bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Conformational Transition Observed in Single HIV-1 Gag Molecules during
In Vitro
Assembly of Virus-Like Particles
Authors: Munro James B. , Nath Abhinav , Färber Michael , Datta Siddhartha A. K. , Rein Alan , Rhoades Elizabeth , Mothes Walther 
Published: January 2014

ABSTRACT

The conformational changes within single HIV-1 Gag molecules that occur during assembly into immature viruses are poorly understood. Using an
in vitro
assembly assay, it has been proposed that HIV-1 Gag undergoes a conformational transition from a compact conformation in solution to an extended rod-like conformation in virus-like particles (VLPs). Here we used single-molecule Förster resonance energy transfer (smFRET) to test this model by directly probing the conformation of single HIV-1 Gag molecules. We demonstrate that monomeric HIV-1 Gag lacking the p6 domain and the N-terminal myristoyl moiety is found in solution predominantly in a compact conformation. Gag in this conformation, and in the presence of nucleic acid, assembles into 30-nm-diameter particles. However, with the addition of inositol hexakisphosphate, Gag adopts a linear conformation and assembles into full-sized ∼100-to-150-nm-diameter VLPs. Parallel fluorescence correlation spectroscopy measurements show that this conformational transition occurs early in the assembly process when Gag oligomers are small, perhaps as early as upon dimerization. Thus, smFRET measurements confirm that HIV-1 Gag transitions from a compact to a linear conformation during the formation of VLPs. Our results are consistent with a model whereby binding of HIV-1 Gag to phosphoinositides at the plasma membrane stabilizes an extended conformation and promotes oligomerization into the radially aligned immature capsid.

IMPORTANCE
The establishment of single-molecule fluorescence techniques reveals the conformational state of individual HIV-1 Gag molecules prior to and during
in vitro
assembly into virus-like particles. The data demonstrate that Gag in distinct conformations forms particles with different morphologies. In the compact conformation, in the presence of nucleic acid, Gag forms spherical particles of a diameter of approximately 30 nm. In the extended conformation, Gag forms spherical virus-like particles of approximately 100-nm diameter. The adoption of the extended conformation required the presence of inositol hexakisphosphate in addition to nucleic acid. Our results are consistent with a model whereby binding of HIV-1 Gag to phosphoinositides at the plasma membrane stabilizes an extended conformation and promotes oligomerization into the radially aligned immature capsid.
Induction of HIV-Blocking Anti-CCR5 IgA in Peyers's Patches without Histopathological Alterations
Authors: Pastori Claudia , Diomede Lorenzo , Venuti Assunta , Fisher Gregory , Jarvik Jonathan , Bomsel Morgane , Sanvito Francesca , Lopalco Lucia 
Published: January 2014

ABSTRACT

The chemokine receptor CCR5 is essential for HIV infection and is thus a potential target for vaccine development. However, because CCR5 is a host protein, generation of anti-CCR5 antibodies requires the breaking of immune tolerance and thus carries the risk of autoimmune responses. In this study, performed in mice, we compared 3 different immunogens representing surface domains of murine CCR5, 4 different adjuvants, and 13 different immunization protocols, with the goal of eliciting HIV-blocking activity without inducing autoimmune dysfunction. In all cases the CCR5 sequences were presented as fusions to the Flock House virus (FHV) capsid precursor protein. We found that systemic immunization and mucosal boosting elicited CCR5-specific antibodies and achieved consistent priming in Peyer's patches, where most cells showed a phenotype corresponding to activated B cells and secreted high levels of IgA, representing up to one-third of the total HIV-blocking activity. Histopathological analysis revealed mild to moderate chronic inflammation in some tissues but failed in reporting signs of autoimmune dysfunction associated with immunizations. Antisera against immunogens representing the N terminus and extracellular loops 1 and 2 (Nter1 and ECL1 and ECL2) of CCR5 were generated. All showed specific anti-HIV activity, which was stronger in the anti-ECL1 and -ECL2 sera than in the anti-Nter sera. ECL1 and ECL2 antisera induced nearly complete long-lasting CCR5 downregulation of the receptor, and especially, their IgG-depleted fractions prevented HIV infection in neutralization and transcytosis assays. In conclusion, the ECL1 and ECL2 domains could offer a promising path to achieve significant anti-HIV activity
in vivo
.

