Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1-Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study

Background.  Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART. Methods.  Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%. Results.  Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), higher education (OR, 4.03; 95% CI, 2.47-7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20-2.80). Older age (OR, 0.55; 95% CI, .42-.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13-.47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998-2001 to 41.2% in 2009-2012, but the employment rates did not increase. Conclusions.  Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV.

Design, synthesis and cellular and molecular pharmacology of 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401): A novel non-cross-resistant anthracycline antibiotic with the intrinsic ability to circumvent P -glycoprotein-mediated drug resistance

We designed and synthesized a novel daunorubicin (DNR) analogue that effectively circumvents P-glycoprotein (P-gp)-mediated drug resistance. The fully protected carbohydrate intermediate 1,2-dibromoacosamine was prepared from acosamine and effectively coupled to daunomycinone in high yield. Deprotection under alkaline conditions yielded 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401). The in vitro cytotoxicity and cellular and molecular pharmacology of WP401 were compared with those of DNR in a panel of wild-type cell lines (KB-3-1, P388S, and HL60S) and their multidrug-resistant (MDR) counterparts (KB-V1, P388/DOX, and HL60/DOX). Fluorescent spectrophotometry, flow cytometry, and confocal laser scanning microscopy were used to measure intracellular accumulation, retention, and subcellular distribution of these agents. All MDR cell lines exhibited reduced DNR uptake that was restored, upon incubation with either verapamil (VER) or cyclosporin A (CSA), to the level found in sensitive cell lines. In contrast, the uptake of WP401 was essentially the same in the absence or presence of VER or CSA in all tested cell lines. The in vitro cytotoxicity of WP401 was similar to that of DNR in the sensitive cell lines but significantly higher in resistant cell lines (resistance index (RI) of 2-6 for WP401 vs 75-85 for DNR). To ascertain whether drug-mediated cytotoxicity and retention were accompanied by DNA strand breaks, DNA single- and double-strand breaks were assessed by alkaline elution. High levels of such breaks were obtained using 0.1-2 $\mu$g/mL of WP401 in both sensitive and resistant cells. In contrast, DNR caused strand breaks only in sensitive cells and not much in resistant cells. We also compared drug-induced DNA fragmentation similar to that induced by DNR. However, in P-gp-positive cells, WP401 induced 2- to 5-fold more DNA fragmentation than DNR. This increased DNA strand breakage by WP401 was correlated with its increased uptake and cytotoxicity in these cell lines. Overall these results indicate that WP401 is more cytotoxic than DNR in MDR cells and that this phenomenon might be related to the reduced basicity of the amino group and increased lipophilicity of WP401. ^

Assessment of the effects of ozone exposure and plant competition on the reproductive ability of three therophytic clover species from Iberian pastures

Ozone (O3) phytototoxicity has been reported on a wide range of crops and wild Central European plantspecies, however no information has been provided regarding the sensitivity of plantspecies from dehesa Mediterranean therophytic grasslands in spite of their great plantspecies richness and the high O3 levels that are recorded in this area. A study was carried out in open-top chambers (OTCs) to assess the effects of O3 and competition on the reproductiveability of threecloverspecies: Trifolium cherleri, Trifolium subterraneum and Trifolium striatum. A phytometer approach was followed, therefore plants of these species were grown in mesoscosms composed of monocultures of four plants of each species, of threeplants of each species competing against a Briza maxima individual or of a single plant of each cloverspecies competing with threeB. maximaplants. Three O3 treatments were adopted: charcoal filtered air (CFA), non-filtered air (NFA) and non-filtered air supplemented with 40 nl l−1 of O3 (NFA+). The different mesocosms were exposed to the different O3 treatments for 45 days and then they remained in the open. Ozoneexposure caused reductions in the flower biomass of the threecloverspecies assessed. In the case of T. cherleri and T. subterraneum this effect was found following their exposure to the different O3 treatments during their vegetative period. An attenuation of these effects was found when the plants remained in the open. Ozone-induced detrimental effects on the seed output of T. striatum were also observed. The flower biomass of the cloverplants grown in monocultures was greater than when competing with one or threeB. maxima individuals. An increased flower biomass was found in the CFA monoculture mesocosms of T. cherleri when compared with the remaining mesocosms, once the plants were exposed in the open for 60 days. The implications of these effects on the performance of dehesa acid grasslands and for the definition of O3 critical levels is discussed

Fenología y capacidad de dispersión de Monochamus galloprovincialis (Olivier 1795) en la Península Ibérica = Phenology and dispersal ability of Monochamus galloprovincialis (Olivier 1795) at Iberian Peninsula

