bluuebunny/crossref_metadata_2025 huggingface dataset:
Translation from the 5′ untranslated region shapes the integrated stress response
Authors: Starck Shelley R. , Tsai Jordan C. , Chen Keling , Shodiya Michael , Wang Lei , Yahiro Kinnosuke , Martins-Green Manuela , Shastri Nilabh , Walter Peter
Published: January 2016

How cells keep going in the face of adversity

When cells experience stresses that affect their ability to process newly synthesized proteins, they turn down their rates of translation to help them survive the stress. They also turn on the translation of proteins that will help them cope with the misfolded proteins generated during stress. How do they turn down translation in general, but maintain or increase translation of specific proteins? Starck
et al.
developed an approach that allowed them to look at the translation of specific messenger RNAs that were not down-regulated by stress. They identified a motif that helped keep chaperone protein synthesis going.

Science
, this issue p.
10.1126/science.aad3867
Simultaneous covalent and noncovalent hybrid polymerizations
Authors: Yu Zhilin , Tantakitti Faifan , Yu Tao , Palmer Liam C. , Schatz George C. , Stupp Samuel I.
Published: January 2016

Doubling down on polymerization

In biology, structural polymers such as cytoskeletal fibers assemble from covalently polymerized monomers through weaker supramolecular interactions such as hydrogen bonds. Yu
et al.
report the synthesis of cylindrical fibers when three monomers react, two covalently and one in a supramolecular fashion. When the reaction proceeded stepwise, lower-molecular-weight flat tapes formed instead, which suggests that supramolecular interactions helped to catalyze the covalent polymerization.

Science
, this issue p.
497
Enhanced East Pacific Rise hydrothermal activity during the last two glacial terminations
Authors: Lund D. C. , Asimow P. D. , Farley K. A. , Rooney T. O. , Seeley E. , Jackson E. W. , Durham Z. M.
Published: January 2016

Searching sediment for climate signals

Sediments on the ocean floor may provide clues about the interplay between ice ages and mid-ocean ridge magma production. Lund
et al.
present well-dated and detailed sediment records from hydrothermal activity along the East Pacific Rise. The sediments show changes in metal fluxes that are tied to the past two glaciations. Ice age changes in sea level alter magma production, which is manifested by changes in hydrothermal systems. The apparent increase in hydrothermal activity at the East Pacific Rise around the past two glacial terminations suggests some role in moderating the size of ice sheets.

Science
, this issue p.
478
Life on the edge
City of Thorns Nine Lives in the World's Largest Refugee Camp
Ben Rawlence
Picador, 2016. 400 pp.
Authors: Hynie Michaela
Published: January 2016

Stories of hardship and resilience take center stage in a probing portrait of the world's largest refugee camp
Reassessment of the Role of Rapid Antigen Detection Tests in Diagnosis of Invasive Group A Streptococcal Infections
Authors: Gazzano Vincent , Berger Anne , Benito Yvonne , Freydiere Anne-Marie , Tristan Anne , Boisset Sandrine , Carricajo Anne , Poyart Claire , Vandenesch François , Descours Ghislaine
Published: January 2016

Rapid antigen detection tests (RADTs) for group A streptococci (GAS) are widely used for diagnosing acute pharyngitis, which has led to a considerable reduction in antibiotic prescriptions over the past decade. Beyond this intended use, their reassessment on invasive samples may be relevant in the management of life-threatening GAS infections. To this end, we evaluated the performances of three RADTs, culture, GAS PCR, and 16S rRNA gene PCR assays, and compared them with a composite gold standard (GAS-PCR assay and/or culture) for the diagnosis of severe GAS infection. A total of 192 specimens from deep-tissue (mostly normally sterile) sites enriched for 75 GAS-positive samples were enrolled in the study. The three evaluated RADTs showed sensitivities ranging from 88.0% to 94.7% versus 98.7% for GAS PCR, 84% for 16S rRNA gene PCR, and 77.3% for culture. The sensitivities of the Immuno
Card
STAT! Strep A test (Meridian Bioscience) and the NADAL Strep A strip (Nal Von Minden) were similar to that of GAS PCR (
P
= 0.25 and 0.03, respectively) and higher than that of culture (
P
= 0.001 and 0.006, respectively), whereas the SD Bioline Strep A test strip (Standard Diagnostics) showed a performance similar to that of culture (
P
= 0.02). The three RADTs detected 10 distinct
emm
types, including a predominance of
emm
1 (33.3%),
emm
89 (10.6%), and
emm
12 (7.6%). No false-positive results were observed, leading to a specificity of 100% for all the evaluated RADTs. The GAS RADTs turned out to be sensitive, specific, and easy-to-use tools that may aid in the management of invasive GAS infections in 24/7 point-of-care laboratories by enabling early diagnosis and focused therapy.
Consolidating and Exploring Antibiotic Resistance Gene Data Resources
Authors: Xavier Basil Britto , Das Anupam J. , Cochrane Guy , De Ganck Sandra , Kumar-Singh Samir , Aarestrup Frank Møller , Goossens Herman , Malhotra-Kumar Surbhi
Published: January 2016

The unrestricted use of antibiotics has resulted in rapid acquisition of antibiotic resistance (AR) and spread of multidrug-resistant (MDR) bacterial pathogens. With the advent of next-generation sequencing technologies and their application in understanding MDR pathogen dynamics, it has become imperative to unify AR gene data resources for easy accessibility for researchers. However, due to the absence of a centralized platform for AR gene resources, availability, consistency, and accuracy of information vary considerably across different databases. In this article, we explore existing AR gene data resources in order to make them more visible to the clinical microbiology community, to identify their limitations, and to propose potential solutions.
Is the Presence of Actinomyces spp. in Blood Culture Always Significant?
Authors: Jeffery-Smith Anna , Nic-Fhogartaigh Caoimhe , Millar Michael
Published: January 2016

