bluuebunny/crossref_metadata_2025_split huggingface dataset:
A macrocyclic HCV NS3/4A protease inhibitor interacts with protease and helicase residues in the complex with its full-length target
Authors: Schiering Nikolaus , D’Arcy Allan , Villard Frederic , Simić Oliver , Kamke Marion , Monnet Gaby , Hassiepen Ulrich , Svergun Dmitri I. , Pulfer Ruth , Eder Jörg , Raman Prakash , Bodendorf Ursula 
Published: December 2011

Hepatitis C virus (HCV) infection is a global health burden with over 170 million people infected worldwide. In a significant portion of patients chronic hepatitis C infection leads to serious liver diseases, including fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV NS3 protein is essential for viral polyprotein processing and RNA replication and hence viral replication. It is composed of an N-terminal serine protease domain and a C-terminal helicase/NTPase domain. For full activity, the protease requires the NS4A protein as a cofactor. HCV NS3/4A protease is a prime target for developing direct-acting antiviral agents. First-generation NS3/4A protease inhibitors have recently been introduced into clinical practice, markedly changing HCV treatment options. To date, crystal structures of HCV NS3/4A protease inhibitors have only been reported in complex with the protease domain alone. Here, we present a unique structure of an inhibitor bound to the full-length, bifunctional protease-helicase NS3/4A and show that parts of the P4 capping and P2 moieties of the inhibitor interact with both protease and helicase residues. The structure sheds light on inhibitor binding to the more physiologically relevant form of the enzyme and supports exploring inhibitor-helicase interactions in the design of the next generation of HCV NS3/4A protease inhibitors. In addition, small angle X-ray scattering confirmed the observed protease-helicase domain assembly in solution.
Solar hydrogen-producing bionanodevice outperforms natural photosynthesis
Authors: Lubner Carolyn E. , Applegate Amanda M. , Knörzer Philipp , Ganago Alexander , Bryant Donald A. , Happe Thomas , Golbeck John H. 
Published: December 2011

Although a number of solar biohydrogen systems employing photosystem I (PSI) have been developed, few attain the electron transfer throughput of oxygenic photosynthesis. We have optimized a biological/organic nanoconstruct that directly tethers F
B
, the terminal [4Fe-4S] cluster of PSI from
Synechococcus
sp. PCC 7002, to the distal [4Fe-4S] cluster of the [FeFe]-hydrogenase (H
2
ase) from
Clostridium acetobutylicum
. On illumination, the PSI–[FeFe]-H
2
ase nanoconstruct evolves H
2
at a rate of 2,200 ± 460
μ
mol mg chlorophyll
-1
h
-1
, which is equivalent to 105 ± 22 e
-
PSI
-1
s
-1
. Cyanobacteria evolve O
2
at a rate of approximately 400
μ
mol mg chlorophyll
-1
h
-1
, which is equivalent to 47 e
-
PSI
-1
s
-1
, given a PSI to photosystem II ratio of 1.8. The greater than twofold electron throughput by this hybrid biological/organic nanoconstruct over in vivo oxygenic photosynthesis validates the concept of tethering proteins through their redox cofactors to overcome diffusion-based rate limitations on electron transfer.
Proton-coupled electron transfer at modified electrodes by multiple pathways
Authors: Chen Zuofeng , Vannucci Aaron K. , Concepcion Javier J. , Jurss Jonah W. , Meyer Thomas J. 
Published: December 2011

In single site water or hydrocarbon oxidation catalysis with polypyridyl Ru complexes such as [Ru
II
(Mebimpy)(bpy)(H
2
O)]
2+
[where bpy is 2,2′-bipyridine, and Mebimpy is 2,6-bis(1-methylbenzimidazol-2-yl)pyridine]
2
, or its surface-bound analog [Ru
II
(Mebimpy)(4,4
′
-bis-methlylenephosphonato-2,2
′
-bipyridine)(OH
2
)]
2+
2
-
PO