La aparición y avance de la enfermedad del marchitamiento del pino (Pine Wilt Desease, PWD), causada por Bursaphelenchus xylophilus (Nematoda; Aphelenchoididae), el nematodo de la madera del pino (NMP), en el suroeste de Europa, ha puesto de manifiesto la necesidad de estudiar la fenología y la dispersión de su único vector conocido en Europa, Monochamus galloprovincialis (Col., Cerambycidae). El análisis de 12 series de emergencias entre 2010 y 2014, registradas en Palencia, València y Teruel, con material procedente de diversos puntos de la península ibérica, demostró una alta variabilidad en la fenología de M. galloprovincialis y la divergencia térmica respecto de las poblaciones portuguesas. Para éstas, el establecimiento de los umbrales térmicos de desarrollo de las larvas post-dormantes del vector (12,2 y 33,5ºC) permitió la predicción de la emergencia mediana para la fecha en la que se acumulaban de 822 grados-día. Ninguna de las series analizadas en este trabajo necesitó de dichos grados-día estimados para la emergencia mediana. Asimismo, la emergencia se adelantó en las regiones más calurosas, mientras que se retrasó en las zonas más templadas. Más allá de la posible variabilidad entre poblaciones locales peninsulares, se detectaron indicios de que la diferencia en la acumulación de calor durante el otoño puede afectar el grado de maduración de las larvas invernantes, y su posterior patrón temporal de emergencia. Por último, también fueron observados comportamientos de protandria en las emergencias. Respecto a la fenología de su vuelo, entre los años 2010 y 2015, fueron ejecutados un total de 8 experimentos de captura de M. galloprovincialis mediante trampas cebadas con atrayentes en diferentes regiones (Castellón, Teruel, Segovia y Alicante) permitiendo el seguimiento del periodo de vuelo. Su análisis permitió constatar la disminución de las capturas y el acortamiento del periodo de vuelo con la altitud, el inicio del vuelo en el mes de mayo/junio a partir de los 14ºC de temperatura media diaria, la influencia de las altas temperaturas en la disminución de las capturas estivales (potencial causante de perfiles bimodales en las curvas de vuelo en las zonas menos frías), la evolución de la proporción de sexos a lo largo del periodo de vuelo (que muestra una mayor captura de hembras al inicio y de machos al final) y el comportamiento diurno y ligado a las altas temperaturas del vuelo circadiano del insecto. Dos redes de muestreo sistemático de insectos saproxílicos instaladas en la Comunitat Valencia (Red MUFFET, 15 parcelas, año 2013) y en Murcia (Red ESFP, 20 parcelas, años 2008-2010) permitieron el estudio de la comunidad de insectos relacionada con M. galloprovincialis. Cada una de las parcelas contaba con una trampa cebada con atrayentes y una estación meteorológica. El registro de más de 250 especies de coleópteros saproxílicos demostró el potencial que tiene el empleo de redes de trampas vigía para la detección temprana de organismos exóticos, además de permitir la caracterización y evaluación de las comunidades de entomofauna útil, representando una de las mejores herramientas de la gestión integrada de plagas. En este caso, la comunidad de saproxílicos estudiada mostró ser muy homogénea respecto a la variación ambiental de las zonas de muestreo, y que pese a las pequeñas variaciones entre las comunidades de los diferentes ecosistemas, el rol que M. galloprovincialis desempeña en ellas a lo largo de todo el gradiente estudiado es el mismo. Con todo, el análisis mediante redes de interacción mostró su relevancia ecológica al actuar de conector entre los diferentes niveles tróficos. Por último, un total de 12 experimentos de marcaje-liberación-recaptura desarrollados entre 2009 y 2012 en Castellón, Teruel, Valencia y Murcia permitieron evaluar el comportamiento dispersivo de M. galloprovincialis. Las detecciones mediante trampas cebadas de los insectos liberados se dieron por lo menos 8 días después de la emergencia. La abundancia de población pareció relacionada con la continuidad, la naturalización de la masa, y con la afección previa de incendios. La dispersión no estuvo influida por la dirección ni la intensidad de los vientos dominantes. La abundancia de material hospedante (en lo referente a las variables de masa y a los índices de competencia) influyó en la captura del insecto en paisajes fragmentados, aunque la ubicación de las trampas optimizó el número de capturas cuando se ubicaron en el límite de la masa y en zonas visibles. Por último también se constató que M. galloprovincialis posee suficiente capacidad de dispersión como para recorrer hasta 1500 m/día, llegando a alcanzar distancias máximas de 13600m o de 22100 m. ABSTRACT The detection and expansion of the Pine Wilt Desease (PWD), caused by Bursaphelenchus xylophilus (Nematoda; Aphelenchoididae), Pine Wood Nematode (PWN), in southwestern Europe since 1999, has triggered off the study of the phenology and the dispersion of its unique vector in the continent, Monochamus galloprovincialis (Coleoptera, Cerambycidae). The analysis of 12 emergence series between 2010 and 2014 registered in Palencia, Teruel and Valencia (Spain), registered from field colonized material collected at several locations of the Iberian Peninsula, showed a high variability in the emergence phenology of M. galloprovincialis. In addition, these patterns showed a very acute thermal divergence regarding a development model fitted earlier in Portugal. Such model forecasted the emergence of 50% of M. galloprovincialis individuals in the Setúbal Peninsula (Portugal) when an average of 822 degree-days (DD) were reached, based on the accumulation of heat from the 1st of March until emergence and lower and upper thresholds of 12.2 ºC and 33,5 °C respectively. In our results, all analyzed series needed less than 822 DD to complete the 50% of the emergence. Also, emergency occurred earlier in the hottest regions, while it was delayed in more temperate areas. Beyond the possible variability between local populations, the difference in the heat accumulation during the fall season may have affected the degree of maturation of overwintering larvae, and subsequently, the temporal pattern of M. galloprovincialis emergences. Therefore these results suggest the need to differentiate local management strategies for the PWN vector, depending on the location, and the climatic variables of each region. Finally, protandrous emergence patterns were observed for M. galloprovincialis in most of the studied data-sets. Regarding the flight phenology of M. galloprovincialis, a total of 8 trapping experiments were carried out in different regions of the Iberian Peninsula (Castellón, Teruel, Segovia and Alicante) between 2010 and 2015. The use of commercial lures and traps allowed monitoring of the flight period of M. galloprovincialis. The analyses of such curves, helped confirming different aspects. First, a decline in the number of catches and a shortening of the flight period was observed as the altitude increased. Flight period was recorded to start in May / June when the daily average temperature went over 14 ° C. A significant influence of high temperatures on the decrease of catches in the summer was found in many occasions, which frequently lead to a bimodal profile of the flight curves in warm areas. The evolution of sex ratio along the flight period shows a greater capture of females at the beginning of the period, and of males at the end. In addition, the circadian response of M. galloprovincialis to lured traps was described for the first time, concluding that the insect is diurnal and that such response is linked to high temperatures. Two networks of systematic sampling of saproxylic insects were installed in the Region of Valencia (Red MUFFET, 15 plots, 2013) and Murcia (Red ICPF, 20 plots, 2008-2010). These networks, intended to serve the double purpose of early-detection and long term monitoring of the saproxylic beetle assemblies, allowed the study of insect communities related to M. galloprovincialis. Each of the plots had a trap baited with attractants and a weather station. The registration of almost 300 species of saproxylic beetles demonstrated the potential use of such trapping networks for the early detection of exotic organisms, while at the same time allows the characterization and evaluation of useful entomological fauna communities, representing one of the best tools for the integrated pest management. In this particular case, the studied community of saproxylic beetles was very homogeneous with respect to environmental variation of the sampling areas, and despite small variations between communities of different ecosystems, the role that M. galloprovincialis apparently plays in them across the studied gradient seems to be the same. However, the analysis through food-webs showed the ecological significance of M. galloprovincialis as a connector between different trophic levels. Finally, 12 mark-release-recapture experiments were carried out between 2009 and 2012 in Castellón, Teruel, Valencia and Murcia (Spain) with the aim to describe the dispersive behavior of M. galloprovincialis as well as the stand and landscape characteristics that could influence its abundance and dispersal. No insects younger than 8 days were caught in lured traps. Population abundance estimates from mark-release-recapture data, seemed related to forest continuity, naturalization, and to prior presence of forest fires. On the other hand, M. galloprovincialis dispersal was not found to be significantly influenced by the direction and intensity of prevailing winds. The abundance of host material, very related to stand characteristics and spacing indexes, influenced the insect abundance in fragmented landscapes. In addition, the location of the traps optimized the number of catches when they were placed in the edge of the forest stands and in visible positions. Finally it was also found that M. galloprovincialis is able to fly up to 1500 m / day, reaching maximum distances of up to 13600 m or 22100 m.

