bluuebunny/crossref_metadata_2025 huggingface dataset:
A new approach to the identification of high-potential materials for cost-efficient membrane-based post-combustion CO2capture
Authors: Roussanaly Simon , Anantharaman Rahul , Lindqvist Karl , Hagen Brede
Published: April 2018

Identification of polymeric materials with a high potential to achieve significant cost-reductions for membrane-based CO2capture from a cement plant.
Disk stars in the Milky Way detected beyond 25 kpc from its center
Authors: López-Corredoira M. , Allende Prieto C. , Garzón F. , Wang H. , Liu C. , Deng L.
Published: April 2018

Context.The maximum size of the Galactic stellar disk is not yet known. Some studies have suggested an abrupt drop-off of the stellar density of the disk at Galactocentric distancesR≳ 15 kpc, which means that in practice no disk stars or only very few of them should be found beyond this limit. However, stars in the Milky Way plane are detected at larger distances. In addition to the halo component, star counts have placed the end of the disk beyond 20 kpc, although this has not been spectroscopically confirmed so far.Aims.Here, we aim to spectroscopically confirm the presence of the disk stars up to much larger distances.

Methods.With data from the LAMOST and SDSS-APOGEE spectroscopic surveys, we statistically derived the maximum distance at which the metallicity distribution of stars in the Galactic plane is distinct from that of the halo populations.

Results.Our analysis reveals the presence of disk stars atR> 26 kpc (99.7% C.L.) and even atR> 31 kpc (95.4% C.L.).
Die Lasertrabekuloplastik in der modernen Glaukomtherapie – ein Überblick
Authors: Greslechner Roman , Spiegel Detlev
Published: April 2018

Hintergrund Die Lasertrabekuloplastik (LTP) stellt neben medikamentöser Therapie und operativen Interventionen eine etablierte Behandlungsmodalität in der Therapie chronischer Offenwinkelglaukome dar. Dabei besteht eine große Variabilität in der praktischen Anwendung.

Methoden Literaturrecherche über PubMed. Darstellung der wichtigsten evidenzbasierten Daten zur Lasertrabekuloplastik.

Ergebnisse Argonlasertrabekuloplastik (ALT) und selektive Lasertrabekuloplastik (SLT) stellen sichere und effektive Verfahren dar, die zu einer Drucksenkung um 20 – 30% führen. Vergleichbare Erfolgsraten werden für beide Prozeduren berichtet. Im Verlauf muss bei 50% mit einem Therapieversagen nach ca. 2 – 5 Jahren gerechnet werden. Die Wiederholung einer ALT ist mit einer deutlich geringeren Drucksenkung und Wirkdauer verbunden. Auch die Wiederholung einer SLT ist mit einem Wirkverlust verbunden. Die Wirksamkeit der SLT nach initialer ALT konnte nachgewiesen werden, wohingegen Daten zur Wirksamkeit einer ALT nach initialer SLT noch fehlen. Bei fortgeschrittenen Glaukomen unter maximaler medikamentöser Therapie wurden in Hinblick auf zusätzliche Interventionen schlechtere Erfolgsraten berichtet.

Schlussfolgerung Die LTP bietet sich als Ersttherapie und ergänzende Therapie in allen Stadien an. Bei fortgeschrittenen Glaukomen unter maximaler medikamentöser Therapie sind die Erfolgsaussichten aufgrund der notwendigen niedrigen Zieldrücke eingeschränkt.
Real-Time PCR Assay for Detection of Kingella kingae in Children
Authors: Madigan Theresa , Cunningham Scott , Ramanan Poornima , Bhatti Micah , Patel Robin
Published: April 2018

Background Kingella kingae is a known cause of osteoarticular infections in children younger than 4 years of age, but it is not always recoverable in culture. Molecular methods are increasingly used for diagnosis.

Methods To facilitate diagnosis of K. kingae septic arthritis, we developed a real-time polymerase chain reaction (PCR) assay for the detection of K. kingae that targets the repeat-in-toxin gene (rtxB).

Results We present three pediatric patients with K. kingae septic arthritis at our institution who were diagnosed using the real-time PCR assay. All underwent arthrotomy with irrigation and debridement and were symptom-free after 3 weeks of therapy with β-lactam antibiotics. Cultures of synovial fluid or tissue grew K. kingae in two of three; K. kingae real-time PCR was positive in all three patients. In addition, 11 cases of K. kingae osteoarticular infection were diagnosed through Mayo Medical Laboratories using this assay. The limit of detection of the real-time PCR assay was 73.7 colony-forming unit (CFU)/µL for tissue and 1.3 CFU/µL for synovial fluid.

Conclusions PCR-based detection methods are faster and more sensitive than conventional culture-based methods for the diagnosis of K. kingae osteoarticular infections in children.
ASCO- und ESMO-Update 2017 – Neuigkeiten vom 53. Meeting der American Society of Clinical Oncology/ASCO 2017 und European Society for Medical Oncology/ESMO-Congress 2017
Authors: Ettrich Thomas , Ebert Matthias , Lorenzen Sylvie , Moehler Markus , Vogel Arndt , Witkowski Lukas , Seufferlein Thomas , Reinacher-Schick Anke
Published: April 2018