3

H

2

, accessing the reactive states, Ru
V
= O
3+
/Ru
IV
= O
2+
, at the electrode interface is typically rate limiting. The higher oxidation states are accessible by proton-coupled electron transfer oxidation of aqua precursors, but access at inert electrodes is kinetically inhibited. The inhibition arises from stepwise mechanisms which impose high energy barriers for 1e
-
intermediates. Oxidation of the Ru
III
-OH
2+
or

forms of
2
-
PO

3

H

2

to Ru
IV
= O
2+
on planar fluoride-doped SnO
2
electrode and in nanostructured films of Sn(IV)-doped In
2
O
3
and TiO
2
has been investigated with a focus on identifying microscopic phenomena. The results provide direct evidence for important roles for the nature of the electrode, temperature, surface coverage, added buffer base, pH, solvent, and solvent H
2
O/D
2
O isotope effects. In the nonaqueous solvent, propylene carbonate, there is evidence for a role for surface-bound phosphonate groups as proton acceptors.
The Demons and the Friars: Illicit Magic and Mendicant Rivalry in Renaissance Bologna*
Authors: Herzig Tamar 
Published: December 2011

AbstractIn 1473 Pope Sixtus IV instructed the vicar of the Bishop of Bologna to investigate rumors concerning Carmelite friars who were preaching that summoning demons in order to obtain responses from them was not heretical. Drawing on newly discovered archival sources, this article elucidates the circumstances that led the Franciscan pope to intervene in a conflict between the Bolognese Carmelites and the Dominican inquisitor Simone of Novara. It proposes that the Carmelite affair, which ended with the inquisitor's defeat, constituted a critical juncture in the Dominicans’ relations with other Mendicant orders, and that it shaped inquisitorial activity in Bologna over the next few decades. This paper suggests that the aftermath of the Carmelite affair may also explain why, when the repression of illicit magic was resumed, Inquisitor Giovanni Cagnazzo decided to turn a female necromancer, and not the friars who had taught her demonic rites, into the main target of his prosecution.
First Report of Potato spindle tuber viroid in Cape Gooseberry in Slovenia
Authors: Marn M. Viršček , Pleško I. Mavrič 
Published: December 2011

Cape gooseberry (Physalis peruviana) was first reported as a host of Potato spindle tuber viroid (PSTVd) in 2009 (4). In Slovenia, 10 young plants of cape gooseberry that were grown in a glasshouse were inspected in April 2011. Plants were multiplied from an adult plant of unknown origin. During sampling, the inspected plants showed no disease symptoms. Total RNA was extracted twice from leaves of five plants with an RNeasy Plant Mini Kit (QIAGEN, Hilden, Germany). Reverse transcription (RT)-PCR assay employing two pairs of semi-universal pospiviroid primers (Pospi1-RE/FW and Vid-RE/FW [3]) yielded amplicons of the expected size (approximately 196 and 360 bp) from each total RNA preparation. All four DNA products were sequenced directly (Macrogen, Amsterdam, the Netherlands). Sequence analysis confirmed the identity of a viroid as PSTVd. Further RT-PCRs using primer pairs of Shamloul et al. (2) and Di Serio (1) were made to obtain a full viroid sequence. The sequence was deposited in the NCBI GenBank under Accession No. JN543964. Sequence analysis confirmed the identity of the viroid as PSTVd. The Slovenian isolate had 358 nucleotides and was 100% identical to the cape gooseberry isolate from Germany (GenBank Accession No. EU862231) and the tomato isolate from New Zealand (GenBank Accession No. AF369530). The analyzed sample was the only sample of cape gooseberry taken from the start of the survey for PSTVd in 2006 because P. peruviana is rarely grown in Slovenia. To our knowledge, this is the first report of PSTVd infection of P. peruviana in Slovenia and the fourth reported case after the detection of PSTVd infection in Germany, Turkey, and New Zealand. This emerging host for PSTVd could potentially serve as a source of infection for tomato and potato, where the viroid can cause severe losses. References: (1) F. Di Serio. J. Plant Pathol. 89:297, 2007. (2) A. M. Shamloul et al. Can. J. Plant Pathol. 19:89, 1997. (3) J. Th. J. Verhoeven et al. Eur. J. Plant Pathol. 110:823, 2004. (4) J. Th. J. Verhoeven et al. Plant Dis. 93:316, 2009.
Evaluation of heparanase and matrix metalloproteinase‐9 in patients with cutaneous malignant melanoma
Authors: CHEN Yanhui , CHEN Ying , HUANG Liyong , YU Jianbin 
Published: December 2011

