bluuebunny/crossref_metadata_2025 huggingface dataset:
Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes
Authors: Landgren O. , Iskander K.
Published: February 2017

In the USA at the beginning of this century, the average overall survival in patients with multiple myeloma was about 3 years. Around that time, three drugs (bortezomib, lenalidomide and thalidomide) were introduced for the treatment of multiple myeloma and, in 2012, carfilzomib received accelerated approval by the US Food and Drug Administration (FDA). Driven by access to better drugs, median overall survival in younger patients (aged <50 years) was >10 years by 2014. The FDA approved 14 new drugs for the treatment of cancer in 2015; four of these were approved for the treatment of myeloma (panobinostat, daratumumab, elotuzumab and ixazomib). In 2015 and 2016, expanded label indications were approved by the FDA for lenalidomide and carfilzomib, respectively. The recent increase in approved, highly effective combination therapies for patients with multiple myeloma has led the way to redefining the goals of therapy. Here, we review and provide a clinical perspective on the treatment goals and management of multiple myeloma in the era of modern therapy. Recent meta‐analyses show that minimal residual disease (MRD) negativity is associated with longer progression‐free and overall survival in patients with multiple myeloma. With the use of modern combination therapy, large proportions (>60–70%) of newly diagnosed multiple myeloma patients achieve complete responses and MRD negativity. Modern combination therapies induce rapid, deep and sustainable responses (including MRD negativity), supporting a treatment paradigm shift away from palliative two‐drug combinations towards the use of modern, potent, three‐ or four‐drug combination regimens in early lines of therapy. Data support the use of modern therapy upfront rather than reserving it for later stages of the disease. As survival time increases with modern combination therapies, development of early reliable surrogate end‐points for survival, such as MRD negativity, are needed for expedited read‐out of future randomized clinical trials.
Overt and Relational Aggression Participant Role Behavior: Measurement and Relations With Sociometric Status and Depression
Authors: Casper Deborah M. , Card Noel A. , Bauman Sheri , Toomey Russell B.
Published: February 2017

This study is the first to measure participant role behavior across overt and relational forms of aggression. The Overt and Relational Aggression Participant Role Behavior Scales were designed to measure aggression, assisting, reinforcing, defending, victimization, and outsider behavior during acts of peer aggression in an ethnically diverse sample of 609 adolescents (M age = 12 years). The data fit the hypothesized 12‐factor model, and measurement invariance was established across gender. Relational victimization, but not overt victimization, was positively associated with all other relational aggression roles. Each participant role subscale was positively associated with depressive symptoms with the exception of the overt and relational outsider subscales. Future research and intervention efforts should consider overt and relational aggression participant roles, separately.
Obesity and kidney disease: Hidden consequences of the epidemic
Authors: Kovesdy Csaba P. , Furth Susan L. , Zoccali Carmine ,   on behalf of the World Kidney Day Steering Committee
Published: February 2017

Obesity has become a worldwide epidemic, and its prevalence has been projected to grow by 40% in the next decade. This increasing prevalence has implications for the risks of diabetes, cardiovascular disease and also for Chronic Kidney Disease. A high body mass index is one of the strongest risk factors for new‐onset Chronic Kidney Disease. In individuals affected by obesity, a series of complex pathophysiologic changes occur that lead to the development of Chronic Kidney Disease. These include on the one hand effects mediated by the downstream consequences of obesity (such as diabetes mellitus and hypertension), but also direct effects of adipose tissue, via humoral factors such as leptin, adiponectin, resistin and visfatin). In obese individuals a compensatory hyperfiltration occurs to meet the heightened metabolic demands of the increased body weight, leading to glomerulomegaly and accompanied by deposition of adipose tissue in the glomerulus and the gradual development of focal segmental glomerulosclerosis. The incidence of obesity‐related glomerulopathy has increased ten‐fold in recent years. In addition to the development of Chronic Kidney Disease, obesity has also been shown to be a risk factor for nephrolithiasis, and for a number of malignancies including kidney cancer. Interventions to stem the tide of obesity are thus extremely important for preventing the development and progression of Chronic Kidney Disease and other disorders of the kidneys. This year the World Kidney Day promotes education on the harmful consequences of obesity and its association with kidney disease, advocating healthy lifestyle and health policy measures that makes preventive behaviors an affordable option.
Integration of chlorophyll a fluorescence and photorespirometry techniques to understand production dynamics in macroaglal communities
Authors: Tait Leigh W. , Hawes Ian , Schiel David R.
Published: February 2017