Auf dem Amerikanischen Krebskongress 2017 und dem Europäischen Krebskongress 2017 wurden eine Reihe von wichtigen Studien vorgestellt, die teilweise zu einer Änderung der aktuellen Therapiestandards in der Viszeralonkologie führen. So gilt nach den Ergebnissen der FLOT4-Studie die Kombination aus Docetaxel, Oxaliplatin und 5-Fluorouracil (FLOT) als der neue Behandlungsstandard in der perioperativen Therapie bei resektablen Adenokarzinomen des gastroösophagealen Übergangs und des Magens. Beim hepatozellulären Karzinom (HCC) hat die selektive interne Radiotherapie (SIRT) in zwei großen Studien keine Verbesserung des Überlebens gegenüber Sorafenib erbracht, sodass ein zunehmender Einsatz der SIRT nicht empfohlen wird. Hingegen scheint der Multityrosinkinase-Inhibitor Lenvatinib eine vielversprechende Alternative zu Sorafenib beim fortgeschrittenen HCC in der Erstlinientherapie zu sein. Beim frühen Kolonkarzinom kann nach den Daten der IDEA-Initiative bei Niedrigrisiko-Tumoren (T1 – 3, N1) nun eine dreimonatige Therapie mit Capecitabin und Oxaliplatin (CAPOX) empfohlen werden. Bei Hochrisikotumoren (T4 oder N2) soll weiterhin eine sechsmonatige Therapie mit 5-FU und Oxaliplatin (FOLFOX) oder CAPOX durchgeführt werden. Neben regelmäßiger Bewegung soll auch ein regelmäßiger Verzehr von Nüssen die Rezidivrate nach Resektion eines Kolonkarzinoms senken. Beim metastasierten kolorektalen Karzinom (mKRK) hat die SIRT in der Erstlinientherapie keinen Stellenwert. Beim BRAF-mutierten mKRK stellt die Kombination von Irinotecan, Cetuximab und Vemurafenib eine gute Therapiemöglichkeit in der Zweitlinientherapie dar. In der adjuvanten Therapie von Gallenwegstumoren stellt durch die positiven Ergebnisse der BILCAP-Studie die sechsmonatige Therapie mit Capecitabin den neuen Behandlungsstandard dar. Für das metastasierte Pankreaskarzinom kann möglicherweise der gezielte Angriff auf das Tumorstroma durch pegylierte Hyaluronidase PEGPH20 eine neue Therapieoption bieten, die derzeit in Phase-III-Studien überprüft wird.
Texture-enhanced Al-Cu electrodes on ultrathin Ti buffer layers for high-power durable 2.6 GHz SAW filters
Authors: Fu Sulei , Wang Weibiao , Xiao Li , Lu Zengtian , Li Qi , Song Cheng , Zeng Fei , Pan Feng
Published: April 2018

Achieving high resistance to acoustomigration and electromigration in the electrodes used in high-power and high-frequency surface acoustic wave (SAW) filters is important to mobile communications development. In this study, the effects of the Ti buffer layers on the textures and acoustomigration and electromigration resistances of the Al-Cu electrodes were studied comprehensively. The results demonstrate that both power durability and electromigration lifetime are positively correlated with the Al-Cu electrode texture quality. Ultrathin (∼2 nm) Ti can lead to the strongest Al-Cu (111) textured electrodes, with a full width at half maximum of the rocking curve of 2.09°. This represents a remarkable enhancement of the power durability of high-frequency 2.6 GHz SAW filters from 29 dBm to 35 dBm. It also produces lifetime almost 7 times longer than those of electrodes without Ti buffer layers in electromigration tests. X-ray diffraction and transmission electron microscopy analyses revealed that these improved acoustomigration and electromigration resistances can be attributed primarily to the reductions in overall and large-angle grain boundaries in the highly Al-Cu (111) textured electrodes. Furthermore, the growth mechanism of highly Al-Cu texture films is discussed in terms of surface-interface energy balance.
Elastohydrodynamic lubrication in point contact on the surfaces of particle-reinforced composite
Authors: Chen Keying , Zeng Liangcai , Wu Zhenpeng , Zheng Feilong
Published: April 2018

Appreciable friction and serious wear are common challenges in the operation of advanced manufacturing equipment, and friction pairs may be susceptible to damage even with oil lubrication when point contact exists. In this study, a type of particle-reinforced composite material is introduced for one of the components of a heavy-load contact pair, and the performance improvement of elastohydrodynamic lubrication (EHL) is analyzed considering the rheological properties of non-Newtonian fluids. The Ree–Eyring EHL model is used considering the surface of the particle-reinforced composite, in which the film thickness includes the particle-induced elastic deformation. The problem of inclusions with different eigenstrains is solved by using Galerkin vectors. The influences of particle properties, size, burial depth, and interparticle distance on point-contact EHL are investigated. Furthermore, using several cases, the structural parameters of the particles in the composites are optimized, and an appropriate parameter range is obtained with the goal of reducing friction. Finally, the results for the EHL traction coefficient demonstrate that appropriate particle properties, size, burial depth, and interparticle distance can effectively reduce the traction coefficient in heavy-load contact.
Fabrication and characterization of uniaxially strained SOI with wafer level by mechanical bending and annealing
Authors: Wu Shujing , Miao Dongming , Dai Xianying , Shao Chenfeng , Hao Yue
Published: April 2018

The successful introduction and micron-scale characterization of uniaxial strain with wafer level play pivotal roles in designing and optimizing of the silicon-on-insulator (SOI) microstructures for next-generation strained-Si transistors. In this paper, the successful fabrication of uniaxially strained SOI with wafer level by simply mechanical bending and annealing was realized. Employing polarized Raman measurements, the Raman intensity as a function of the angle between the crystal-axis and the polarization-direction of the scattered light for the strained top Si layer demonstrated the uniaxial character of the induced strain. Micro-Raman measurements revealed that the strain was uniaxially compressive with 0.114% strain value. The transmission electron microscopy characterization was used to reveal the little effect of process on crystallinity, which was confirmed by XRD measurements. The crystal symmetry change from cubic to tetragonal structure of the strained Si was further discussed.
Generalised monopole equations on Kähler surfaces
Authors: Biswas Indranil , Thakre Varun
Published: April 2018