AbstractElevated heparanase and matrix metalloproteinase (MMP)‐9, frequently found in human cancer, is a major cause of degradation of the extracellular matrix (ECM) and basement membrane (BM), thus facilitating tumor cell migration and invasion. Although a lot of work has been done, the role of heparanase and MMP‐9 has not been delineated in skin cancer progression. The purpose of this study was to do such an exploration. To investigate the role of heparanase and MMP‐9 in cutaneous malignant melanoma (CMM) development, we performed immunohistochemical analysis to detect the alternation of these two factors in paraffin‐embedded biopsy specimens of normal skin, junctional nevi and CMM. It is interesting to note that the expression profile of heparanase and MMP‐9 was similar. Contrary to negative staining in normal skin, overexpression of heparanase and cytoplasmic MMP‐9 was observed in as many as 70% of CMM, whereas only 10% of the junctional nevi exhibited faint staining (P = 0.0005, P = 0.0000). Considering the lymph node (LN) metastasis, the expression of the two factors is significantly higher in LN‐positive lesions than that in LN‐negative lesions (P = 0.0295, P = 0.0013). Meanwhile, there was positive correlation between the expression of MMP‐9 and heparanase (r = 0.689, P = 0.003). The first expression of MMP‐9 and heparanase occurs at benign lesions. However, the significantly increased expression in advanced CMM stages, particularly in LN‐positive metastasis lesions, might synergistically contribute to degradation of ECM and BM, therefore promoting carcinogenesis and metastasis.
Influence of acute bupropion pre‐treatment on the effects of intranasal cocaine
Authors: Stoops William W. , Lile Joshua A. , Glaser Paul E. A. , Hays Lon R. , Rush Craig R. 
Published: December 2011

ABSTRACTAims  The aim of this experiment was to determine the influence of acute bupropion pre‐treatment on subject‐rated effects and choice of intranasal cocaine versus money.Design  A randomized, within‐subject, placebo‐controlled, double‐blind experiment.Setting  An out‐patient research unit.Participants  Eight cocaine‐using adults.Measurements  Subjects completed nine experimental sessions in which they were pre‐treated with 0, 100 or 200 mg oral immediate release bupropion. Ninety minutes later they sampled an intranasal cocaine dose [4 (placebo), 15 or 45 mg] and made six choices between that dose and an alternative reinforcer (US$0.25), available on independent, concurrent progressive ratio schedules. Subjects also completed a battery of subject‐rated, performance and physiological measures following the sample doses of cocaine.Findings  After 0 mg bupropion, the high dose of cocaine (45 mg) was chosen five of six times on average compared to 2.25 of six choices for placebo cocaine (4 mg) (P < 0.05). Active bupropion reduced choice of 45 mg cocaine to 3.13 (100 mg) or 4.00 (200 mg) out of six drug choices on average. Bupropion also consistently enhanced positive subject‐rated effects of cocaine (e.g. good effects; willing to take again) while having no effects of its own.Conclusions  The atypical antidepressant, bupropion, acutely appears to reduce preference for intranasal cocaine versus a small amount of money but to increase reported positive experiences of the drug.
Prevalence and effects of Argemone Mexicana (Papaveraceae) on biodiversity in Ethiopia
Authors: Alemayehu Kefyalew 
Published: December 2011