The isolation of
Actinomyces
spp. from sterile clinical samples is traditionally regarded as significant. We reviewed the demographic characteristics, clinical risk factors, and outcomes of patients with
Actinomyces
spp. isolated from blood cultures in our NHS Trust and found that this is not necessarily the case.
Pneumococcus with the “6E”
cps
Locus Produces Serotype 6B Capsular Polysaccharide
Authors: Burton Robert L. , Geno K. Aaron , Saad Jamil S. , Nahm Moon H.
Published: January 2016

Genetic studies of serogroup 6 isolates of
Streptococcus pneumoniae
identified putative serotype 6E. Although its capsular polysaccharide structure has not been elucidated, putative serotype 6E is described in an increasing number of studies as a potentially new serotype. We show here that SPEC6B, which is widely used as a target strain for serotype 6B opsonophagocytosis assays, has the genetic features of the putative serotype 6E but produces capsular polysaccharide identical to 6B capsular polysaccharide as determined by one-dimensional (1D) and 2D nuclear magnetic resonance (NMR). Thus, putative serotype 6E is a mere genetic variant of serotype 6B. Also, SPEC6B is appropriate as a target strain for serotype 6B opsonophagocytosis assays. This example illustrates the difficulties of assigning new bacterial serotypes based on genetic findings alone.
Chimeric Filoviruses for Identification and Characterization of Monoclonal Antibodies
Authors: Ilinykh Philipp A. , Shen Xiaoli , Flyak Andrew I. , Kuzmina Natalia , Ksiazek Thomas G. , Crowe James E. , Bukreyev Alexander
Published: January 2016

Recent experiments suggest that some glycoprotein (GP)-specific monoclonal antibodies (MAbs) can protect experimental animals against the filovirus Ebola virus (EBOV). There is a need for isolation of MAbs capable of neutralizing multiple filoviruses. Antibody neutralization assays for filoviruses frequently use surrogate systems such as the rhabdovirus vesicular stomatitis Indiana virus (VSV), lentiviruses or gammaretroviruses with their envelope proteins replaced with EBOV GP or pseudotyped with EBOV GP. It is optimal for both screening and in-depth characterization of newly identified neutralizing MAbs to generate recombinant filoviruses that express a reporter fluorescent protein in order to more easily monitor and quantify the infection. Our study showed that unlike neutralization-sensitive chimeric VSV, authentic filoviruses are highly resistant to neutralization by MAbs. We used reverse genetics techniques to replace EBOV GP with its counterpart from the heterologous filoviruses Bundibugyo virus (BDBV), Sudan virus, and even Marburg virus and Lloviu virus, which belong to the heterologous genera in the filovirus family. This work resulted in generation of multiple chimeric filoviruses, demonstrating the ability of filoviruses to tolerate swapping of the envelope protein. The sensitivity of chimeric filoviruses to neutralizing MAbs was similar to that of authentic biologically derived filoviruses with the same GP. Moreover, disabling the expression of the secreted GP (sGP) resulted in an increased susceptibility of an engineered virus to the BDBV52 MAb isolated from a BDBV survivor, suggesting a role for sGP in evasion of antibody neutralization in the context of a human filovirus infection.

IMPORTANCE
The study demonstrated that chimeric rhabdoviruses in which G protein is replaced with filovirus GP, widely used as surrogate targets for characterization of filovirus neutralizing antibodies, do not accurately predict the ability of antibodies to neutralize authentic filoviruses, which appeared to be resistant to neutralization. However, a recombinant EBOV expressing a fluorescent protein tolerated swapping of GP with counterparts from heterologous filoviruses, allowing high-throughput screening of B cell lines to isolate MAbs of any filovirus specificity. Human MAb BDBV52, which was isolated from a survivor of BDBV infection, was capable of partially neutralizing a chimeric EBOV carrying BDBV GP in which expression of sGP was disabled. In contrast, the parental virus expressing sGP was resistant to the MAb. Thus, the ability of filoviruses to tolerate swapping of GP can be used for identification of neutralizing MAbs specific to any filovirus and for the characterization of MAb specificity and mechanism of action.
ESCRT-0 Component Hrs Promotes Macropinocytosis of Kaposi's Sarcoma-Associated Herpesvirus in Human Dermal Microvascular Endothelial Cells
Authors: Veettil Mohanan Valiya , Kumar Binod , Ansari Mairaj Ahmed , Dutta Dipanjan , Iqbal Jawed , Gjyshi Olsi , Bottero Virginie , Chandran Bala
Published: January 2016