Global declines of macroalgal beds in coastal waters have prompted a plethora of studies attempting to understand the drivers of change within dynamic nearshore ecosystems. Photosynthetic measurements are good tools for assessing the consequences of numerous stressors of macroalgae, but there is somewhat of a disconnection between studies that focus on organism‐specific ecophysiological responses and those that address causes and consequences of shifts in macroalgal productivity. Our goal is to highlight the applications of two complementary tools for measuring photosynthesis—variable chlorophyll a fluorescence and photorespirometry—and provide guidance for the integration of physiology and ecology to understand the drivers of change in macroalgal communities. Photorespirometry can provide an integrated measure of whole‐community metabolism, including an estimate of the physiological costs associated with stressors, while fluorescence‐based techniques provide point measures of the efficiency of the photosynthetic apparatus within communities. Variable chlorophyll a fluorescence does not provide an estimate of carbon balance or integrated photosynthesis across either whole plants or whole communities but can be used to estimate the contribution of individual community components in the dynamic subcanopy environment to help us understand the mechanisms underlying observed responses. We highlight the importance of the highly dynamic light environment within macroalgal communities and call for better integration of physiological techniques in an ecological context to enhance our understanding of the responses of whole communities to local and global stressors.
Multiple Principals and Legislative Cohesion
Authors: Meserve Stephen , Robbins Joseph , Thames Frank
Published: February 2017

In many systems, legislators find themselves accountable to multiple principals. This article seeks to further answer how legislators decide between their principals and what factors condition legislators to choose one over the other. We argue that electoral uncertainty, operationalized as electoral volatility, pushes legislators towards the principal that has the greatest influence over their re‐election. Using European Parliament electoral results and roll‐call data from the second to the sixth European Parliaments (1984–2009), we show that increases in electoral volatility decreased European group cohesion and pushed legislators to side more with the positions of their national parties over their European group when the two disagreed.
Functional assessment of the kidneys in a 10 month‐old child with renal artery stenosis by intravoxel incoherent motion
Authors: Herrmann Jochen , Ittrich Harald , Kaul Michael Gerhard , Groth Michael , Tozakidou Magdalini , Blohm Martin , Oh Jun , Adam Gerhard
Published: February 2017

Renovascular stenosis is an important cause for arterial hypertension in childhood. We report a 10‐month‐old girl with arterial hypertension caused by right‐sided renal artery stenosis detected by Doppler ultrasound. Magnetic resonance imaging (MRI) was performed before renal artery angioplasty to depict vascular anatomy in detail and to retrieve additional functional information of the kidneys by analysis of intravoxel incoherent motion (IVIM). The value of quantitative diffusion weighted imaging of the kidneys prior to percutaneous transluminal renal angioplasty (PTRA) is discussed.
Quality of life, coping strategies, social support and self‐efficacy in women after acute myocardial infarction: a mixed methods approach
Authors: Fuochi G. , Foà C.
Published: February 2017

Background

Quality of life, coping strategies, social support and self‐efficacy are important psychosocial variables strongly affecting the experience of acute myocardial infarction (AMI) in women.

Aims

To gain a more in‐depth understanding of how coping strategies, self‐efficacy, quality of life and social support shape women's adjustment to AMI.

Design

Mixed methods study. Quantitative data were collected through a standardised questionnaire on coping strategies, self‐efficacy, quality of life and social support. Qualitative data stemmed from 57 semistructured interviews conducted with post‐AMI female patients on related topics.

Methods

Quantitative data were analysed with unpaired two‐sample t‐tests on the means, comparing women who experienced AMI (N = 77) with a control group of women who did not have AMI (N = 173), and pairwise correlations on the AMI sample. Qualitative data were grouped into coding families and analysed through thematic content analysis. Qualitative and quantitative results were then integrated, for different age groups.

Results

Quantitative results indicated statistically significant differences between women who experienced AMI and the control group: the former showed lower self‐perceived health, perceived social support and social support coping, but greater self‐efficacy, use of acceptance, avoidance and religious coping. Pairwise correlations showed that avoidance coping strategy was negatively correlated with quality of life, while the opposite was true for problem‐oriented coping, perceived social support and self‐efficacy. Qualitative results extended and confirmed quantitative results, except for coping strategies: avoidance coping seemed more present than reported in the standardised measures.

Conclusion

Mixed methods provide understanding of the importance of social support, self‐efficacy and less avoidant coping strategies to women's adjustment to AMI.

Relevance to clinical practice

Women need support from health professionals with knowledge of these topics, to facilitate their adaptation to AMI.
Integrating Community‐Based Family Planning Services with Local Marine Conservation Initiatives in Southwest Madagascar: Changes in Contraceptive Use and Fertility
Authors: Robson Laura , Holston Martine , Savitzky Caroline , Mohan Vik
Published: February 2017