AbstractThe prevalence and potentials of Argemone mexicana on biodiversity was assessed at Farta, Gondar and Bahir Dar zuria districts. The study areas were stratified into 100 m by 5 m as roadside, fallow land and farmland transect belts. Its effects as poultry feed component were studied on three poultry breeds. Body weights, abnormalities in appetite, egg production and health were recorded. The results indicated that the mean prevalence of Argemone per transect belt in roadside land (17.41 ± 5.9) was higher than that of fallow land (3.35 ± 0.8) and farmland (2.65 ± 0.8) at Farta district. The number and distribution of native plant species under the shed of A. mexicana in roadside, fallow land and farmland per transect belts were 1.15 ± 1.6, 2.25 ± 1.8 and 1.15 ± 0.5, respectively. The number and distribution of Argemone plants in the roadside land per transect increased by 163.4%, 158.5% and 151.9% from 2006 to 2010 in above respective districts. The mean losses in appetite, body weight and egg production were higher in exotic and cross bred than in indigenous chicken ecotypes. Therefore, A. mexicana had negative impacts on biodiversity, native plant species and when used as animal feed components.
MicroRNA‐494 suppresses cell proliferation and induces senescence in A549 lung cancer cells
Authors: Ohdaira H. , Sekiguchi M. , Miyata K. , Yoshida K. 
Published: December 2011

AbstractObjectives:  MicroRNAs (miRNAs) are small functional RNAs that regulate mRNAs for degradation or translational suppression. In the present study, we aimed to reveal functional importance of miRNA‐494 (miR‐494) in A549 human lung cancer cells.Materials and methods:  We established A549 cells that constitutively expressed miR‐494. Next, we sought to investigate insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) mRNA as an miR‐494 target. For this, we constructed a reporter plasmid bearing potential miR‐494 binding sequences derived from the 3′‐untranslated region (3′‐UTR) of IGF2BP1 mRNA in the 3′‐UTR of the luciferase gene.Results:  Through comparison between miR‐494 expressing cells and control cells, we revealed that miR‐494 suppressed cell proliferation and colony forming activity, and induced senescence. Reporter activity was inhibited by miR‐494. In addition, IGF2BP1 mRNA levels were down‐regulated in A549 cells that constitutively expressed miR‐494. IGF2BP1 has been shown to bind and suppress IGF2 mRNA, and this could be a reason why IGF2BP1 can regulate cell function. Therefore, we analysed IGF2 mRNA levels and revealed that IGF2 was up‐regulated in A549 cells that constitutively expressed miR‐494. Finally, elevated IGF2 mRNA levels in A549 cells that constitutively expressed miR‐494 were suppressed to basal level by an miR‐494 inhibitor.Conclusions:  Taken together, IGF2BP1 and its downstream target IGF2 could be a crucial axis for miR‐494 in regulation of the destiny of A549 cells.
Evaluation of kisspeptin levels in obese pregnancy as a biomarker for pre‐eclampsia
Authors: Logie James J. , Denison Fiona C. , Riley Simon C. , Ramaesh Thayalini , Forbes Shareen , Norman Jane E. , Reynolds Rebecca M. 
Published: December 2011