In this article, we establish a Hitchin-Kobayashi type correspondence for generalised Seiberg-Witten monopole equations on Kähler surfaces. We show that the “stability” criterion we obtain, for the existence of solutions, coincides with that of the usual Seiberg-Witten monopole equations. This enables us to construct a map from the moduli space of solutions to the generalised equations to effective divisors.
Rapid evaluation of fatigue limit in AZ31B magnesium alloy using acoustic emission
Authors: Li Chenghao , Yan Zhifeng , Dong Peng , Su Yinghu , Wang Xiaojiao , Wang Tianpeng , Han Xi , Li Jinpeng , Zhang Hong-xia
Published: April 2018

Acoustic emission (AE) was used in a fatigue experiment to characterise AE signals and to rapidly determine the fatigue limit of AZ31B magnesium (Mg) alloy. The AE signals during fatigue were characterised according to waveforms and frequency. Meanwhile, the energy dissipation in the process of fatigue, which was represented by the accumulative AE energy, can be used to determine the fatigue limit. Based on the AE parameters, the fatigue limit was 97 MPa, with an 8% error value when compared with the results obtained by the conventional S–N curve method. This model only requires the accumulated energy of the signals during strain hardening. Therefore, the fatigue limit can be determined rapidly.
Single-round isolation of diverse RNA aptamers from a random sequence pool
Authors: Imashimizu Masahiko , Takahashi Masaki , Amano Ryo , Nakamura Yoshikazu
Published: April 2018

Aptamers are oligonucleotide ligands with specific binding affinity to target molecules. Generally, RNA aptamers are selected from an RNA pool with random sequences, using the technique termed SELEX, in which the target-binding RNA molecules are repeatedly isolated and exponentially amplified. Despite several advantages, SELEX often produces uncertain results during the iterative amplifications of the rare target-binding RNA molecules. Here, we develop a non-repeated, primer-less and target immobilization-free isolation method for generating RNA aptamers, which is robust to experimental noise. Uniquely, this method focuses on finding and removal of non-aptamer sequences from the RNA pool by RNase digestion leaving target-bound aptamer molecules, and thus is independent of aptamer types. The undigested RNA sequences remaining are so few in number that they must be mixed with a large excess of a known sequence for further manipulations and this sequence is then removed by restriction digestion followed by high-throughput sequencing analysis to identify aptamers. Using this method, we generated multiple RNA aptamers targeting α-thrombin and TGFβ1 proteins, independently. This method potentially generates thousands of sequences as aptamer candidates, which may enable us to predict a common average sequence or structural property of these aptamers that is different from input RNA.
SILVERRUSH. VI. A simulation of Lyα emitters in the reionization epoch and a comparison with Subaru Hyper Suprime-Cam survey early data
Authors: Inoue Akio K , Hasegawa Kenji , Ishiyama Tomoaki , Yajima Hidenobu , Shimizu Ikkoh , Umemura Masayuki , Konno Akira , Harikane Yuichi , Shibuya Takatoshi , Ouchi Masami , Shimasaku Kazuhiro , Ono Yoshiaki , Kusakabe Haruka , Higuchi Ryo , Lee Chien-Hsiu
Published: April 2018

The survey of Lyman α emitters (LAEs) with the Subaru Hyper Suprime-Cam, called SILVERRUSH (Ouchi et al. 2018, PASJ, 70, S13), is producing massive data of LAEs at z ≳ 6. Here we present LAE simulations to compare the SILVERRUSH data. In 1623 comoving Mpc3 boxes, where numerical radiative transfer calculations of reionization were performed, LAEs have been modeled with physically motivated analytic recipes as a function of halo mass. We have examined 23 models depending on the presence or absence of dispersion of halo Lyα emissivity, dispersion of the halo Lyα optical depth, τα, and halo mass dependence of τα. The unique free parameter in our model, a pivot value of τα, is calibrated so as to reproduce the z = 5.7 Lyα luminosity function (LF) of SILVERRUSH. We compare our model predictions with Lyα LFs at z = 6.6 and 7.3, LAE angular auto-correlation functions (ACFs) at z = 5.7 and 6.6, and LAE fractions in Lyman break galaxies at 5 < z < 7. The Lyα LFs and ACFs are reproduced by multiple models, but the LAE fraction turns out to be the most critical test. The dispersion of τα and the halo mass dependence of τα are essential to explain all observations reasonably. Therefore, a simple model of one-to-one correspondence between halo mass and Lyα luminosity with a constant Lyα escape fraction has been ruled out. Based on our best model, we present a formula to estimate the intergalactic neutral hydrogen fraction, $x_{\rm H\, \small {I}}$, from the observed Lyα luminosity density at z ≳ 6. We finally obtain $x_{\rm H\, \small {I}}=0.5_{-0.3}^{+0.1}$ as a volume-average at z = 7.3.
Recess environment and curriculum intervention on children’s physical activity: IPLAY
Authors: Nigg Claudio R , Kutchman Eve , Amato Katie , Schaefer Christine A , Zhang Guangxiang , Anwar Md Mahabub Ul , Anthamatten Peter , Browning Raymond C , Brink Lois , Hill James
Published: April 2018