IMPORTANCE
The study was the first to adopt a systematic strategy to compare the immunogenicities of all extracellular domains of the CCR5 molecule and to set optimal conditions leading to generation of specific antibodies in the mouse model. There were several relevant findings, which could be translated into human trials. (i) Prime (systemic) and boost (mucosal) immunization is the best protocol to induce anti-self antibodies with the expected properties. (ii) Aluminum is the best adjuvant in mice and thus can be easily used in nonhuman primates (NHP) and humans. (iii) The Flock House virus (FHV) system represents a valid delivery system, as the structure is well known and is not pathogenic for humans, and it is possible to introduce constrained regions able to elicit antibodies that recognize conformational epitopes. (iv) The best CCR5 vaccine candidate should include either extracellular loop 1 or 2 (ECL1 or ECL2), but not N terminus domains.
Comparative effectiveness study on human papillomavirus detection methods used in the cervical cancer screening programme
Authors: Nygård Mari , Røysland Kjetil , Campbell Suzanne , Dillner Joakim 
Published: January 2014

ObjectivesTo compare the short-term and long-term effectiveness of human papillomavirus (HPV) tests in Norwegian Cervical Cancer Screening Programme (NCCSP).DesignNationwide register-based prospective follow-up study.SettingIn 2005, the NCCSP implemented HPV testing in follow-up of unsatisfactory, atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) cytology.Participants19 065 women with repeat cytology and HPV test after unsatisfactory ASC-US or LSIL screening result in 2005–2009.InterventionsThrough individual registry linkages we observed how women were treated in the regular medical care.Main outcome measuresWe estimated cumulative incidence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) in 6 months and 3 years after repeat cytology and HPV test. Patients diagnosed with CIN2+ in 6 months and 3 years were assessed for initial HPV positivity.Results5392 had ASC-US/LSIL and 13 673 had normal/unsatisfactory repeat cytology; for HPV detection 4715 used AMPLICOR HPV Test (Roche Diagnostics, Basel, Switzerland), 9162 Hybrid Capture 2 (HC2) High-Risk HPV DNA Test (QIAGEN, Gaithersburg, Maryland, USA) and 5188 PreTect HPV-Proofer (NorChip, Klokkarstua, Norway). Among those with ASC-US/LSIL repeat cytology, 3-year risk of CIN2+ was 15-fold in Amplicor/HC2-positives compared with Amplicor/HC2-negatives and sevenfold in Proofer-positives compared with Proofer-negatives; a 3-year risk of CIN2+ was 2.1% (95% CI 0.7% to 3.4%) in Amplicor-negatives and 7.2% (95% CI 5.4% to 8.9%) in Proofer-negatives. Close to 100% of patients with CIN2+ diagnosed within 6 months tested positive to HPV (all methods). Considering all patients diagnosed with CIN2+ in 3-year follow-up, 97% were initially positive in the Amplicor group and more than 94% in the HC2 group, compared with less than 80% in the Proofer group.ConclusionsWhile the long-term evaluation of new screening routines showed a good overall performance of triage-HPV DNA testing, the management of HPV-negative women with persistent ASC-US/LSIL was suboptimal.
The prognostic value of Ki67 in systemically untreated patients with node-negative breast cancer
Authors: Pathmanathan Nirmala , Balleine Rosemary L , Jayasinghe Upali W , Bilinski Kellie L , Provan Pamela J , Byth Karen , Bilous A Michael , Salisbury Elizabeth L , Boyages John 
Published: January 2014

AimTo evaluate the utility of Ki67 as a prognostic marker in a series of patients with node-negative breast cancer untreated with adjuvant systemic therapy.MethodsThe cohort consisted of 203 cases treated with breast conserving surgery and radiation only; median follow-up was 183 months (range 156–277 months). An immunohistochemical panel of oestrogen receptor (ER), progesterone receptor (PR), cytokeratin (CK)5/6 and Ki67 and human epidermal growth factor 2 in situ hybridization (HER2-ISH) was performed on the tumour samples. Ki67 scores were evaluable in 193/203 patients (95.1%). The primary outcome was breast cancer specific survival (BCSS).ResultsOf the cohort, 29 (14.2%) died of breast cancer. A cut off of 10% separated tumours into a ‘Ki67-low’ (n=70) or ‘Ki67-high’ group (n=123). The breast cancer specific survival was 97.1% and 77.6% for Ki67-low and Ki67-high groups, respectively. Univariate analysis showed that in this lymph node-negative cohort, the predictors for BCSS were tumour size, Ki67, LVI, age and histological grade 3. Multivariable analysis showed that Ki67 index and lymphovascular space invasion were independent predictors of breast cancer death. To examine the utility of Ki67 in assignment of immunohistochemically molecular subtypes, cases were assigned into Luminal A (ER-positive, HER2-negative, Ki67 ≤14%), Luminal B (ER-positive, HER2-negative, Ki67 >14%) and triple negative (ER/PR-negative and HER2-negative, any Ki67). The 15-year breast cancer specific survival was 91.7%, 79.4% and 75.8%, respectively.ConclusionsA statistically significant difference in breast cancer specific survival is seen in groups defined using Ki67 and receptor status, whereas histological grading was not a significant predictor of survival. Ki67 immunostaining provides prognostic information beyond traditionally assessed clinicopathological variables.
High-tech in the middle Palaeolithic: Neandertal-manufactured pitch identified
Authors: Koller Johann , Baumer Ursula , Mania Dietrich 
Published: January 2014