Kaposi's sarcoma-associated herpesvirus (KSHV) enters human dermal microvascular endothelial cells (HMVEC-d), its natural
in vivo
target cells, by lipid raft-dependent macropinocytosis. The internalized viral envelope fuses with the macropinocytic membrane, and released capsid is transported to the nuclear vicinity, resulting in the nuclear entry of viral DNA. The endosomal sorting complexes required for transport (ESCRT) proteins, which include ESCRT-0, -I, -II, and -III, play a central role in endosomal trafficking and sorting of internalized and ubiquitinated receptors. Here, we examined the role of ESCRT-0 component Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) in KSHV entry into HMVEC-d by macropinocytosis. Knockdown of Hrs by short hairpin RNA (shRNA) transduction resulted in significant decreases in KSHV entry and viral gene expression. Immunofluorescence analysis (IFA) and plasma membrane isolation and proximity ligation assay (PLA) demonstrated the translocation of Hrs from the cytosol to the plasma membrane of infected cells and association with α-actinin-4. In addition, infection induced the plasma membrane translocation and activation of the serine/threonine kinase ROCK1, a downstream target of the RhoA GTPase. Hrs knockdown reduced these associations, suggesting that the recruitment of ROCK1 is an Hrs-mediated event. Interaction between Hrs and ROCK1 is essential for the ROCK1-induced phosphorylation of NHE1 (Na
+
/H
+
exchanger 1), which is involved in the regulation of intracellular pH. Thus, our studies demonstrate the plasma membrane association of ESCRT protein Hrs during macropinocytosis and suggest that KSHV entry requires both Hrs- and ROCK1-dependent mechanisms and that ROCK1-mediated phosphorylation of NHE1 and pH change is an essential event required for the macropinocytosis of KSHV.

IMPORTANCE
Macropinocytosis is the major entry pathway of KSHV in human dermal microvascular endothelial cells, the natural target cells of KSHV. Although the role of ESCRT protein Hrs has been extensively studied with respect to endosomal movement and sorting of ubiquitinated proteins into lysosomes, its function in macropinocytosis is not known. In the present study, we demonstrate for the first time that upon KSHV infection, the endogenous Hrs localizes to the plasma membrane and the membrane-associated Hrs facilitates assembly of signaling molecules, macropinocytosis, and virus entry. Hrs recruits ROCK1 to the membrane, which is required for the activation of NHE1 and an increase in submembranous intracellular pH occurring during macropinocytosis. These studies demonstrate that the localization of Hrs from the cytosol to the plasma membrane is important for coupling membrane dynamics to the cytosolic signaling events during macropinocytosis of KSHV.
Disappearing large calcified thoracic disc herniation in a patient with thalassaemia
Authors: Ahmad Faiz U , Schallert Erica , Bregy Amade , Post Judith D , Vanni Steven
Published: January 2016

Regression of herniated disc fragments with subsequent improvement in clinical symptoms has been reported in the lumbar and cervical spine. Such regressions in the thoracic spine are extremely rare. We report a case of a 38-year-old patient with thalassaemia who had regression of a large calcified herniated thoracic disc causing cord compression, with subsequent herniation of a second calcified disc at a different level and discuss the possible aetiopathogenesis. This is the first such case reported in the thalassaemia population.
Target prices for mass production of tyrosine kinase inhibitors for global cancer treatment
Authors: Hill Andrew , Gotham Dzintars , Fortunak Joseph , Meldrum Jonathan , Erbacher Isabelle , Martin Manuel , Shoman Haitham , Levi Jacob , Powderly William G , Bower Mark
Published: January 2016

Objective

To calculate sustainable generic prices for 4 tyrosine kinase inhibitors (TKIs).

Background

TKIs have proven survival benefits in the treatment of several cancers, including chronic myeloid leukaemia, breast, liver, renal and lung cancer. However, current high prices are a barrier to treatment. Mass production of low-cost generic antiretrovirals has led to over 13 million people being on HIV/AIDS treatment worldwide. This analysis estimates target prices for generic TKIs, assuming similar methods of mass production.

Methods

Four TKIs with patent expiry dates in the next 5 years were selected for analysis: imatinib, erlotinib, lapatinib and sorafenib. Chemistry, dosing, published data on per-kilogram pricing for commercial transactions of active pharmaceutical ingredient (API), and quotes from manufacturers were used to estimate costs of production. Analysis included costs of excipients, formulation, packaging, shipping and a 50% profit margin. Target prices were compared with current prices. Global numbers of patients eligible for treatment with each TKI were estimated.

Results

API costs per kg were $347–$746 for imatinib, $2470 for erlotinib, $4671 for lapatinib, and $3000 for sorafenib. Basing on annual dose requirements, costs of formulation/packaging and a 50% profit margin, target generic prices per person-year were $128–$216 for imatinib, $240 for erlotinib, $1450 for sorafenib, and $4020 for lapatinib. Over 1 million people would be newly eligible to start treatment with these TKIs annually.

Conclusions

Mass generic production of several TKIs could achieve treatment prices in the range of $128–$4020 per person-year, versus current US prices of $75161–$139 138. Generic TKIs could allow significant savings and scaling-up of treatment globally, for over 1 million eligible patients.
Treatment with bone-seeking radionuclides for painful bone metastases in patients with lung cancer: a systematic review
Authors: Zacho Helle D , Karthigaseu Nita N , Fonager Randi F , Petersen Lars J
Published: January 2016

Treatment with bone-seeking radionuclides may provide palliation from pain originating from bone metastases. However, most studies have been conducted in patients with prostate cancer and patients with breast cancer. We aimed to perform a systematic review of the use of radionuclide treatment in lung cancer in accordance with the PRISMA guidelines. In the eligible trials, pain relief was reported in 75% of the patients included in the studies. The onset of pain relief was seen within 1–5 weeks after treatment, lasting up to 6 months. However, the methodology in the included trials was poor—only two randomised trials were eligible, and none of them compared radionuclide treatments with placebo or best standard of care. The remaining trials were case series with inherent problems of methodology reporting. Particularly challenging was the lack of reporting of baseline disease status and use of prior/concomitant analgaesics. Large randomised controlled trials are needed to clarify the efficacy of radionuclide treatment in lung cancer.
Molecular characteristics and potential therapeutic targets in Merkel cell carcinoma
Authors: Mauzo Shakuntala H , Ferrarotto Renata , Bell Diana , Torres-Cabala Carlos A , Tetzlaff Michael T , Prieto Victor G , Aung Phyu P
Published: January 2016