Understanding the impacts of the built environment on physical activity (PA) is essential to promoting children’s PA. The purpose of this study was to investigate the effects of schoolyard renovations and a PA recess curriculum alone and in combination on children’s PA. This was a 2 (learning landscape [LL] vs. non-LL) × 2 (curriculum intervention vs. no curriculum intervention) factorial design with random assignment to the curriculum intervention, and six elementary schools per condition. PA outcomes were assessed preprogram, mid-program, immediate postprogram, and one year postprogram. No meaningful intervention effects were found. Lack of an effect may be due to the brief dose of recess, the curriculum not being integrated within the schoolyard, the LL implementation occurring prior to the study, or the already high levels of PA. Potential avenues to promote PA include making recess longer, integrating recess into the school curricula, and developing recess PA curricula integrating schoolyards.
The Lisfranc Joint: Multimodality Imaging to Avoid Missteps in the Diagnosis of Acute Injuries
Authors: Reyes Emmanuel J. , Lee Michael Jinpyo , Chong Suzanne T.
Published: April 2018

Named after Jacques Lisfranc de St. Martin (1790–1847), a French surgeon in Napoleon's army who described amputations through the tarsometatarsal joint, the Lisfranc joint is the junction between the midfoot and the forefoot and represents a complex articulation composed of nine bones: the five metatarsal bases, the three cuneiforms, and the cuboid. The stability of the Lisfranc joint depends largely on its bony architecture and ligamentous integrity, with additional support provided by the peroneus longus, anterior tibialis, and posterior tibialis tendons; the long plantar ligament; the plantar fascia; and the intrinsic muscles of the foot.1
A-101 Understanding for targeting the HIV reservoir
Authors: Benkirane Monsef
Published: April 2018

HIV infection is suppressed but not cured by Anti-Retroviral Therapy (ART). This is due to the establishment of a viral reservoir that is responsible for the persistence of low levels of plasma viremia in patients under ART. Viral rebound is observed immediately after ART interruption. HIV persistence may arise from ongoing residual virus replication and/or from latentlyinfected cells in which long-lived resting memory CD4+ T cells harbouring transcriptionally silent provirus represent the largest pool in the blood. Addressing the source of HIV persistence is required to achieve a cure for HIV. We will discuss our recent data showing that CD32a is marker of HIV persistent CD4 T cell.
A-105 NO EVIDENCE FOR HIV REPLICATION IN LYMPH NODES DURING ART
Authors: McManus William , Spindler Jonathan , Bale Michael , Wiegand Ann , Musick Andrew , Wu Xiaolin , Wells David , Hughes Stephen , Kearney Mary
Published: April 2018

To better understand the mechanisms of HIV persistence and to further investigate the question on ongoing viral replication in lymph nodes, we characterized HIV proviral populations, their levels of expression, and their sites of host integration in paired lymph node mononuclear cells (LNMC) and peripheral blood mononuclear cells (PBMC) collected after long-term ART and compared to them to the HIV populations prior to ART initiation. Three donors initiated ART in chronic infection and had viremia suppressed for 4-12 years; one donor initiated ART in acute infection and had viremia suppressed for 18 years. Proviral populations and expression were characterized by single-cell analyses and expanded clones were identified using the integration sites assay (ISA). Populations were compared phylogenetically, using a test for panmixia (well-mixed or divergent), by determining the fraction of expressing vs. latent proviruses, determining the levels of expression in single cells with actively-transcribing proviruses, and by comparing the expanded clonal populations. Proviruses in LNMC and PBMC were well mixed and were not significantly divergence from the pre-ART populations. The fraction of proviruses that were latent vs. actively transcribing during ART were not different (5%-8% in the PBMC and 2%-20% in the LNMC) (p=0.4). The levels of expression in actively-infected cells were low in both compartments, typical of suppression of viral replication. The same clonal populations were detected in PBMC and LNMC (p=0.8). These findings are not consistent with continued viral replication during ART in either the peripheral blood or the lymph nodes. Our results also suggest that infected cells migrate freely between the peripheral blood and the lymph nodes and demonstrate that the HIV reservoir is long-lived and proliferating populations of cells that were infected prior to initiating ART.
A-107 Early ART and HIV Remission: Experience from the RV254 and related HIV remission studies
Authors: Ananworanich Jintanat
Published: April 2018

Early antiretroviral therapy (ART) is an important step in the path towards an HIV cure. Acute HIV infection studies have demonstrated the ability to identify and treat very early infection in adults, resulting in significantly smaller HIV reservoirs, preserved immune functions with little viral escape to immune pressure. These results have been illustrated in the ongoing RV254 acute HIV infection study in Thailand that has enrolled close to 500 individuals. It has served as a platform to learn the effects of early ART and recruit participants for HIV remission trials.

Despite the favorable qualities, the majority of early treated individuals do not achieve HIV remission. Indeed this has been the experience to date in the RV254 HIV remission trials, which include 3 completed studies and one ongoing, with others in development. The interventions have included latency-reversing agent, broadly neutralizing antibody and therapeutic HIV vaccine. However, there are important lessons to be learned that would inform the design of future HIV remission trials.

There continues to be exciting new development of immune-based interventions. It is highly likely that combination therapies that can generate persistent and effective immune responses to control HIV will be required for a durable ART-free sustained remission of HIV.
A-108 The Contribution of memory CD4+ T cell subset phenotype to latency reversal efficiency
Authors: Kulpa Deanna , Talla Aarthi , Ribeiro Susan , Barnard Richard , Hazuda Daria , Chomont Nicolas , Sekaly Rafick
Published: April 2018