This study assessed changes in contraceptive use and fertility between 2009 and 2013 in the Velondriake locally managed marine area of southwest Madagascar where marine conservation organization Blue Ventures began implementing an integrated health‐environment program in 2007. The proportion of sexually active women aged 15 to 49 years using hormonal contraception and/or condoms during last intercourse increased more than twofold from 25 percent in 2009 to 59 percent in 2013. The number of births in the last 12 months per 1,000 women of reproductive age declined by 28 percent over the same period from 196 in 2009 to 141 in 2013. This program increased access to family planning for previously under‐served communities, leading to uptake of modern contraceptives with an associated decline in fertility. These results suggest that this program has enabled couples to avoid unintended pregnancies, thereby bolstering local marine conservation initiatives.
I love you from the bottom of my hypothalamus: The role of stress physiology in romantic pair bond formation and maintenance
Authors: Mercado Evelyn , Hibel Leah C.
Published: February 2017

Monogamous pair bonds helped solve ancestral problems pertinent to our survival as a species. In order for these pair bonds to succeed, biological systems were co‐opted to support and reinforce attachment bonds through feelings of pleasure and reward. One of the major biological systems that may play an important role in the formation of romantic attachments is the stress response system (autonomic nervous system and hypothalamic–pituitary–adrenal axis). Research suggests attraction, mate preference, and emotional connectedness may be supported by the activation or inhibition of the stress response system. Further, as romantic relationships progress, new findings suggest partners' physiological patterns coalesce, potentially serving a regulatory function that reinforces the pair bond and affects overall well‐being. Based on this evidence, the current paper puts forth the Physiology of Romantic Pair Bond Initiation and Maintenance Model, which will provide researchers with a new perspective on the function of the stress response system in romantic relationships.
RNA processing and protein expression of HLA‐B*07:44N
Authors: Balas A. , García‐Sánchez F. , Vicario J. L.
Published: February 2017

Background

The assignment of human leukocyte antigen (HLA) null alleles is clinically relevant in the setting of stem cell transplantation. Cell surface expression profiling and mRNA processing analysis of the HLA‐B allele previously designated as B*07:44, have been performed.

Materials and Methods

Cell surface expression of HLA‐B*07:44 was determined using flow cytometry. Genomic full‐length and HLA‐B*07‐specific cDNA sequencing were carried out by Sanger procedure.

Results

Flow cytometric analysis confirmed previous serologic results and demonstrated a lack of cell membrane expression of the HLA‐B protein. The mRNA processing, studied using direct
HLA‐B*07‐specific cDNA sequencing, revealed the presence of a unique, aberrantly spliced mRNA, with a deletion of the last 43 bp on the 5’‐end of exon 4. The substitution from T to G at genomic position 1799 compared to B*07:02:01 introduced a new and stronger splice donor site at exon 4. This alternative splicing produced an mRNA containing a premature stop codon at position 280, explaining the absence of mature HLA‐B7 protein on the cell surface.

Conclusion

These findings led us to consider this HLA‐B variant as a HLA null allele. The World Health Organization (WHO) Nomenclature Committee has since renamed this variant B*07:44N
.
Detection of a novel HLA‐A*11 variant, A*11:255, in a Taiwanese individual
Authors: Yang K. L. , Ng J. , Lazaro A. , Lin P. Y.
Published: February 2017

One nucleotide substitution at residue 532 of HLA‐A*11:02:01 results in a novel allele, HLA‐A*11:255.
Stabilization of renal function after the first year of follow‐up in kidney transplant recipients treated for significant BK polyomavirus infection or BK polyomavirus‐associated nephropathy
Authors: Simard‐Meilleur Marie‐Christine , Bodson‐Clermont Paule , St‐Louis Gilles , Pâquet Michel R. , Girardin Catherine , Fortin Marie‐Chantal , Cardinal Héloïse , Hébert Marie‐Josée , Lévesque Renée , Renoult Edith
Published: February 2017

Background

BK polyomavirus virus (BKPyV) screening and immunosuppression reduction effectively prevent graft loss due to BKPyV‐associated nephropathy (BKPVAN) during the first year after transplantation. The aim of our study was to evaluate the impact of this infection during longer follow‐up periods.

Methods

We reviewed the outcome of our screening and immunosuppression reduction protocol in 305 patients who received a kidney transplant between March 2008 and January 2013. Quantitative BKPyV DNA surveillance in plasma was performed at 1, 2, 3, 6, 9, and 12 months after transplantation. Patients with significant viremia and/or biopsy‐proven BKPVAN were treated with immunosuppression reduction and leflunomide.

Results

During the first post‐transplant year, 24 patients (7.9%) developed significant viremia at a median time of 95 days, and 18 patients had BKPVAN; 23 of the 24 (7.5%) were treated according to our protocol (group BKV+); 225 patients (73.8%) did not develop any BK viremia (group BKV−). Allograft function was similar in both groups at 1 month post transplantation (P=.87), but significantly worse at 1 year in the BKV+ group (P=.002). Thereafter, kidney function stabilized in the BKV+ group and no differences in patient and graft survival were seen between the groups after a median follow‐up of 4 years.