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin tumour occurring preferentially in elderly and immunosuppressed individuals. Multiple studies have provided insight into the molecular alterations of MCC, leading to the design of several ongoing clinical trials testing chemotherapy, targeted therapy and immunotherapy in patients with recurrent or metastatic disease. The results of some of these studies are available, whereas others are eagerly awaited and will likely shed light on the understanding of MCC biology and potentially improve the clinical outcomes of patients with this rare disease.
Diary of a parliamentary intern
Authors: Ridge Anthony
Published: January 2016

Anthony Ridge, parliamentary intern to Lord Trees, compares the process of preparing for a debate in the House with consulting in practice.
Pathogenic cellular role of the p.L104P human cationic trypsinogen variant in chronic pancreatitis
Authors: Balázs Anita , Hegyi Péter , Sahin-Tóth Miklós
Published: January 2016

Mutations in the PRSS1 gene encoding human cationic trypsinogen are associated with hereditary and sporadic chronic pancreatitis. High-penetrance PRSS1 mutations found in hereditary pancreatitis alter activation and/or degradation of cationic trypsinogen, thereby promoting intrapancreatic trypsinogen activation. In contrast, a number of rare PRSS1 variants identified in subjects with sporadic chronic pancreatitis cause misfolding and endoplasmic reticulum (ER) stress. Mutation p.L104P is unique among natural PRSS1 variants, since it affects the substrate binding site of trypsin. The aim of the present study was to establish the clinical significance of variant p.L104P through functional analysis. We found that p.L104P trypsin exhibited decreased activity on peptide and protein substrates; however, autoactivation was slightly accelerated. Remarkably, binding of the physiological trypsin inhibitor serine protease inhibitor Kazal type 1 (SPINK1) was decreased by 70-fold. In the presence of the trypsinogen-degrading enzyme chymotrypsin C, mutant p.L104P autoactivated to higher trypsin levels than wild-type trypsinogen. This apparent resistance to degradation was due to slower cleavage at Arg122 rather than Leu81. Finally, secretion of mutant p.L104P from transfected cells was markedly reduced due to intracellular retention and aggregation with concomitant elevation of ER stress markers. We conclude that PRSS1 variant p.L104P exhibits a variety of phenotypic changes that can increase risk for chronic pancreatitis. Mutation-induced misfolding and associated ER stress are the dominant effects that support a direct pathogenic role in chronic pancreatitis.
The tactile motion aftereffect suggests an intensive code for speed in neurons sensitive to both speed and direction of motion
Authors: McIntyre S. , Birznieks I. , Vickery R. M. , Holcombe A. O. , Seizova-Cajic T.
Published: January 2016

Neurophysiological studies in primates have found that direction-sensitive neurons in the primary somatosensory cortex (SI) generally increase their response rate with increasing speed of object motion across the skin and show little evidence of speed tuning. We employed psychophysics to determine whether human perception of motion direction could be explained by features of such neurons and whether evidence can be found for a speed-tuned process. After adaptation to motion across the skin, a subsequently presented dynamic test stimulus yields an impression of motion in the opposite direction. We measured the strength of this tactile motion aftereffect (tMAE) induced with different combinations of adapting and test speeds. Distal-to-proximal or proximal-to-distal adapting motion was applied to participants' index fingers using a tactile array, after which participants reported the perceived direction of a bidirectional test stimulus. An intensive code for speed, like that observed in SI neurons, predicts greater adaptation (and a stronger tMAE) the faster the adapting speed, regardless of the test speed. In contrast, speed tuning of direction-sensitive neurons predicts the greatest tMAE when the adapting and test stimuli have matching speeds. We found that the strength of the tMAE increased monotonically with adapting speed, regardless of the test speed, showing no evidence of speed tuning. Our data are consistent with neurophysiological findings that suggest an intensive code for speed along the motion processing pathways comprising neurons sensitive both to speed and direction of motion.
Mechanism of Forelimb Motor Function Restoration after Cervical Spinal Cord Hemisection in Rats: A Comparison of Juveniles and Adults
Authors: Hasegawa Atsushi , Takahashi Masahito , Satomi Kazuhiko , Ohne Hideaki , Takeuchi Takumi , Sato Shunsuke , Ichimura Shoichi
Published: January 2016

The aim of this study was to investigate forelimb motor function after cervical spinal cord injury in juvenile and adult rats. Both rats received a left segmental hemisection of the spinal cord after C3-C4 laminectomy. Behavioral evaluation of motor function was monitored and assessed using the New Rating Scale (NRS) and Forelimb Locomotor Scale (FLS) and by measuring the range of motion (ROM) of both the elbow and wrist. Complete left forelimb motor paralysis was observed in both rats. The NRS showed motor function recovery restored to50.2±24.7%in juvenile rats and34.0±19.8%in adult rats. FLS was60.4±26.8%in juvenile rats and46.5±26.9%in adult rats. ROM of the elbow and wrist were88.9±20.6%and44.4±24.1%in juvenile rats and70.0±29.2%and40.0±21.1%in adult rats. Thus, the NRS and ROM of the elbow showed a significant difference between age groups. These results indicate that left hemisection of the cervical spinal cord was not related to right-sided motor functions. Moreover, while motor paralysis of the left forelimb gradually recovered in both groups, the improvement was greater in juvenile rats.
Conjunctival Lymphangiogenesis Was Associated with the Degree of Aggression in Substantial Recurrent Pterygia
Authors: Zhao Wei , Wang Tao , Deng Juan , Zhong Lei , Huang Weilan , Ling Shiqi
Published: January 2016