The latent HIV reservoir persists in individuals on ART predominantly in memory CD4+ T cells, a heterogeneous population comprised of central memory (CM), transitional memory (TM) and effector memory (EM) subsets. Current HIV eradication strategies that aim to reverse latency in this heterogeneous pool of cells have had limited success. To characterize HIV latency reversal in all memory CD4+ T cell subsets that contribute to the HIV reservoir in vivo, we developed LARA (Latency and Reversion Assay), a primary cell based in vitro model of HIV latency. To identify pathways associated with latency reversal in each subset, we exposed latently infected cells from both HIV-infected individuals and LARA to different classes of latency reversing agents (LRAs). Memory subsets showed distinct responses that resulted in varying efficiencies to the LRAs tested. Importantly, the most effective LRAs triggered the differentiation into cells that expressed an EM phenotype. Transcriptional profiling of CD4+ T cells from HIV-infected individuals exposed to bryostatin, the LRA that showed the highest latency reversal, identified several EM specific pathways that were significantly upregulated in both the CM and EM subsets, including genes encoding for cytokines and effector molecules such as IFN-γ, IL-2, IL-4, and TNF. Together, these results support LRA exposure triggering differentiation toward an EM subset phenotype to be linked to higher latency reversal efficiency. Identification of these pathways is a critical prerequisite to understand factors that influence latency reversal in vivo as well as contributing to the most effective design of regimens capable of comprehensive reactivation of the HIV reservoir in eradication strategies.
B-102 Results from a First-In-Human study with BNZ-1, a novel, selective inhibitor of IL-2, IL-9, and IL-15 at the common gamma-chain receptor, in clinical development for the treatment of HAM/TSP and T-cell malignancies
Authors: Frohna Paul , Tagaya Yutaka , Ratnayake Anoshie , Doerr Nick , Basheer Asjad , Al-Mawsawi Laith , Kim Woo Jae , Zapata Juan
Published: April 2018

Aberrant signaling of IL-2, IL-9, and IL-15, members of the γγγc cytokine family, is involved in multiple human diseases (eg, T-cell malignancies, GvHD, HAM/TSP) that are not effectively or safely treated by the currently available anti-cytokine approaches.

BNZ-1 is a selective inhibitor of IL-2, IL-9 and IL-15 signaling through γγc, without altering IL-4, -7, or -21. In this open-label, single-dose study (NCT03046459), 18 healthy adults (n = 3/dose) received a single IV dose of 0.2, 0.4, 0.8, 1.6, 3.2 or 6.4 mg/kg and were monitored for 30 days. BNZ-1 was well-tolerated with a good safety profile (no serious/severe AEs, no DLTs, and no clinically-significant changes on labs, vital signs or ECGs).

BNZ-1 exposure was dose proportional with an elimination t1/2 of ∼5 days, supporting weekly or every other week dosing. PD activity was characterized by flow cytometry of Tregs (IL-2), NK cells (IL-15) and CD8+ central memory T-cells (Tcm; IL-2 & IL-15) in PBMCs from days 4, 15 and 31. Tregs were decreased by 50%–60% after doses of 0.4–1.6 mg/kg on day 4 and by 80%–93% at 3.2 and 6.4 mg/kg on day 15. On day 4 NK cells decreased by 20%, 40% and 60% at 0.2, 0.4 and 0.8 mg/kg, respectively, and plateaued at 70%–80% decreases at doses a1.6 mg/kg. Tcm were decreased at day 4 for the top 3 doses that continued to decline to day 15 when all doses, except 0.2 mg/kg, showed a mean decrease ranging from 10% to 81% that trended with dose. Tregs, NK cells, and Tcm returned to/toward baseline by day 31. CD4+ and CD8+ T-cells, B-cells, and monocytes were unchanged at all time points.

These clinical data suggest that BNZ-1 is a highly-active, selective immunomodulator that safely decreases Tregs, NKs and Tcm, while sparing the major leukocyte populations.
P-E5 Whole genome deep sequencing of HIV reveals extensive multi-class drug resistance in Nigerian patients failing first-line antiretroviral therapy
Authors: Ndembi Nicaise , Elbouzidi Kate , Kwaghe Vivian , Ogbanufe Obinna , Murtala-Ibrahim Fati , Charurat Man , Dakum Patrick , Sabin Caroline
Published: April 2018

Background:

Whole genome deep sequencing (WGS) could improve understanding of treatment failure and the emergence of resistance by revealing the distribution of mutations throughout the viral population over time.

Methods:

Adult patients receiving 1L ART (2 NRTI and 1 NNRTI) at the University of Abuja Teaching Hospital, Nigeria, were included if they had experienced virological failure (HIV-1 RNA >1000 copies/mL, at least 6 months after ART initiation, confirmed by clinician-driven testing), and had a stored plasma sample available for WGS.

Results:

Sixty participants were sampled during 1L failure (73% female; median age 30 (interquartile ratio [IQR] 28–35); median CD4+ cell count 110 cells/mm3 (IQR 63–191); median 28 months after ART initiation (IQR 18–41)). At 1L failure, 57% of participants had thymidine analogue mutations (TAMs), with 30% harbouring 3 or more TAMs, 95% had other (non-TAM) NRTI mutations and 100% had NNRTI mutations. The most common mutations were M184V, Y181C, G190A, K65R and K103N. Overall, 17% (61/367) of the mutations identified were low-level minority variants (present at 2%–20% of the intra-host viral population), which would not have been detected by standard resistance testing methods, 24% (88/367) were present at 20%–90% frequency, and 59% (218/367) were dominant majority variants representing >90% of the participant's viral population.

Conclusions:

Diverse Nigerian HIV clades exhibit multi-class drug resistance at 1LART failure. The predominance of high-frequency mutations suggests that emergent resistance had become fixed in the viral population by the time of sampling.
P-E6 Hepatitis B and Hepatitis C: Viral infections among pregnant women in some Nigerian major cities: A review
Authors: Itelima Janet
Published: April 2018

Background:

Worldwide, viral hepatitis is the commonest cause of hepatitis dysfunction in pregnancy. During pregnancy, viral hepatitis is associated with high risk of maternal complications and has become a leading cause of foetal death.

Aim:

This review was done to assess the status of hepatitis B and hepatitis C viral infection among pregnant women in some Nigerian major cities.