Conclusions

We confirm the early occurrence of BKPyV replication after transplantation and the short‐term decline in renal function. However, early detection of BKPyV replication, prompt diagnosis, and reduction in immunosuppression may offer long‐term benefits for graft function.
Are bilateral and multilateral aid‐for‐trade complementary?
Authors: Tadesse Bedassa , Shukralla Elias , Fayissa Bichaka
Published: February 2017

Using the first comprehensive estimates of ad valorem tariff equivalent bilateral trade costs spanning the time period 2002–10, we examine whether the aid‐for‐trade (AFT) inflows reduce bilateral trade costs facing aid recipients. If so, we ask whether the trade costs reduction effects of AFT from bilateral and multilateral sources are complementary. By showing the extent to which the observed trade cost reduction effects of AFT from bilateral (multilateral) sources correlate with the magnitudes of AFT disbursements from multilateral (bilateral) sources, we present plausible explanation for the cross‐country variations in the extent to which AFT promotes trade flows. Our findings have, thus, important policy implications for shaping future discourses on the coordination of disbursements for enhancing the effectiveness of AFT.
Cross-Flow Heat Exchanger: Volume-Averaging Formulation of a Unit Cell Model and Thermal Performance Analysis
Authors: Zhang Hengyun , Wang Zhaoqiang
Published: February 2017

A formulation of the unit cell model and the corresponding thermal performance analysis for the cross-flow heat exchanger are carried out, with the design goal of dissipating 175 W from a high-power electronic chip in a compact space. A liquid to liquid heat exchanger in the cross-flow arrangement is preferred due to its compact size and high effectiveness. The unit cell model is formulated based on the volume-averaging method to determine the heat transfer coefficient involving two heat exchanging fluids and a solid. The various factors such as channel shape, channel edge length, channel size, and heat exchanger material can be examined based on the unit cell model. The obtained heat transfer coefficients are used for the estimation of the heat exchanger thermal performance based on the effectiveness–number of transfer units (NTU) correlation. To verify the model formulation, the heat and fluid flow over the cross-flow heat exchangers are investigated through the full-field numerical computation. The amount of heat exchanged from the numerical computation is extracted and compared with the predicted results from the unit cell model. A fairly good agreement is obtained between the two approaches. Based on the unit cell model, an aluminum cross heat exchanger with eight channel layers for the hot and cold fluids, 15 channels in each layer with a channel diameter of 2 mm, is able to meet the design target.
Modified Outlet Boundary Condition Schemes for Large Density Ratio Lattice Boltzmann Models
Authors: Li Long , Jia Xiaodong , Liu Yongwen
Published: February 2017

Outlet boundary conditions (OBCs) and their numerical descriptions are critical to computational fluid dynamics (CFD) since they have significant influence on the numerical accuracy and stability. They present significant challenges to the two-phase lattice Boltzmann (LB) method, especially in the limit of large density ratio. In this study, three commonly used OBCs: convection boundary condition (CBC), Neumann boundary condition (NBC), and extrapolation boundary condition (EBC), are investigated and improved on basis of two LB models for large density ratios (single and double distribution function models). The existing numerical schemes for the OBCs are not directly applicable to the LB models because of the deviation of the momentum balance at the outlet boundary. The deviation becomes substantial at a large density ratio. Thus, in this work, modified OBC schemes are proposed to make the OBCs suitable for the two-phase LB models by adding an independent equation to obtain the outlet velocity. Numerical tests on droplet flowing in a channel are performed to evaluate the performance of the modified OBC schemes. Results indicate that the modified OBC schemes may be extended to tackle large density ratio situations. The modified NBC and EBC schemes are only suitable for the LB model with single distribution function. Three modified CBC schemes exhibit optimum performance for both single and double distribution function LB models which can be implemented for large density ratios.
Study of Microstructure-Based Effective Thermal Conductivity of Graphite Foam
Authors: Chai Y. , Yang X. H. , Zhao M. , Chen Z. Y. , Meng X. Z. , Jin L. W. , Zhang Q. L. , Hu W. J.
Published: February 2017

As a relatively new type of functional material, porous graphite foam exhibits unique thermophysical properties. It possesses the advantages of low density, high specific surface area, and high bulk thermal conductivity and could be used as the core component of compact, lightweight, and efficient heat exchangers. Effective thermal conductivity serves one of the key thermophysical properties of foam-based heat exchangers. The complex three-dimensional topology and interstitial fluids significantly affect the heat conduction in the porous structure, reflecting a topologically based effective thermal conductivity. This paper presents a novel geometric model for representing the microstructure of graphite foams with simplifications and modifications made on the realistic pore structure, where the complex surfaces and tortuous ligaments were converted into a simplified geometry with cylindrical ligaments connected between cuboid nodes. The multiple-layer method was used to divide the proposed geometry into solvable areas, and the series–parallel relation was used to derive the analytical model for the effective thermal conductivity. To explore heat conduction mechanisms at the pore scale, direct numerical simulation was also conducted on the realistic geometric model. Achieving good agreement with experimental data, the simplified geometric model was validated. The numerically simulated conductivity followed the simplified model prediction that the two geometries are equivalent from thermal aspect. It validates further that the simplified model is capable of reflecting the internal microstructure of graphite foam, which would benefit the understandings of the thermophysical mechanisms of pore-scaled heat conduction and microstructures of graphite foam.
Current-driven interface magnetic transition in complex oxide heterostructure
Authors: Fang F. , Zhai H. , Ma X. , Yin Y. W. , Li Qi , Lüpke G.
Published: February 2017