Objective. To examine conjunctival lymphatic vessels and to analyze the relationship between lymphangiogenesis and aggressive recurrent pterygia.Methods. Tissues from 60 excised recurrent (including 19 of Grade 1, 28 of Grade 2, and 13 of Grade 3) pterygia were used in the study. Tissues from 9 nasal epibulbar conjunctivae segments were used as controls. Pterygium slices from each patient were immunostained with LYVE-1 monoclonal antibodies to identify lymphatic microvessels in order to calculate the lymphovascular area (LVA), the lymphatic microvessel density (LMD), and the lymphovascular luminal diameter (LVL). The relationship between lymphangiogenesis (LVA, LMD, and LVL) and pterygium aggression (width, extension, and area) was clarified.Results. Few LYVE-1 positive lymphatic vessels were found in the normal epibulbar conjunctiva segments. Lymphatic vessels were slightly increased in Grades 1 and 2 and were dramatically increased in Grade 3 recurrent pterygia. The LMD was correlated with the pterygium area in Grade 1 and 2 pterygia. In Grade 3, both LVA and LMD were significantly correlated with the pterygium area.Conclusions. Lymphangiogenesis was associated with the degree of aggression in recurrent pterygia, particularly in substantial Grade 3 recurrent pterygia.
Adaptive Randomized Ensemble Tracking Using Appearance Variation and Occlusion Estimation
Authors: Li Weisheng , Lin Yanjun
Published: January 2016

Tracking-by-detection methods have been widely studied with promising results. These methods usually train a classifier or a pool of classifiers in an online manner and use previous tracking results to generate a new training set for object appearance and update the current model to predict the object location in subsequent frames. However, the updating process may easily cause drifting in terms of appearance variation and occlusion. The previous methods for updating the classifier(s) decided whether or not to update the classifier(s) by a fixed learning rate parameter in all scenarios. The learning rate parameter has a great influence on the tracker’s performance and should be dynamically adjusted according to the change of scene during tracking. In this paper, we propose a novel method to model the time-varying appearance of an object that takes appearance variation and occlusion of local patches into consideration. In contrast with the existing methods, the learning rate for updating classifier ensembles adaptively is adjusted by estimating the appearance variation with sparse optical flow and the possible occlusion of the object between consecutive frames. Experiments and evaluations on some challenging video sequences have been done and the results demonstrate that the proposed method is more robust against appearance variation and occlusion than those state-of-the-art approaches.
Effects of Ginger Phenylpropanoids and Quercetin on Nrf2-ARE Pathway in Human BJ Fibroblasts and HaCaT Keratinocytes
Authors: Schadich Ermin , Hlaváč Jan , Volná Tereza , Varanasi Lakshman , Hajdúch Marián , Džubák Petr
Published: January 2016

Quercetin and phenylpropanoids are well known chemoprotective compounds identified in many plants. This study was aimed at determining their effects on activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element (Nrf2-ARE) signalling pathway and expression of its important downstream effector phase II detoxification enzyme glutathione-S-transferase P1 (GSTP1) in BJ foreskin fibroblasts and skin HaCaT keratinocytes. Cell lines and their corresponding Nrf2-ARE luciferase reporter cells were treated by ginger phenylpropanoids and quercetin for 10 h and the level of Nrf2 activity was subsequently determined. Both, ginger phenylpropanoids and quercetin, significantly increased the level of Nrf2 activity. Subsequent western blot analyses of proteins showed the increased expression level of glutathione-S-transferase P1 (GSTP1) in BJ cells but not in HaCaT cells. Such phenomenon of unresponsive downstream target expression in HaCaT cells was consistent with previous studies showing a constitutive expression of their GSTP1. Thus, while both ginger phenylpropanoids and quercetin have the property of increasing the level of Nrf2 both in HaCaT and in BJ cells, their effects on its downstream signalling were mediated only in BJ cells.
Descriptive Osteology of a Newly Described Stone Loach,Oxynoemacheilus chomanicus(Kamangar et al., 2014) (Cypriniformes, Nemacheilidae)
Authors: Mafakheri Parvin , Eagderi Soheil , Qadermarzi Amir
Published: January 2016

Oxynoemacheilus chomanicusis a newly described species of the family Nemacheilidae from the Choman River drainage of the Tigris basin. This study was conducted to provide the detailed osteological characteristics of this species and comparing them with those of other endemic species of the genusOxynoemacheilusfrom inland water basins of Iran, namely,kiabii,O. persa,O. brandtii,O. kermanshahensis, andO. bergianus. For this purpose, nine specimens ofO. chomanicuswere collected, cleaned, and stained for osteological examination. Then, a detailed description of their skeletal structure was provided. The results showed thatO. chomanicuscan be distinguished from other studied species of the genusOxynoemacheilusdue to possessing an orbital shelf, number of the vertebrae, number of the hypurals, number of the unbranched rays in anal fin, features of the hemal and neural spines, and connection pattern of the parietal and frontal.
Xyloglucan Based In Situ Gel of Lidocaine HCl for the Treatment of Periodontosis
Authors: Pandit Ashlesha P. , Pol Vaibhav V. , Kulkarni Vinit S.
Published: January 2016