Methodology:

The information used for this review was from published works in Nigeria and elsewhere. The information was extracted over the period of 7 months from November 2015 to June 2017.

Results:

In Nigeria, the prevalence of hepatitis B and Hepatitis C viral infection is on the increase and the nation has been classified among the group of countries endemic for the infection with about 18 million of the populace infected. The prevalence of hepatitis B viral infection among pregnant women in many parts of the country has been reported; with Port Harcourt having the prevalence of (4.9%), Yenagoa (5.3%), Benin (12.5%) Jos (10.3%, 15.9% and 23.9%), Ibadan (21.3%). Anti-HCV antibody prevalence among pregnant women has also been reported in various parts of Nigeria; with Benin having the prevalence of (3.6%), Yenagoa (0.5%), Osogbo (9.2%), Enugu (14.9%), Jos (5.2%), Kaduna (11.9%), Kano (7.3%) and Zaria (18.2%). In Nigeria, the transmission of hepatitis B and Hepatitis C viral infections occur mainly during childhood as a result of maternal-neonatal transmission and by other risk factors like blood transfusion, sexual promiscuity, history of sharing of toothbrush, sharp objects such as razor blades, nail cutters and scissors and instruments for pedicure and manicure. Other modes of the viral infection common in the country include high risk groups such as health care workers, poor socioeconomic status. Thus, all the risk factors implicated elsewhere in the spread of the viral infections in the general population also play role in Nigeria.

Conclusion:

The prevalence of hepatitis B virus (HBV) and Hepatitis C virus (HCV) among pregnant women in Nigeria is of intermediate endemicity. Therefore, there is the need to institute public health measures such as routine screening of all pregnant women's blood and blood products for hepatitis, personal and environmental sanitation, and the discouragement of unsupervised injections to reduce disease burden and transmission in the population.
P-G3 Unravelling the mechanism of action of HLBT-100 molecule against Adult T-Cell leukemia
Authors: Reid Terry-Elinor , Geh Josephine , Toyang Ngeh , Zapata Juan , Lowe Henry , Bryant Joseph , Tagaya Yutaka
Published: April 2018

Adult T-cell leukemia-lymphoma (ATL) is a leukemia of mature CD4 T cells that develops after long-term infection of human T-cell leukemia virus (HTLV-1). The prognosis for patients living with the disease is poor, with chronic ATL median survival is 2 years. Once they are diagnosed with acute/lymphomatous ATL, patients have less than 1 year of life left. Current standard of care involves chemotherapy, combination of zidovudine (AZT) and IFN-α or Arsenic Trioxide and IFNa, antibody therapy (CD25, CCR4) and/or allogeneic stem cell transplantation, all of which will improve the median survival but are not effective for long term treatment. Hence there is an unmet need to discover and develop new and effective treatments against ATL. Strategies targeting signaling networks activated in ATL has been tried with some success. We have been testing a novel targeting of the JAK-STAT pathway with our novel small molecule inhibitor HLBT-100. In vitro experiments showed that HLBT-100 enhances serine-threonine phophorylation of STAT3 by blocking the tyrosine phosphorylation of this molecule. In normal cells, this would allow mitochondrial translocation of the phosphorylated STAT3 after which STAT3 sustains homeostasis of cells through the enhancement of mitochondrial energy generation. However this pathway seems non-functional in ATL cells. Thus, we hypothesize HLBT-100 seems to preferentially induce apoptotic death of ATL cells without damaging normal cells. We are currently validating this using a novel in vivo mouse model of ATL.
P-G4 Molecular characterization of hippocampal changes in an animal model of HIV associated primary central nervous system lymphoma
Authors: Katuri Akhil , Andhavarapu Sanketh , Asemu Girma , Davis Harry , Bryant Joseph , Makar Tapas , Chander Guda Poorna
Published: April 2018

Primary Central Nervous System Lymphoma (PCNSL) is a rare form of extra nodal non-Hodgkin's lymphoma. HIV patients are more prone to PCNSL. It may arise from a systemic lymphoma that seeds multiple organs, including the brain. The predominant histology of PCNSL is large B-cell lymphoma. Molecular studies on systemic AIDS/NHL is well characterized, however, information on molecular studies of PCNSL is limited due in part to accessibility of tissue and lack of animal model. To date, no animal model has been developed, which recapitulates both histopathologic and molecular features of this disease, including the immune phenotypic state. We recently developed an animal model of PCNSL. The observation of a phenotype of a HIV -1 transgenic mouse model that develops a B- cell lymphoma that mimics the disease is seen in AIDS patients with NHL Brain lymphoma patients. HIV associated B-cell lymphoma patients as well as HIV infected patients suffer from cognatic impairment. Brain hippocampus region regulates cognatic behavior. Therefore, we were interested in finding the cellular and molecular changes in the hippocampus of these animals. Interestingly, we identified a significant increase of infiltrating leucocytes, T cells, B cells, and macrophages/microglial cells in the hippocampal region of those mice. Astrogliosis is also observed. Aquaporin-4 (AQP4) is the predominant water channel expressed by astrocytes. The regulation of AQP4 has been extensively investigated in various neuropathological conditions; however, the functional role of AQP4 in synaptic plasticity, learning, and memory is only beginning to be elucidated. We have explored the role of AQP4 and its influence on hippocampus and its potential relationship with synaptic plasticity of these mice. Recent in vitro and in vivo studies using AQP4-null and wild-type mice, in particular, the impairment of cognatic function observed in the hippocampus. (Szu JI and Binder DK. Front Integr Neurosci. 2016 Feb 24; 10:8). In this context we found increased AQP4 and synaptic plasticity (by detecting synaptophysin and synapsine-1) in the hippocampus of these animals. This suggests that AQP4 plays an important role in regulating synaptic plasticity in the hippocampus of these mice. Astrocytes play a role in synaptic plasticity. However, there are only a few studies that implicate a direct relationship of AQP4 in synaptic plasticity. All together, these studies highlight the potential influence of AQP4 in synaptic plasticity and memory of these animals probably due to compensatory mechanism.
P-I1 Monotherapy with integrase inhibitors does not maintain viral suppression in humanized mice with chronic HIV infection
Authors: Heredia Alonso , Hassounah Said , Medina-Moreno Sandra , Zapata Juan , Le Nhut , Han Yingshan , Foulke James , Davis Charles
Published: April 2018