The interfacial spin state of n-type BaTiO3/La0.5Ca0.5MnO3/La0.7Sr0.3MnO3 heterojunction and its dependence on gate voltage is investigated with magnetic second-harmonic generation at 78 K. The injection of minority spins alters the interface magnetization of La0.7Sr0.3MnO3 from ferromagnetic to antiferromagnetic exchange coupled, while the bulk magnetization remains unchanged. The emergent interfacial antiferromagnetic interactions are attributed to modulations of the strong double-exchange interaction between conducting electron spins and local magnetic moments. The results will help promote the development of new interface-based functionalities and device concepts.
Characterizing the binaural contribution to speech-in-noise reception in elderly hearing-impaired listeners
Authors: Neher Tobias
Published: February 2017

To scrutinize the binaural contribution to speech-in-noise reception, four groups of elderly participants with or without audiometric asymmetry <2 kHz and with or without near-normal binaural intelligibility level difference (BILD) completed tests of monaural and binaural phase sensitivity as well as cognitive function. Groups did not differ in age, overall degree of hearing loss, or cognitive function. Analyses revealed an influence of BILD status but not audiometric asymmetry on monaural phase sensitivity, strong correlations between monaural and binaural detection thresholds, and monaural and binaural but not cognitive BILD contributions. Furthermore, the N0Sπ threshold at 500 Hz predicted BILD performance effectively.
Effect of the relationship between target and masker sex on infants' recognition of speech
Authors: Newman Rochelle S. , Morini Giovanna
Published: February 2017

When faced with multiple people speaking simultaneously, adult listeners use the sex of the talkers as a cue for separating competing streams of speech. As a result, adult listeners show better performance when a target and a background voice differ from one another in sex. Recent research suggests that infants under 1 year do not show this advantage. So when do infants begin to use talker-gender cues for stream segregation? These studies find that 16-month-olds do not show an advantage when the masker and target differ in sex. However, by 30 months, toddlers show the more adult-like pattern of performance.
Improving undergraduate STEM education: The efficacy of discipline-based professional development
Authors: Manduca Cathryn A. , Iverson Ellen R. , Luxenberg Michael , Macdonald R. Heather , McConnell David A. , Mogk David W. , Tewksbury Barbara J.
Published: February 2017

Effective teaching practices are more common in courses taught by faculty who spend time learning about teaching.
Flocking ferromagnetic colloids
Authors: Kaiser Andreas , Snezhko Alexey , Aranson Igor S.
Published: February 2017

Energized by a vertical alternating magnetic field, colloidal particles roll and flock together.
Intrinsic paleointensity bias and the long-term history of the geodynamo
Authors: Smirnov Aleksey V. , Kulakov Evgeniy V. , Foucher Marine S. , Bristol Katie E.
Published: February 2017

A key mechanism responsible for a systematic bias in the global geomagnetic paleointensity database.
Deep reefs are not universal refuges: Reseeding potential varies among coral species
Authors: Bongaerts Pim , Riginos Cynthia , Brunner Ramona , Englebert Norbert , Smith Struan R. , Hoegh-Guldberg Ove
Published: February 2017

Genome-wide assessment reveals opposing patterns of vertical connectivity in two depth-generalist coral species.
Ensuring scientific integrity in the Age of Trump
Authors: Goldman Gretchen T. , Berman Emily , Halpern Michael , Johnson Charise , Kothari Yogin , Reed Genna , Rosenberg Andrew A.
Published: February 2017

Policies to protect government scientists must be defended
Beyond imaging: Macro- and microscale medical robots actuated by clinical MRI scanners
Authors: Martel Sylvain
Published: February 2017

Magnetic resonance actuation has potential for use in medical therapies. See the related Research Article by Rahmer
et al
.
Discovery of Novel Pneumococcal Serotype 35D, a Natural WciG-Deficient Variant of Serotype 35B
Authors: Geno K. Aaron , Saad Jamil S. , Nahm Moon H.
Published: February 2017