The present study was aimed at formulating thermoreversible in situ gel of local anesthetic by using xyloglucan based mucoadhesive tamarind seed polysaccharide (TSP) into periodontal pocket. Temperature-sensitive in situ gel of lidocaine hydrochloride (LH) (2% w/v) was formulated by cold method. A full 32 factorial design was employed to study the effect of independent variables concentrations of Lutrol F127 and TSP to optimize in situ gel. The dependent variables evaluated were gelation temperature (Y1) and drug release (Y2). The results revealed the surface pH of 6.8, similar to the pH of saliva. Viscosity study showed the marked increase in the viscosity of gel at 37°C due to sol-gel conversion. TSP was found to act as good mucoadhesive component to retain gel at the site of application in dental pocket. Gelation of formulation occurred near to body temperature. In vitro study depicted the fast onset of drug action but lasting the release (90%) till 2 h. Formulation F7 was considered as optimized batch, containing 18% Lutrol F127 and 1% tamarind seed polysaccharide. Thus, lidocaine hydrochloride thermoreversible in situ gel offered an alternative to painful injection therapy of anesthesia during dental surgery, with fast onset of anesthetic action lasting throughout the dental procedure.
Cronkhite-Canada Syndrome: A Rare Cause of Chronic Diarrhoea in a Young Man
Authors: Bandyopadhyay Dhrubajyoti , Hajra Adrija , Ganesan Vijayan , Kar Suvrendu Sankar , Bhar Debarati , Layek Manas , Mukhopadhyay Sabyasachi , Choudhury Cankatika , Choudhary Vivek , Banerjee Prasun
Published: January 2016

A young Indian man presented with nine-month history of chronic diarrhea, occasionally mixed with blood and intermittent colicky abdominal pain. He also complained of generalized body swelling for the last three months. On examination, he had diffuse hyperpigmentation of the skin and dystrophic nail changes. Upper and lower gastrointestinal endoscopy revealed multiple sessile polyps in the stomach, small bowel, and colon and rectum. Biopsy of polyps showed adenomatous changes with stromal edema and dilated glands. Cronkhite-Canada syndrome (CCS) was diagnosed and treated with glucocorticoids and enteral nutritional supplementation. There was an associated small intestinal bacterial overgrowth (SIBO) and stool was positive for clostridium difficile toxin. After 12 weeks of treatment, the patient achieved remission. Close correlation with clinical findings, including pertinent ectodermal abnormalities, endoscopic studies, and careful examination of biopsies will ensure a timely and correct diagnosis of CCS.
Upscaling Arbuscular Mycorrhizal Symbiosis and Related Agroecosystems Services in Smallholder Farming Systems
Authors: Oruru Marjorie Bonareri , Njeru Ezekiel Mugendi
Published: January 2016

Smallholder farming systems form unique ecosystems that can protect beneficial soil biota and form an important source of useful genetic resources. They are characterized by high level of agricultural diversity mainly focused on meeting farmers’ needs. Unfortunately, these systems often experience poor crop production mainly associated with poor planning and resource scarcity. Soil fertility is among the primary challenges faced by smallholder farmers, which necessitate the need to come up with affordable and innovative ways of replenishing soils. One such way is the use of microbial symbionts such as arbuscular mycorrhizal fungi (AMF), a beneficial group of soil microbiota that form symbiotic associations with majority of cultivated crops and play a vital role in biological soil fertility, plant nutrition, and protection. AMF can be incorporated in smallholder farming systems to help better exploit chemical fertilizers inputs which are often unaffordable to many smallholder farmers. The present review highlights smallholder farming practices that could be innovatively redesigned to increase AMF symbiosis and related agroecosystem services. Indeed, the future of global food security depends on the success of smallholder farming systems, whose crop productivity depends on the services provided by well-functioning ecosystems, including soil fertility.
Investigation of Rheological Behavior of Low Pressure Injection Molded Stainless Steel Feedstocks
Authors: Aslam Muhammad , Ahmad Faiz , Yusoff Puteri Sri Melor Binti Megat , Altaf Khurram , Omar Mohd Afian , Abdul Khalil H. P. S. , Raza M. Rafi
Published: January 2016

The purpose of this research is to investigate the influence of different powder loadings of 316L stainless steel (SS) powders on rheological behavior of feedstocks required for low pressure powder injection molding (L-PIM) process. The main idea consists in development of various formulations by varying 316L SS powder contents in feedstocks and evaluating the temperature sensitivity of feedstock via flow behavior index and activation energy. For this purpose, the irregular shape, spherical shape, and combination of both shapes and sizes (bimodal approach) of 316L SS powders are compounded with wax based composite binder. Moreover, the influence of elemental nanosized boron (nB) addition (up to 1.5 wt.%) on rheological properties of irregular shape 316L SS powders is also evaluated using capillary rheometer method. It is observed that rheological parameters for solid powder loading of powder gas atomized (PGA) and bimodal powder P25/75 316L SS underwent sudden change from PGA-69 vol.% to PGA-72 vol.% and P25/75-67 vol.% to P25/75 316L SS 70 vol.%, respectively. Thus it is concluded that PGA-69 vol.% and P25/75-67 vol.% are optimal powder solid loadings corresponding to the lowest values of activation energies.
Elevated Transforming Growth Factor-β2 in the Aqueous Humor: A Possible Explanation for High Rate of Capsular Contraction Syndrome in High Myopia
Authors: Zhang Keke , Zhu Xiangjia , Chen Minjie , Sun Xinghuai , Yang Jin , Zhou Peng , Lu Yi
Published: January 2016