Any new knowledge that goes beyond the stone tools and techniques used in the Palaeolithic and Mesolithic is most significant as it reveals the cultural and technical capabilities of the people living in these periods. In 1963, two pitch finds were discovered in a lignite open-mining pit in the northern foothills of the Harz Mountains, in a layer the geological age of which was dated as being older than 80,000 years. The great significance of these finds was therefore immediately apparent. One of the finds showed a fingerprint as well as the imprints of a flint stone tool and the structure of wood cells. This was indicative of the pitch piece having served as an adhesive to secure a wooden haft to a flint stone blade.Over 30 years later these finds were transferred to the Doerner Institut for investigation. The GC and GC/MS analyses revealed that, in both cases, birch pitches, well-known historical adhesives, had been used. These consist predominantly of pentacyclic triterpenoid components of the lupane type, with betulin forming the major component. The comparison with birch bark extracts showed that the biological peak profile (bio-marker) was surprisingly well preserved in these pitch finds and that hardly any degradation products were present.Today, comparable pitches can easily be produced with modern technical methods, i.e. using airtight laboratory flasks and temperature control facilities. However, any attempt at simulating the conditions of the Neandertal period and at producing these birch pitches without any of these modern facilities will soon be met with many difficulties. This implies that the Neandertals did not come across these pitches by accident but must have produced them with intent. Conscious action is, however, always a clear sign of considerable technical capabilities.
Women's Employment in Industrial Libraries and Information Bureaux in Britain, ca. 1918–1960
Authors: Plant Helen 
Published: January 2014

Historical studies to date on the employment of women in librarianship have focused overwhelmingly on the public library sector. However, after the First World War, a different kind of library career also emerged for women in the technical libraries and scientific information bureaux of individual industrial enterprises and co-operative trade and industry research associations. Women's employment experiences in this field were shaped not by the discourses and practices of traditional librarianship, but by those of the industrial sector. Technical library and information work was the only branch of industry to which women science graduates were routinely appointed, but it also attracted a significant number of male recruits. Drawing on a range of sources including company archives, the records of Aslib and the Women's Employment Federation, and contemporary periodical and other literature, this paper explores the status and roles of women engaged in industrial library and information work between 1918 and 1960. It argues that deeply gendered workplace ideology restricted even as it permitted women's employment, but also illuminates how some women scientists were able to seize on this rare opening as a means both of negotiating responsible careers in the overwhelmingly hostile industrial environment and of making influential contributions to the development of the technical library and information field. This paper is based on research undertaken for the AHRB-funded research project 'The early information society in Britain, 1900–1975' in the School of Information Management, Leeds Metropolitan University. Thanks to Alistair Black and David Muddiman for helpful discussions on earlier drafts of this work.
Painful ophthalmoplegia with normal cranial imaging
Authors: Hung Chih-Hsien , Chang Kuo-Hsuan , Chu Chun-Che , Liao Ming-Feng , Chang Hong-Shiu , Lyu Rong-Kuo , Wu Yi-Ming , Chen Yao-Liang , Lai Chiou-Lian , Tseng Hsiao-Jung , Ro Long-Sun 
Published: January 2014

Abstract

Background
Painful ophthalmoplegia with normal cranial imaging is rare and confined to limited etiologies. In this study, we aimed to elucidate these causes by evaluating clinical presentations and treatment responses.

Methods
Cases of painful ophthalmoplegia with normal cranial MRI at a single center between January 2001 and June 2011 were retrospectively reviewed. Diagnoses of painful ophthalmoplegia were made according to the recommendations of the International Headache Society.