Pneumococcus (
Streptococcus pneumoniae
) remains a significant cause of morbidity and mortality, especially among those at the extremes of age. Its capsular polysaccharide is essential for systemic virulence. Over 90 serologically distinct pneumococcal capsular polysaccharides (serotypes) are recognized, but they are unequal in prevalence. Because antibodies against the capsule are protective, polysaccharide conjugate vaccines, which are constructed against the most prevalent serotypes, have caused great reductions in pneumococcal disease caused by these serotypes. In response, however, the relative prevalences of serotypes have shifted. Certain previously rare serotypes, such as serotype 35B, are increasing in prevalence. Serotype 35B is thus a likely future vaccine candidate, but due to their previous rarity, serotype 35B strains have not been scrutinized for underlying heterogeneity. We studied putative serotype 35B clinical isolates to assess the uniformity of their serological reactions. While most isolates exhibited the accepted serology of serotype 35B, one isolate failed to bind to critical serotyping reagents. We determined that the genetic basis for this aberrant serology was the presence of inactivating mutations in the
O
-acetyltransferase gene
wciG
. Complementation studies in a
wciG
deletion strain verified that the mutant WciG was nonfunctional, and the serology of the mutant could be restored through complementation with a construct encoding a functional WciG. Nuclear magnetic resonance studies confirmed that the capsule of the WciG-deficient isolate lacked
O
-acetylation but was otherwise identical to serotype 35B. As this isolate expresses a unique serology with unique biochemistry and a stable genetic basis, we named its novel capsule serotype 35D.
High Prevalence and Diversity of Hepatitis Viruses in Suspected Cases of Yellow Fever in the Democratic Republic of Congo
Authors: Makiala-Mandanda Sheila , Le Gal Frédéric , Ngwaka-Matsung Nadine , Ahuka-Mundeke Steve , Onanga Richard , Bivigou-Mboumba Berthold , Pukuta-Simbu Elisabeth , Gerber Athenaïs , Abbate Jessica L. , Mwamba Dieudonné , Berthet Nicolas , Leroy Eric Maurice , Muyembe-Tamfum Jean-Jacques , Becquart Pierre
Published: February 2017

The majority of patients with acute febrile jaundice (>95%) identified through a yellow fever surveillance program in the Democratic Republic of Congo (DRC) test negative for antibodies against yellow fever virus. However, no etiological investigation has ever been carried out on these patients. Here, we tested for hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), and hepatitis E (HEV) viruses, all of which can cause acute febrile jaundice, in patients included in the yellow fever surveillance program in the DRC. On a total of 498 serum samples collected from suspected cases of yellow fever from January 2003 to January 2012, enzyme-linked immunosorbent assay (ELISA) techniques were used to screen for antibodies against HAV (IgM) and HEV (IgM) and for antigens and antibodies against HBV (HBsAg and anti-hepatitis B core protein [HBc] IgM, respectively), HCV, and HDV. Viral loads and genotypes were determined for HBV and HVD. Viral hepatitis serological markers were diagnosed in 218 (43.7%) patients. The seroprevalences were 16.7% for HAV, 24.6% for HBV, 2.3% for HCV, and 10.4% for HEV, and 26.1% of HBV-positive patients were also infected with HDV. Median viral loads were 4.19 × 10
5
IU/ml for HBV (range, 769 to 9.82 × 10
9
IU/ml) and 1.4 × 10
6
IU/ml for HDV (range, 3.1 × 10
2
to 2.9 × 10
8
IU/ml). Genotypes A, E, and D of HBV and genotype 1 of HDV were detected. These high hepatitis prevalence rates highlight the necessity to include screening for hepatitis viruses in the yellow fever surveillance program in the DRC.
Towards a New Strategy for Diagnosis of Congenital Trypanosoma cruzi Infection
Authors: Abras Alba , Muñoz Carmen , Ballart Cristina , Berenguer Pere , Llovet Teresa , Herrero Mercedes , Tebar Silvia , Pinazo María-Jesús , Posada Elizabeth , Martí Carmen , Fumadó Victoria , Bosch Jordi , Coll Oriol , Juncosa Teresa , Ginovart Gemma , Armengol Josep , Gascón Joaquim , Portús Montserrat , Gállego Montserrat
Published: February 2017