SummaryObjectives  Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre‐eclampsia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre‐eclampsia.Design  Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic.Patients  Severely obese (body mass index, BMI > 40kg/m2, n = 194) and lean (BMI < 25kg/m2, n = 78) pregnant women.Measurements  A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma samples at 16, 28 and 36 weeks gestation. Pre‐eclampsia, defined using International Society for the Study of Hypertension in Pregnancy guidelines; blood pressure; delivery gestation; birthweight.Results  Kisspeptin concentrations were lower in early pregnancy in obese women (P < 0·001), and in women who later developed pre‐eclampsia (P < 0·05), compared with women with uncomplicated pregnancies. For 16‐week plasma kisspeptin in prediction of pre‐eclampsia, area under the receiver‐operator characteristic curve was 0·80 (P < 0·01), positive and negative likelihood ratios were 3·0 and 0·2, and test sensitivity and specificity were 85·7 and 71·4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P < 0·05) and birthweight (P < 0·0001), and negatively with 28‐ and 36‐week blood pressure (P < 0·0001).Conclusions  Kisspeptin concentration in early pregnancy is a promising biomarker for pre‐eclampsia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large‐scale studies are required to assess its potential in a panel of biomarkers.
Mixed testicular atrophy related to atherosclerosis: first lessons from the ApoE−/−/ LDL receptor−/− double knockout mouse model
Authors: Langheinrich A. C. , Paradowska A. , Kilinski R. , Kampschulte M. , Steinfeld K. , Altinkilic B. , Steger K. , Stieger P. , Bergmann M. , Weidner W. 
Published: December 2011

SummaryAge‐related testicular changes are associated with declining spermatogenesis and testosterone levels. A relationship to atherosclerosis has never been investigated systematically. The ApoE−/−/LDL receptor−/− double knockout mouse model, providing a remarkable homology to human atherosclerosis, is an ideal tool to investigate spermatogenetic alterations in this context. Testes (n = 10) from ApoE−/−/LDL receptor−/− double knockout mice at the age of 80 weeks were perfused in vivo with contrast agent, harvested and scanned with micro‐CT at (4.9 μm³) voxel size. Testes (n = 8) of C57/BL mice at the same age served as controls. Testis volume (mm³) and total vascular volume fraction (mm³) were quantified using micro‐CT. Serum testosterone levels were determined. Testicular histology and epididymal sections were analysed for tubular structure, spermatogenetic scores and sperm count. The expression of protamine 2 as a marker for elongated spermatids, inflammation markers (CD4, F4/80) and hypoxia inducible factor 1 alpha (HIF1 alpha) were investigated using immunohistochemistry. ApoE−/−/LDL receptor−/− double knockout mice exhibit diminished testis and vascular volume fraction with respect to that of controls (p < 0.001). These findings were associated with a reduction of testosterone levels (p < 0.001). Mixed atrophy was present in 41% of the seminiferous tubuli in ApoE−/−/LDL receptor−/− double knockout mice at the age of 80 weeks. Sperm counts from the epididymis demonstrated a significant decrease in ApoE−/−/LDL receptor−/− double knockout mice (p < 0.001). In addition, sperm specific protamine 2 expression was decreased in testicular tissue and epididymis of ApoE−/−/LDL receptor−/− double knockout mice compared with that of control mice. Peritubular inflammatory infiltration and the expression of the hypoxia related marker was observed. Mixed testicular atrophy in ApoE−/−/LDL receptor−/− double knockout mice is linked to reduced testis volume, vascular volume fraction and low testosterone serum levels, suggesting a direct relation between atherosclerosis and disturbed spermatogenesis.
Trends in sex hormone concentrations in US males: 1988–1991 to 1999–2004
Authors: Nyante S. J. , Graubard B. I. , Li Y. , McQuillan G. M. , Platz E. A. , Rohrmann S. , Bradwin G. , McGlynn K. A. 
Published: December 2011