Purpose.The purpose of the study was to elucidate the role of transforming growth factor-beta 2 (TGF-β2) in the development of high myopic capsular contraction syndrome.Methods.Nineteen cases of capsular contraction syndrome, including 14 with high myopia, were collected, and their clinical data were reviewed. Aqueous humor and anterior capsular membranes were obtained during capsulotomy. Hematoxylin-eosin and immunohistochemical staining with anti-TGF-β2 antibody were performed on capsular membranes. TGF-β2 levels in aqueous humor were assayed using ELISA and western blot.Results.High myopia was significantly associated with the incidence of capsular contraction syndrome (odds ratio: 14.74,P<0.001, 95% CI: 5.29–41.05). Histopathological analysis revealed proliferation of fibroblast-like lens epithelial cells on the shrunken anterior capsule, labeled with TGF-β2 antibodies. ELISA and Western blot showed higher levels of TGF-β2 in aqueous humor of patients with capsular contraction syndrome and high myopia.Conclusions.High myopia is a risk factor for capsular contraction syndrome. Elevated TGF-β2 levels in high myopic cataract patients may play an important role in the pathogenesis of capsular contraction syndrome.
Transcription Factor HBP1 Enhances Radiosensitivity by Inducing Apoptosis in Prostate Cancer Cell Lines
Authors: Chen Yicheng , Wang Yueping , Yu Yanlan , Xu Liwei , Zhang Youyun , Yu Shicheng , Li Gonghui , Zhang Zhigeng
Published: January 2016

Radiotherapy for prostate cancer has been gradually carried out in recent years; however, acquired radioresistance often occurred in some patients after radiotherapy. HBP1 (HMG-box transcription factor 1) is a transcriptional inhibitor which could inhibit the expression of dozens of oncogenes. In our previous study, we showed that the expression level of HBP1 was closely related to prostate cancer metastasis and prognosis, but the relationship between HBP1 and radioresistance for prostate cancer is largely unknown. In this study, the clinical data of patients with prostate cancer was compared, and the positive correlation was revealed between prostate cancer brachytherapy efficacy and the expression level of HBP1 gene. Through research on prostate cancer cells in vitro, we found that HBP1 expression levels were negatively correlated with oncogene expression levels. Furthermore, HBP1 overexpression could sensitize prostate cancer cells to radiation and increase apoptosis in prostate cancer cells. In addition, animal model was employed to analyze the relationship between HBP1 gene and prostate cancer radiosensitivity in vivo; the result showed that knockdown of HBP1 gene could decrease the sensitivity to radiation of xenograft. These studies identified a specific molecular mechanism underlying prostate cancer radiosensitivity, which suggested HBP1 as a novel target in prostate cancer radiotherapy.
Development of Immunocapture-LC/MS Assay for Simultaneous ADA Isotyping and Semiquantitation
Authors: Chen Lin-Zhi , Roos David , Philip Elsy
Published: January 2016

Therapeutic proteins and peptides have potential to elicit immune responses resulting in anti-drug antibodies that can pose problems for both patient safety and product efficacy. During drug development immunogenicity is usually examined by risk-based approach along with specific strategies for developing “fit-for-purpose” bioanalytical approaches. Enzyme-linked immunosorbent assays and electrochemiluminescence immunoassays are the most widely used platform for ADA detection due to their high sensitivity and throughput. During the past decade, LC/MS has emerged as a promising technology for quantitation of biotherapeutics and protein biomarkers in biological matrices, mainly owing to its high specificity, selectivity, multiplexing, and wide dynamic range. In fully taking these advantages, we describe here an immunocapture-LC/MS methodology for simultaneous isotyping and semiquantitation of ADA in human plasma. Briefly, ADA and/or drug-ADA complex is captured by biotinylated drug or anti-drug Ab, immobilized on streptavidin magnetic beads, and separated from human plasma by a magnet. ADA is then released from the beads and subjected to trypsin digestion followed by LC/MS detection of specific universal peptides for each ADA isotype. The LC/MS data are analyzed using cut-point and calibration curve. The proof-of-concept of this methodology is demonstrated by detecting preexisting ADA in human plasma.
Characterization of Glasses in One Type of Alumina Rich Fly Ash by Chemical Digestion Methods: Implications for Alumina Extraction
Authors: Zhao Lijun , Xiao Hanshuang , Wang Baodong , Sun Qi
Published: January 2016

In recent years, one type of alumina rich fly ash (ARFA) with about 50 wt% of alumina has been extensively investigated for alumina extraction in China. Due to the silica in ARFA, alumina extraction would have to generate a huge amount of solid waste. There is a growing interest in the glasses in ARFA, because they are composed mainly of silica and could be removed prior to alumina extraction. In this work, the glasses in ARFA have been investigated by chemical methods, that is, acid and base digestions. The chemical compositions have been measured by XRF for ARFA from the digestion processes. The K2O standard, XRD, and FTIR spectroscopies were successfully used to define the digestions processes, and size analysis and SEM-EDX provided rich information on particle transformations. As a result, acid and base digestion methods were found to produce very similar results for the glasses in ARFA. The K2O standard was attributed to the formation of glasses by illites, and TiO2and Fe2O3were proposed to originate from ilmenite in alumina rich coals (ARC). Some implications of the results were also discussed for the alumina extraction from ARFA.
Two-Dimensional Speckle Tracking Echocardiography Detects Subclinical Left Ventricular Systolic Dysfunction among Adult Survivors of Childhood, Adolescent, and Young Adult Cancer
Authors: Yu Anthony F. , Raikhelkar Jayant , Zabor Emily C. , Tonorezos Emily S. , Moskowitz Chaya S. , Adsuar Roberto , Mara Elton , Huie Kevin , Oeffinger Kevin C. , Steingart Richard M. , Liu Jennifer E.
Published: January 2016