The immigration of Latin American women of childbearing age has spread the congenital transmission of Chagas disease to areas of nonendemicity, and the disease is now a worldwide problem. Some European health authorities have implemented screening programs to prevent vertical transmission, but the lack of a uniform protocol calls for the urgent establishment of a new strategy common to all laboratories. Our aims were to (i) analyze the trend of passive IgG antibodies in the newborn by means of five serological tests for the diagnosis and follow-up of congenital
Trypanosoma cruzi
infection, (ii) assess the utility of these techniques for diagnosing a congenital transmission, and (iii) propose a strategy for a prompt, efficient, and cost-effective diagnosis of
T. cruzi
infection. In noninfected newborns, a continuous decreasing trend of passive IgG antibodies was observed, but none of the serological assays seroreverted in any the infants before 12 months. From 12 months onwards, serological tests achieved negative results in all the samples analyzed, with the exception of the highly sensitive chemiluminescent microparticle immunoassay (CMIA). In contrast, in congenitally infected infants, the antibody decline was detected only after treatment initiation. In order to improve the diagnosis of congenital
T. cruzi
infection, we propose a new strategy involving fewer tests that allows significant cost savings. The protocol could start 1 month after birth with a parasitological test and/or a PCR. If negative, a serological test would be carried out at 9 months, which if positive, would be followed by another at around 12 months for confirmation.
Reactivity of Porcine Epidemic Diarrhea Virus Structural Proteins to Antibodies against Porcine Enteric Coronaviruses: Diagnostic Implications
Authors: Gimenez-Lirola Luis Gabriel , Zhang Jianqiang , Carrillo-Avila Jose Antonio , Chen Qi , Magtoto Ronaldo , Poonsuk Korakrit , Baum David H. , Piñeyro Pablo , Zimmerman Jeffrey
Published: February 2017

The development of porcine epidemic diarrhea virus (PEDV) antibody-based assays is important for detecting infected animals, confirming previous virus exposure, and monitoring sow herd immunity. However, the potential cross-reactivity among porcine coronaviruses is a major concern for the development of pathogen-specific assays. In this study, we used serum samples (
n
= 792) from pigs of precisely known infection status and a multiplex fluorescent microbead-based immunoassay and/or enzyme-linked immunoassay platform to characterize the antibody response to PEDV whole-virus (WV) particles and recombinant polypeptides derived from the four PEDV structural proteins, i.e., spike (S), nucleocapsid (N), membrane (M), and envelope (E). Antibody assay cutoff values were selected to provide 100% diagnostic specificity for each target. The earliest IgG antibody response, mainly directed against S1 polypeptides, was observed at days 7 to 10 postinfection. With the exception of nonreactive protein E, we observed similar antibody ontogenies and patterns of seroconversion for S1, N, M, and WV antigens. Recombinant S1 provided the best diagnostic sensitivity, regardless of the PEDV strain, with no cross-reactivity detected against transmissible gastroenteritis virus (TGEV), porcine respiratory coronavirus (PRCV), or porcine deltacoronavirus (PDCoV) pig antisera. The WV particles showed some cross-reactivity to TGEV Miller and TGEV Purdue antisera, while N protein presented some cross-reactivity to TGEV Miller. The M protein was highly cross-reactive to TGEV and PRCV antisera. Differences in the antibody responses to specific PEDV structural proteins have important implications in the development and performance of antibody assays for the diagnosis of PEDV enteric disease.
JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1
Authors: Quan Yudong , Xu Hongtao , Han Yingshan , Mesplède Thibault , Wainberg Mark A.
Published: February 2017

HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor. Specifically, two T cell activators, interleukin-2 (IL-2) and phorbol 12-myristate 13-acetate (PMA), both capable of activation of JAK-STAT pathways, were able to inhibit cell-to-cell viral transmission. In contrast, but consistent with the above result, a number of JAK-STAT and mTOR inhibitors actually promoted HIV-1 transmission and reversion. Hence, JAK-STAT signaling pathways may differentially affect the replication of a variety of HIV Env mutants in ways that differ from the role that these pathways play in the replication of wild-type viruses.

IMPORTANCE
Specific alterations in HIV Env close to the CD4 binding site can differentially change the ability of HIV to mediate infection for cell-free and cell-associated viruses. However, such differences are dependent to some extent on the types of target cells used. JAK-STAT signaling pathways are able to play major roles in these processes. This work sheds new light on factors that can govern HIV infection of target cells.
The Viral Gene ORF79 Encodes a Repressor Regulating Induction of the Lytic Life Cycle in the Haloalkaliphilic Virus ϕCh1
Authors: Selb Regina , Derntl Christian , Klein Reinhard , Alte Beatrix , Hofbauer Christoph , Kaufmann Martin , Beraha Judith , Schöner Léa , Witte Angela
Published: February 2017

In this study, we describe the construction of the first genetically modified mutant of a halovirus infecting haloalkaliphilic
Archaea
. By random choice, we targeted ORF79, a currently uncharacterized viral gene of the haloalkaliphilic virus ϕCh1. We used a polyethylene glycol (PEG)-mediated transformation method to deliver a disruption cassette into a lysogenic strain of the haloalkaliphilic archaeon
Natrialba magadii
bearing ϕCh1 as a provirus. This approach yielded mutant virus particles carrying a disrupted version of ORF79. Disruption of ORF79 did not influence morphology of the mature virions. The mutant virus was able to infect cured strains of
N. magadii
, resulting in a lysogenic, ORF79-disrupted strain. Analysis of this strain carrying the mutant virus revealed a repressor function of ORF79. In the absence of gp79, onset of lysis and expression of viral proteins occurred prematurely compared to their timing in the wild-type strain. Constitutive expression of ORF79 in a cured strain of
N. magadii
reduced the plating efficiency of ϕCh1 by seven orders of magnitude. Overexpression of ORF79 in a lysogenic strain of
N. magadii
resulted in an inhibition of lysis and total absence of viral proteins as well as viral progeny. In further experiments, gp79 directly regulated the expression of the tail fiber protein ORF34 but did not influence the methyltransferase gene ORF94. Further, we describe the establishment of an inducible promoter for
in vivo
studies in
N. magadii
.