Introduction and Methods:

Simplification of current triple ART to dual ART or monotherapy may suffice to maintain HIV suppression while sparing drug toxicities. We evaluated and compared the efficacy of 20-week monotherapy with dolutegravir or raltegravir in humanized mice (HSC-NSG) infected with HIVBaL. Plasma HIV RNA was measured by qRT-PCR (limit of detection of 150 copies/40 μL plasma) and drug levels by LC/MS/MS. Escape viruses were genotyped and analyzed for replication capacity and drug susceptibility in tissue culture.

Results:

Drug untreated control mice maintained constant viremia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC50 <8 nM) and dolutegravir (EC50 <1 nM). Mice treated with raltegravir or dolutegravir had plasma drug levels comparable to those in humans. Monotherapy with raltegravir initially suppressed HIV viremia, but failed to maintain suppression in 4/4 mice. Viruses from raltegravir failing mice had the G140S and Q148H/K substitutions, and were resistant to both raltegravir (EC50 values of >100 nM) and dolutegravir (EC50 values ranging 8.8–13.3 nM) in drug susceptibility assays using human PBMCs. Monotherapy with dolutegravir suppressed viremia in 5/5 of mice, but viremia rebounded in one animal after 12 weeks of treatment. The virus from this mouse had mutations E138K, G140S, Q148H, N155H and S230R, was highly resistant to both raltegravir (EC50 >1000 nM) and dolutegravir (EC50 of 550 nM), and replicated to high levels in PBMCs.

Discussion:

Raltegravir or dolutegravir monotherapy does not ultimately maintain HIV suppression in humanized mice, suggesting that dual therapy will most likely be required for simplification of ART treatment. Eleven (OR = 10.93) & 7 (OR = 6.53) times more likely respectively, to have HIV negative infants compared to prophylaxis regimen.

Conclusion:

HAART prior to and during pregnancy is associated with an increased likelihood of achieving a favorable EID result.
P-A12 Discordant HIV populations with discordant V3 tropism in CSF and Plasma: Implications for establishing HIV reservoirs
Authors: Lange Camille , Manion Maura , Hullsiek Kathy , Keele Brandon , Highbarger Helene , Meya David , Boulware David , Maldarelli Frank
Published: April 2018

CNS reservoirs of HIV are established early in infection and may be distinct from HIV populations in peripheral lymphoid organs, but the mechanisms responsible for compartmentalization are not well understood. To determine if HIV compartmentalization occurs during CNS infections, we investigated HIV populations in plasma and CSF in patients with active cryptococcal meningitis (CM). HIV infected patients with CM (N=73) from the COAT, ASTRO-CM studies, had lumbar punctures and phlebotomy. HIV RNA was quantified in plasma and CSF prior to initiating anti-CM or antiretroviral therapy. A subset (N=9) with CSF RNA >plasma RNA and another subset (N=9) with plasma RNA >CSF RNA underwent single genome sequencing (SGS) of HIV env from plasma and CSF. SGS of cellular DNA was also performed on a subset of patients (N=5) with lymphocytic pleocytosis. Nine hundred ninety-two SG sequences were obtained. Sequences were aligned and subjected to phylogenetic analyses, compartmentalization analyses (panmyxia) and cell tropism of the V3 loop in env for R5/X4 predictions (GENO2PHENO). Patients with CSF pleocytosis (WBC > 5 cells/μL), had higher levels of HIV in CSF than in plasma (p<0.05). In general, proportions of R5 and X4 variants in CSF and plasma were similar, but there was strong discordance in 4 patients, reflecting compartmentalization. Sensitive population analyses revealed viral compartmentalization between CSF and plasma (N=5). In patients with pleocytosis, HIV variants in CSF-derived cells were distinct from those in CSF, but were indistinguishable from PBMC-derived HIV. Overall, CSF compartmentalization of HIV was detectable in the majority of patients with CM. CSF pleocytosis does not contribute substantially to establishing HIV populations in CNS.
P-C3 A Modified Vaccinia Ankara vector expressing Lassa virus-like particles (MVA-LasVLP) protects mice from lethal challenge with a Lassa-Mopeia reassortant virus
Authors: Guzman M. Camila , Medina-Moreno Sandra , Zapata Juan , Hsu Hao-Ting , Guirakhoo Farshad , Domi Arban , McCurley Nathanael , Basu Rahul
Published: April 2018

