN A cross-sectional study was carried out. PARTICIPANTS A total of 1,847 participants were studied, of which 387 were randomly selected for inflammatory biomarker assessment. PREDICTORS AND OUTCOMES: The primary predictors were 25D and 1,25D. The outcome was albuminuria (urine albumin to creatinine ratio [UACR]: >30 mg/g). RESULTS Albuminuric patients were more likely to have decreased 25D and 1,25D levels and higher interleukin-6 (IL-6) levels compared with normoalbuminuric patients. The lowest tertiles of 25D and 1,25D were associated with 2 to 3 times increased odds of albuminuria compared with the highest tertiles when adjusted for age, gender, race, systolic blood pressure, and diabetes (OR for 25D: 3.0; 95% CI: 1.3 to 7.0; OR for 1,25D: 2.6; 95% CI: 1.7 to 3.9). In analogous linear regression models, 25D and 1,25D were significantly associated with log UACR (P < .0001, for both). In participants for whom inflammatory markers were measured, demographics-adjusted linear regression models that included IL-6 described attenuation of the relationship between 25D, 1,25D, and UACR. CONCLUSIONS Low 25D and 1,25D levels are independently associated with albuminuria. IL-6 may be an important intermediary between vitamin D deficiency and albuminuria, or vitamin D deficiency may contribute to inflammation and subsequent albuminuria.
Expression, Purification, and Characterization of an Active RNase H Domain of the Hepatitis B Viral Polymerase*

The replication of the hepatitis B viral DNA genome proceeds through a pregenomic RNA intermediate. This pregenomic RNA subsequently serves as the template for the formation of the viral DNA by the reverse transcriptase activity of the viral P gene product. The P gene product is believed to be a multifunctional enzyme with DNA-dependent DNA polymerase, RNA-dependent DNA polymerase, and RNase H activities. Detailed biochemical studies of this protein have not been performed because of the inability to obtain sufficient amounts of the enzyme from the virus and by the inability to produce the enzyme in heterologous expression systems. The RNase H activity is essential for viral replication and is believed to be responsible for the degradation of the RNA pregenomic intermediate as well as for generating the short RNA primer that is required for DNA second strand synthesis. We have assembled an expression vector which directs the synthesis of a protein that corresponds to the putative RNase H domain of the P gene product and having a carboxyl-terminal polyhistidine tag to facilitate purification. The protein has been expressed in Escherichia coli and purified to yield 1-2 mg of protein/liter of culture. This protein has RNase H activity as defined by its ability to degrade the RNA component of RNA-DNA hybrids but not the DNA component. The RNase H has a basic optimum pH, is active only in the presence of reducing agents, and is dependent on the presence of divalent cations, with magnesium being preferred over manganese.