IMPORTANCE
Genetic analyses of haloalkaliphilic
Archaea
or haloviruses are only rarely reported. Therefore, only little insight into the
in vivo
roles of proteins and their functions has been gained so far. We used a reverse genetics approach to identify the function of a yet undescribed gene of ϕCh1. We provide evidence that gp79, a currently unknown protein of ϕCh1, acts as a repressor protein of the viral life cycle, affecting the transition from the lysogenic to the lytic state of the virus. Thus, repressor genes in other haloviruses could be identified by sequence homologies to gp79 in the future. Moreover, we describe the use of an inducible promoter of
N. magadii
. Our work provides valuable tools for the identification of other unknown viral genes by our approach as well as for functional studies of proteins by inducible expression.
Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly
Authors: Wang Hong , Guo Haoran , Su Jiaming , Rui Yajuan , Zheng Wenwen , Gao Wenying , Zhang Wenyan , Li Zhaolong , Liu Guanchen , Markham Richard B. , Wei Wei , Yu Xiao-Fang
Published: February 2017

The lentiviral accessory proteins Vpx and Vpr are known to utilize CRL4 (DCAF1) E3 ligase to induce the degradation of the host restriction factor SAMHD1 or host helicase transcription factor (HLTF), respectively. Selective disruption of viral CRL4 (DCAF1) E3 ligase could be a promising antiviral strategy. Recently, we have determined that posttranslational modification (neddylation) of Cullin-4 is required for the activation of Vpx-CRL4 (DCAF1) E3 ligase. However, the mechanism of Vpx/Vpr-CRL4 (DCAF1) E3 ligase assembly is still poorly understood. Here, we report that zinc coordination is an important regulator of Vpx-CRL4 E3 ligase assembly. Residues in a conserved zinc-binding motif of Vpx were essential for the recruitment of the CRL4 (DCAF1) E3 complex and Vpx-induced SAMHD1 degradation. Importantly, altering the intracellular zinc concentration by treatment with the zinc chelator
N
,
N
,
N
′-tetrakis-(2′-pyridylmethyl)ethylenediamine (TPEN) potently blocked Vpx-mediated SAMHD1 degradation and inhibited wild-type SIVmac (simian immunodeficiency virus of macaques) infection of myeloid cells, even in the presence of Vpx. TPEN selectively inhibited Vpx and DCAF1 binding but not the Vpx-SAMHD1 interaction or Vpx virion packaging. Moreover, we have shown that zinc coordination is also important for the assembly of the HIV-1 Vpr-CRL4 E3 ligase. In particular, Vpr zinc-binding motif mutation or TPEN treatment efficiently inhibited Vpr-CRL4 (DCAF1) E3 ligase assembly and Vpr-mediated HLTF degradation or Vpr-induced G
2
cell cycle arrest. Collectively, our study sheds light on a conserved strategy by the viral proteins Vpx and Vpr to recruit host CRL4 (DCAF1) E3 ligase, which represents a target for novel anti-human immunodeficiency virus (HIV) drug development.

IMPORTANCE
The Vpr and its paralog Vpx are accessory proteins encoded by different human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) lentiviruses. To facilitate viral replication, Vpx has evolved to induce SAMHD1 degradation and Vpr to mediate HLTF degradation. Both Vpx and Vpr perform their functions by recruiting CRL4 (DCAF1) E3 ligase. In this study, we demonstrate that the assembly of the Vpx- or Vpr-CRL4 E3 ligase requires a highly conserved zinc-binding motif. This motif is specifically required for the DCAF1 interaction but not for the interaction of Vpx or Vpr with its substrate. Selective disruption of Vpx- or Vpr-CRL4 E3 ligase function was achieved by zinc sequestration using
N
,
N
,
N
′-tetrakis-(2′-pyridylmethyl)ethylenediamine (TPEN). At the same time, zinc sequestration had no effect on zinc-dependent cellular protein functions. Therefore, information obtained from this study may be important for novel anti-HIV drug development.
Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents
Authors: Petravic Janka , Rasmussen Thomas A. , Lewin Sharon R. , Kent Stephen J. , Davenport Miles P.
Published: February 2017

Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3- to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life > 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment.

IMPORTANCE
Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.