Results
Of the 58 painful ophthalmoplegia cases (53 patients), 26 (44.8%) were diagnosed as ocular diabetic neuropathy, 27 (46.6%) as benign Tolosa-Hunt syndrome (THS), and 5 (8.6%) as ophthalmoplegic migraine (OM). Patients with ocular diabetic neuropathy were significantly older (62.8 ± 7.8 years) than those with benign THS (56.3 ±12.0 years) or OM (45.8 ± 23.0 years) (p < 0.05). Cranial nerve involvement was similar among groups. Pupil sparing was dominant in each group. Patients with benign THS and OM responded exquisitely to glucocorticoid treatment with resolved diplopia, whereas patients with ocular diabetic neuropathy didn’t (p < 0.05). Patients with OM recovered more rapidly than the other groups did (p < 0.05). Overall, most patients (94.8%) recovered completely during the follow-up period.

Conclusions
Ocular diabetic neuropathy and benign THS accounted for most of the painful ophthalmoplegias in patients with normal cranial imaging. Patient outcomes were generally good.
Accuracy of 16/18G core needle biopsy for ultrasound-visible breast lesions
Authors: Zhou Jie-Ying , Tang Jie , Wang Zhi-Li , Lv Fa-Qin , Luo Yu-Kun , Qin Hong-Zhen , Liu Mei 
Published: January 2014

Abstract

Background
To assess the accuracy of ultrasound-guided 16G or 18G core needle biopsy (CNB) for ultrasound-visible breast lesions, and to analyze the effects of lesion features.

Methods
Between July 2005 and July 2012, 4,453 ultrasound-detected breast lesions underwent ultrasound-guided CNB and were retrospectively reviewed. Surgical excision was performed for 955 lesions (566 with 16G CNB and 389 with 18G CNB) which constitute the basis of the study. Histological findings were compared between the ultrasound-guided CNB and the surgical excision to determine sensitivity, false-negative rate, agreement rate, and underestimation rate, according to different lesion features.

Results
Final pathological results were malignant in 84.1% (invasive carcinoma, ductal carcinoma in situ, lymphoma, and metastases), high-risk in 8.4% (atypical lesions, papillary lesions, and phyllodes tumors), and benign in 7.5%. False-negative rates were 1.4% for 16G and 18G CNB. Agreement rates between histological findings of CNB and surgery were 92.4% for 16G and 92.8% for 18G CNB. Overall underestimate rates (high-risk CNB becoming malignant on surgery and ductal carcinoma in situ becoming invasive carcinoma) were 47.4% for 16G and 48.9% for 18G CNB. Agreements were better for mass lesions (16G: 92.7%; 18G: 93.7%) than for non-mass lesions (16G, 85.7%; 18G, 78.3%) (P <0.01). For mass lesions with a diameter ≤10 mm, the agreement rates (16G, 83.3%; 18G, 86.7%) were lower (P <0.01).

Conclusions
Ultrasound-guided 16G and 18G CNB are accurate for evaluating ultrasound-visible breast mass lesions with a diameter >10 mm.
Best proximity point results for modified Suzuki α-ψ-proximal contractions
Authors: Hussain Nawab , Latif Abdul , Salimi Peyman 
Published: January 2014

Abstract
In this paper, we introduce a modified Suzuki α-ψ-proximal contraction. Then we establish certain best proximity point theorems for such proximal contractions in metric spaces. As an application, we deduce best proximity and fixed point results in partially ordered metric spaces. The results presented generalize and improve various known results from best proximity and fixed point theory. Moreover, some examples are given to illustrate the usability of the obtained results.

MSC:46N40, 47H10, 54H25, 46T99.
An algorithm for finding common solutions of various problems in nonlinear operator theory
Authors: Ofoedu Eric U , Odumegwu Jonathan N , Zegeye Habtu , Shahzad Naseer 
Published: January 2014

Abstract
In this paper, it is our aim to prove strong convergence of a new iterative algorithm to a common element of the set of solutions of a finite family of classical equilibrium problems; a common set of zeros of a finite family of inverse strongly monotone operators; the set of common fixed points of a finite family of quasi-nonexpansive mappings; and the set of common fixed points of a finite family of continuous pseudocontractive mappings in Hilbert spaces on assumption that the intersection of the aforementioned sets is not empty. Moreover, the common element is shown to be the metric projection of the initial guess on the intersection of these sets.