SummaryPrevious studies suggest that male testosterone concentrations have declined over time. To explore this in a large US population, we examined testosterone and free testosterone concentrations in National Health and Nutrition Examination Surveys (NHANES) from 1988–1991 and 1999–2004. We also examined sex hormone‐binding globulin (SHBG), estradiol, and androstanediol glucuronide (3α‐diol‐G) over the same period. Non‐Hispanic white, non‐Hispanic black, and Mexican‐American men from 1988–1991 and 1999–2004 NHANES surveys who were ≥20 years old and had serum from morning blood draws were included in this analysis (1988–1991: N = 1,413; 1999–2004: N = 902). Testosterone, estradiol and SHBG were measured by competitive electrochemiluminescence immunoassays and 3α‐diol‐G was measured by enzyme immunoassay. Free testosterone was calculated using testosterone and SHBG values. Adjusted mean hormone concentrations were estimated using linear regression, accounting for NHANES sampling weights and design, age, race/ethnicity, body mass index, waist circumference, alcohol use and smoking. Differences in adjusted mean concentrations (Δ) and two‐sided p‐values were calculated; p < 0.05 was statistically significant. Overall, 3α‐diol‐G and estradiol declined between 1988–1991 and 1999–2004, but there was little change in testosterone, free testosterone, or SHBG (Δ: 3α‐diol‐G = −1.83 ng/mL, p < 0.01; estradiol = −6.07 pg/mL, p < 0.01; testosterone = −0.03 ng/mL, p = 0.75; free testosterone = −0.001 ng/mL, p = 0.67; SHBG = −1.17 nmol/L, p = 0.19). Stratification by age and race revealed that SHBG and 3α‐diol‐G declined among whites 20–44 years old (Δ: SHBG = −5.14 nmol/L, p < 0.01; 3α‐diol‐G = −2.89 ng/mL, p < 0.01) and free testosterone increased among blacks 20–44 years old (Δ: 0.014 ng/mL, p = 0.03). Estradiol declined among all ages of whites and Mexican‐Americans. In conclusion, there was no evidence for testosterone decline between 1988–1991 and 1999–2004 in the US general population. Subgroup analyses suggest that SHBG and 3α‐diol‐G declined in young white men, estradiol declined in white and Mexican‐American men, and free testosterone increased in young black men. These changes may be related to the increasing prevalence of reproductive disorders in young men.
Exposure of neonatal rats to anti‐androgens induces penile mal‐developments and infertility comparable to those induced by oestrogens
Authors: Simon L. , Avery L. , Braden T. D. , Williams C. S. , Okumu L. A. , Williams J. W. , Goyal H. O. 
Published: December 2011

SummaryWe previously reported that oestrogen exposure in neonatal rats induced permanent infertility and malformed penis characterized by fat accumulation, which replaced most of the smooth muscle cells and cavernous spaces in the body of the penis, structures essential for erection. The objective of this study was to determine if reduced androgen production/action in the neonatal period, in the absence of exogenous oestrogen exposure, induces penile deformities similar to those caused by oestrogen. Male rats were treated from postnatal days 1–6 with GnRH antagonist antide (A, 10 mg/kg) or androgen receptor (AR) antagonist flutamide (F, 50 mg/kg) or F + A, with or without AR agonist dihydrotestosterone (DHT, 20 mg/kg). For comparison, pups received diethylstilbestrol (DES, 0.1 mg/kg), with or without DHT. Tissues were collected at ages 7 and 12 days and at adulthood. Flutamide alone decreased penile length and weight significantly (p < 0.05), but it caused neither fat accumulation, nor affected fertility (80% vs. 87% in controls). Antide alone reduced penile length and weight significantly, and induced fat accumulation in 4/11 rats and infertility in 13/14 rats. Conversely, all 11 F + A‐treated rats, similar to all nine DES‐treated rats, had fat accumulation and loss of smooth muscle cells and cavernous spaces in the body of the penis and were infertile. In addition, reductions in penile length and weight were higher than in rats treated with F or A alone. DHT co‐administration mitigated penile deformities in the DES group, but did not in the F + A group. Testicular testosterone was reduced by 70–95% at 7 or 12 days of age in all treated groups, except in the F group, which had threefold higher testosterone than controls. Collectively, data unequivocally show that reduced androgen production/action in the neonatal period, in the absence of oestrogen exposure, induces permanent infertility and malformed penis similar to that caused by oestrogen.