The Lassa-endemic areas of West Africa, including the embattled areas of northern Nigeria have been experiencing more frequent outbreaks of Lassa fever (early 2016 through the summer of 2017). Consequently an international effort has been launched to produce a Lassa vaccine, including a test of the MVA-LASV-VLP (GEO-LM02). The MVA vector has been developed by Dr. B. Moss' lab at NIH in collaboration with GeoVax to deliver a variety of vaccine antigens. The GeoVAX-MVA-HIV-VLP has been used in human trials involving more than 500 participants, it has the capacity to express large recombinant antigens, it elicits robust T and B cell responses, and is relatively safe due to its inability to replicate in mammalian cells. Of all the current Lassa vaccine candidates, GEO-LM02 is the only one that produces VLP in vivo. Our experiments tested the optimum route of vaccination. We used young CBA/J mice that were challenged 2 weeks after vaccination with an intracerebral (ic) dose of a Lassa-Mopeia reassortant virus. Mice were given a single dose of GEO-LM02 by subcutaneous (sc), intraperitoneal (ip), and intramuscular (im) routes. One hundred percent of those given im vaccine survived the lethal challenge, whereas the other routes were slightly less protective. All unvaccinated mice died within 8d post challenge. A second round of experiments confirmed the previous results and demonstrated a robust cell-mediated immunity after a single dose im vaccination. Again 100% of the un-vaccinated mice succumbed to lethal challenge and experienced erosion of their blood-brain-barrier. Subsequent experiments will test the durability of immunity in surviving mice.
P-C4 Associating HIV-1 Env trimer structures with functional Env conformational states by smFRET analysis
Authors: Lu Maolin , Ma Xiaochu , Castillo-Menendez Luis , Gorman Jason , Munro James , Kwong Peter , Blanchard Scott , Sodroski Joseph , Mothes Walther
Published: April 2018

The HIV-1 envelope glycoprotein (Env) trimer mainly exists in a closed conformation (state 1), which is driven by CD4 binding through an intermediate conformation (state 2) to the open CD4-bound conformation (state 3). These functional Env states can be visualized by single-molecule Fluorescence Resonance Energy Transfer (smFRET). A breakthrough in the structural characterization of the HIV-1 Env trimer has been the generation of recombinant cleaved soluble gp140 SOSIP.664 trimers. Parallel cryoelectron microscopy studies have been performed with the mature HIV-1JR-FL Env in complex with the PGT151 neutralizing antibody. Both approaches resulted in similar structures. It is currently generally assumed that these structures represent the ground state of HIV-1 Env (state 1). Here we apply smFRET to probe the conformational state of HIV-1 Env in these constructs and antibody complexes. Fluorophores were introduced at the identical positions in the HIV-1 Env proteins used for structural studies and the native Env on the surface of virions, and the resulting smFRET values compared. Surprisingly, smFRET data reveal that both the soluble gp140 SOSIP.664 and PGT151-HIV-1JR-FL Env structures correspond to the state 2 gp120 conformation observed on the virus. Our data suggest that the all-important structure of state 1 of HIV-1 Env, which is the target of the majority of broadly neutralizing antibodies, remains unknown. Determining the structure of this additional conformation observed on native virions should allow the design of second generation immunogens that specifically present the state 1 conformation of HIV-1 Env.
P-D2 TRIM22 binds to CIITA and sequesters it into nuclear bodies containing TRIM19/PML and Cyclin T1: Implications for HIV-1 infection
Authors: Forlani Greta , Turrini Filippo , Poli Guido , Vicenzi Elisa , Accolla Roberto
Published: April 2018

Host restriction factors represent a defence mechanism of the innate immune system against viral pathogens, such as HIV-1. Many studies focused on the interplay between restriction factors and HIV-1 have greatly improved our knowledge about the biology of the virus and the response of the host, but to date there is no evidence on of a possible interaction between host restriction factors to counteract the virus. Here we show that TRIM22 and CIITA, 2 cellular proteins previously shown by us to inhibit HIV-1 proviral transcription with different mechanisms, interact in vivo and co-localize in nuclear bodies whose formation is hierarchically controlled by TRIM22. Importantly, TRIM19/Promyelocytic Leukemia (PML) protein, another repressor of HIV-1 transcription also acting before proviral integration, co-localized in these nuclear bodies upon TRIM22 expression induced by IFN-γ. Finally, TRIM22 nuclear bodies also contained CyclinTI, a crucial elongation factor of HIV-1 primary transcripts. These findings show that TRIM22 nuclear bodies are a site of recruitment of factors crucial for the regulation of HIV-1 transcription and highlight the potential existence of a concerted action between TRIM22, CIITA and TRIM19/PML to maintain a state of proviral latency at least in myeloid cells.
P-D4 HIV-1 Env trimer conformational implications of peptide fusion inhibitor resistance
Authors: Keller Paul , Morrison Orrianne , Vassell Russell , Weiss Carol
Published: April 2018

Viral entry of HIV-1 is mediated by the envelope glycoprotein (Env), which consists of gp120 and gp41 trimer subunits. Entry begins when gp120 binds the CD4 receptor on the host cell. This induces conformational changes that expose the binding site for the CCR5 or CXCR4 chemokine co-receptors. Subsequently, heptad repeat 1 (HR1) and heptad repeat 2 (HR2) of gp41 self-assemble to form a 6-helix bundle (6HB) that drives membrane fusion needed for viral entry. Previously, we identified HR1 peptide resistant Envs with key resistance mutations in HR1 or HR2 of gp41 that impact 6HB stability. These key gp41 resistance mutations defined 2 resistance pathways that were each associated with additional mutations in gp120 and gp41. Here, we further characterized the relative contribution of individual gp120 and gp41 mutations on Env conformational structure and sensitivity to CD4-induced conformational changes. Mutant Envs were assessed using a panel of conformation-dependent broadly neutralizing antibodies, temperature sensitivity studies, and soluble CD4-mediated entry into CD4-CCR5+ cells. Our data show that Envs from both resistance pathways have relaxed (more open) trimer conformations in their native state that is primarily mediated by individual mutations in gp120. Despite increased sensitivity to CD4 neutralization, gp41 mutations decrease conformational reactivity to CD4 binding by altering the transition of Envs from a fusion-competent to the inactive form. Our findings identify gp41 residues, particularly those in HR1, as important regulators of Env conformational transitions.