MSC:47H06, 47H09, 47J05, 47J25.
Acid Evoked Thermal Hyperalgesia Involves Peripheral P2Y1 Receptor Mediated TRPV1 Phosphorylation in a Rodent Model of Thrombus Induced Ischemic Pain
Authors: Kwon Soon-Gu , Roh Dae-Hyun , Yoon Seo-Yeon , Moon Ji-Young , Choi Sheu-Ran , Choi Hoon-Seong , Kang Suk-Yun , Han Ho-Jae , Beitz Alvin J , Oh Seog Bae , Lee Jang-Hern 
Published: January 2014

Background: We previously developed a thrombus-induced ischemic pain (TIIP) animal model, which was characterized by chronic bilateral mechanical allodynia without thermal hyperalgesia (TH). On the other hand we had shown that intraplantar injection of acidic saline facilitated ATP-induced pain, which did result in the induction of TH in normal rats. Because acidic pH and increased ATP are closely associated with ischemic conditions, this study is designed to: (1) examine whether acidic saline injection into the hind paw causes the development of TH in TIIP, but not control, animals; and (2) determine which peripheral mechanisms are involved in the development of this TH. Results: Repeated intraplantar injection of pH 4.0 saline, but not pH 5.5 and 7.0 saline, for 3 days following TIIP surgery resulted in the development of TH. After pH 4.0 saline injections, protein levels of hypoxia inducible factor-1α (HIF-1α) and carbonic anhydrase II (CA II) were elevated in the plantar muscle indicating that acidic stimulation intensified ischemic insults with decreased tissue acidity. At the same time point, there were no changes in the expression of TRPV1 in hind paw skin, whereas a significant increase in TRPV1 phosphorylation (pTRPV1) was shown in acidic saline (pH 4.0) injected TIIP (AS-TIIP) animals. Moreover, intraplantar injection of chelerythrine (a PKC inhibitor) and AMG9810 (a TRPV1 antagonist) effectively alleviated the established TH. In order to investigate which proton- or ATP-sensing receptors contributed to the development of TH, amiloride (an ASICs blocker), AMG9810, TNP-ATP (a P2Xs antagonist) or MRS2179 (a P2Y1 antagonist) were pre-injected before the pH 4.0 saline. Only MRS2179 significantly prevented the induction of TH, and the increased pTRPV1 ratio was also blocked in MRS2179 injected animals. Conclusion: Collectively these data show that maintenance of an acidic environment in the ischemic hind paw of TIIP rats results in the phosphorylation of TRPV1 receptors via a PKC-dependent pathway, which leads to the development of TH mimicking what occurs in chronic ischemic patients with severe acidosis. More importantly, peripheral P2Y1 receptors play a pivotal role in this process, suggesting a novel peripheral mechanism underlying the development of TH in these patients.
Whole-genome sequencing of matched primary and metastatic hepatocellular carcinomas
Authors: Ouyang Limei , Lee Jeeyun , Park Cheol-Keun , Mao Mao , Shi Yujian , Gong Zhuolin , Zheng Hancheng , Li Yingrui , Zhao Yonggang , Wang Guangbiao , Fu Huiling , Kim Jhingook , Lim Ho Yeong 
Published: January 2014

Abstract

Background
To gain biological insights into lung metastases from hepatocellular carcinoma (HCC), we compared the whole-genome sequencing profiles of primary HCC and paired lung metastases.

Methods
We used whole-genome sequencing at 33X-43X coverage to profile somatic mutations in primary HCC (HBV+) and metachronous lung metastases (> 2 years interval).

Results
In total, 5,027-13,961 and 5,275-12,624 somatic single-nucleotide variants (SNVs) were detected in primary HCC and lung metastases, respectively. Generally, 38.88-78.49% of SNVs detected in metastases were present in primary tumors. We identified 65–221 structural variations (SVs) in primary tumors and 60–232 SVs in metastases. Comparison of these SVs shows very similar and largely overlapped mutated segments between primary and metastatic tumors. Copy number alterations between primary and metastatic pairs were also found to be closely related. Together, these preservations in genomic profiles from liver primary tumors to metachronous lung metastases indicate that the genomic features during tumorigenesis may be retained during metastasis.

Conclusions
We found very similar genomic alterations between primary and metastatic tumors, with a few mutations found specifically in lung metastases, which may explain the clinical observation that both primary and metastatic tumors are usually sensitive or resistant to the same systemic treatments.