Two-dimensional speckle tracking echocardiography (2DSTE) provides a sensitive measure of left ventricular (LV) systolic function and may aid in the diagnosis of cardiotoxicity. 2DSTE was performed in a cross-sectional study of 134 patients (mean age:31.4±8.8years; 55% male; mean time since diagnosis:15.4±9.4years) previously treated with anthracyclines (mean cumulative dose:320±124 mg/m2), with (n=52) or without (n=82) mediastinal radiotherapy. The prevalence of LV systolic dysfunction, defined as fractional shortening < 27%, LV ejection fraction (LVEF) < 55%, and global longitudinal strain (GLS) ≤ 16%, was 5.2%, 6.0%, and 23.1%, respectively. Abnormal GLS was observed in 24 (18%) patients despite a normal LVEF. Indices of LV systolic function were similar regardless of anthracycline dose. However, GLS was worse (18.0 versus 19.0,p=0.003) and prevalence of abnormal GLS was higher (36.5% versus 14.6%,p=0.004) in patients treated with mediastinal radiotherapy. Mediastinal radiotherapy was associated with reduced GLS (p=0.040) after adjusting for sex, age, and cumulative anthracycline dose. In adult survivors of childhood, adolescent, and young adult cancer, 2DSTE frequently detects LV systolic dysfunction despite a normal LVEF and may be useful for the long-term cardiac surveillance of adult cancer survivors.
Implementation of an Internet Weight Loss Program in a Worksite Setting
Authors: Ross Kathryn M. , Wing Rena R.
Published: January 2016

Background.Worksite wellness programs typically produce modest weight losses. We examined whether an efficacious Internet behavioral weight loss program could be successfully implemented in a worksite setting.Methods.Participants were 75 overweight or obese employees/dependents of a large healthcare system who were given access to a 12-week Internet-based, multicomponent behavioral weight loss program. Assessments occurred at baseline, Month 3 (end of intervention), and Month 6 (follow-up).Results.Retention was excellent (93% at Month 3 and 89% at Month 6). Intent-to-treat analyses demonstrated that participants lost an average (±SE) of-5.8±.60 kg from baseline to Month 3 and regained1.1±.31 kg from Month 3 to Month 6; overall, weight loss from baseline to Month 6 was-4.7±.71 kg,p<.001. Men lost more weight than women,p=.022, and individuals who had a college degree or higher lost more weight than those with less education,p=.005. Adherence to viewing lessons (8 of 12) and self-monitoring (83% of days) was excellent and significantly associated with weight loss,ps<.05.Conclusions.An Internet-based behavioral weight management intervention can be successfully implemented in a worksite setting and can lead to clinically significant weight losses. Given the low costs of offering this program, it could easily be widely disseminated.
Statin Use and Prostate Cancer Aggressiveness: Results from the Population-Based North Carolina–Louisiana Prostate Cancer Project
Authors: Allott Emma H. , Farnan Laura , Steck Susan E. , Arab Lenore , Su L. Joseph , Mishel Merle , Fontham Elizabeth T.H. , Mohler James L. , Bensen Jeannette T.
Published: January 2016

Background: Although statin use has been associated with reduced prostate cancer aggressiveness, the impact of race and patient characteristics on this association is not well understood. We examined the association between statin use and prostate cancer aggressiveness in Caucasians (CA) and African Americans (AA) and explored effect modification by health-seeking behaviors associated with statin use.

Methods: Of 1,930 cases from The North Carolina-Louisiana Prostate Cancer Project, 344 (18%) were classified as aggressive based on clinical criteria. Utilizing nonaggressive cases as referent, logistic regression was used to examine the association between statin use and prostate cancer aggressiveness, overall and stratified by race. Smoking and prostate cancer screening were examined as effect modifiers of this association.

Results: There was an inverse association between statin use and prostate cancer aggressiveness [OR, 0.74; 95% confidence interval (CI), 0.56–0.96], with comparable effect estimates in both races. Although not statistically significant, statin use was associated with reduced ORs for aggressive prostate cancer in never-screened men (OR, 0.79; 95% CI, 0.45–1.39), men screened at low/recommended frequency (≤once/year; OR, 0.66; 95% CI, 0.41–1.06), and men screened at high frequency (>once/year; OR, 0.78; 95% CI, 0.53–1.15). Inverse associations between statins and aggressive prostate cancer were strongest in never smokers (OR, 0.42; 95% CI, 0.25–0.72), attenuated in former smokers (OR, 0.84; 95% CI, 0.59–1.19), and absent in current smokers (OR, 1.36; 95% CI, 0.70–2.64).

Conclusions: Statin use was associated with reduced prostate cancer aggressiveness in CA and AAs, with strongest inverse associations in nonsmokers.

Impact: Health-seeking behaviors associated with statin use should be considered when examining the impact of statins on prostate cancer aggressiveness. Cancer Epidemiol Biomarkers Prev; 25(4); 670–7. ©2016 AACR.
7-(2-Thienyl)-7-Deazaadenosine (AB61), a New Potent Nucleoside Cytostatic with a Complex Mode of Action
Authors: Perlíková Pavla , Rylová Gabriela , Nauš Petr , Elbert Tomáš , Tloušťová Eva , Bourderioux Aurelie , Slavětínská Lenka Poštová , Motyka Kamil , Doležal Dalibor , Znojek Pawel , Nová Alice , Harvanová Monika , Džubák Petr , Šiller Michal , Hlaváč Jan , Hajdúch Marián , Hocek Michal
Published: January 2016

7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK-OV-3, BT-549, and HT-29 xenografts. The results indicate that AB61 is a promising compound with unique mechanism of action and deserves further development as an anticancer agent. Mol Cancer Ther; 15(5); 922–37. ©2016 AACR.