Co-aggregation ability of cell Wall components of Saccharomyces cerevisiae to pathogenic bacteria

Autoaggregation in bacteria is the phenomenon of aggregation between cells of the same strain, whereas coaggregation is due to aggregation occurring among different species. Aggregation ability of prebiotic bacteria is related to adhesion ability, which is a prerequisite for the colonization and protection of the gastrointestinal tract in all animal species; however, coaggregation ability of prebiotic bacteria offers a possibility of close interaction with pathogenic bacteria.

Attempted hydrogen–deuterium exchange of the protio-trimethyloxonium dication (CH3)3OH2+, study of methylating ability of (CH3)3O+ in superacids and theoretical investigations

Attempted hydrogen–deuterium exchange of trimethyloxonium ion, (CH3)3O+ with excess of 1:1 2HF/SbF5 superacid at −30°C over a period of 30 days showed no exchange. Theoretical calculations at the MP2/6–31G** level are in accord with the lack of hydrogen–deuterium exchange in the methyl group of the (CH3)3O+ cation as protonation (protosolvation) prefers the oxygen lone pair of electrons, instead of a C—H bond. Methylation of aromatics with the (CH3)3O+CF3SO3− in CF3SO3H and 2CF3SO3H:B(O3SCF3)3 was also studied. Whereas in triflic acid no alkylation was observed, in triflatoboric acid, a powerful superacid, alkylation takes place, indicating protolytic activation of the trimethyloxonium ion.

The ability of HIV type 1 to use CCR-3 as a coreceptor is controlled by envelope V1/V2 sequences acting in conjunction with a CCR-5 tropic V3 loop

Although infection by primary HIV type 1 (HIV-1) isolates normally requires the functional interaction of the viral envelope protein with both CD4 and the CCR-5 coreceptor, a subset of such isolates also are able to use the distinct CCR-3 receptor. By analyzing the ability of a series of wild-type and chimeric HIV-1 envelope proteins to mediate CCR-3-dependent infection, we have determined that CCR-3 tropism maps to the V1 and V2 variable region of envelope. Although substitution of the V1/V2 region of a CCR-3 tropic envelope into the context of a CCR-5 tropic envelope is both necessary and sufficient to confer CCR-3 tropism, this same substitution has no phenotypic effect when inserted into a CXCR-4 tropic HIV-1 envelope context. However, this latter chimera acquires both CCR-3 and CCR-5 tropism when a CCR-5 tropic V3 loop sequence also is introduced. These data demonstrate that the V1/2 region of envelope can, like the V3 loop region, encode a particular coreceptor requirement and suggest that a functional envelope:CCR-3 interaction may depend on the cooperative interaction of CCR-3 with both the V1/V2 and the V3 region of envelope.

A thymidine triphosphate shape analog lacking Watson–Crick pairing ability is replicated with high sequence selectivity

Compound 1 (F), a nonpolar nucleoside analog that is isosteric with thymidine, has been proposed as a probe for the importance of hydrogen bonds in biological systems. Consistent with its lack of strong H-bond donors or acceptors, F is shown here by thermal denaturation studies to pair very poorly and with no significant selectivity among natural bases in DNA oligonucleotides. We report the synthesis of the 5′-triphosphate derivative of 1 and the study of its ability to be inserted into replicating DNA strands by the Klenow fragment (KF, exo− mutant) of Escherichia coli DNA polymerase I. We find that this nucleotide derivative (dFTP) is a surprisingly good substrate for KF; steady-state measurements indicate it is inserted into a template opposite adenine with efficiency (Vmax/Km) only 40-fold lower than dTTP. Moreover, it is inserted opposite A (relative to C, G, or T) with selectivity nearly as high as that observed for dTTP. Elongation of the strand past F in an F–A pair is associated with a brief pause, whereas that beyond A in the inverted A–F pair is not. Combined with data from studies with F in the template strand, the results show that KF can efficiently replicate a base pair (A–F/F–A) that is inherently very unstable, and the replication occurs with very high fidelity despite a lack of inherent base-pairing selectivity. The results suggest that hydrogen bonds may be less important in the fidelity of replication than commonly believed and that nucleotide/template shape complementarity may play a more important role than previously believed.

Evolution of the folding ability of proteins through functional selection

An evolutionary process is simulated with a simple spin-glass-like model of proteins to examine the origin of folding ability. At each generation, sequences are randomly mutated and subjected to a simulation of the folding process based on the model. According to the frequency of local configurations at the active sites, sequences are selected and passed to the next generation. After a few hundred generations, a sequence capable of folding globally into a native conformation emerges. Moreover, the selected sequence has a distinct energy minimum and an anisotropic funnel on the energy surface, which are the imperative features for fast folding of proteins. The proposed model reveals that the functional selection on the local configurations leads a sequence to fold globally into a conformation at a faster rate.

CM101-mediated recovery of walking ability in adult mice paralyzed by spinal cord injury

CM101, an antiangiogenic polysaccharide derived from group B streptococcus, was administered by i.v. injection 1 hr post-spinal-cord crush injury in an effort to prevent inflammatory angiogenesis and gliosis (scarring) in a mouse model. We postulated that gliosis would sterically prevent the reestablishment of neuronal connectivity; thus, treatment with CM101 was repeated every other day for five more infusions for the purpose of facilitating regeneration of neuronal function. Twenty-five of 26 mice treated with CM101 survived 28 days after surgery, and 24 of 26 recovered walking ability within 2–12 days. Only 6 of 14 mice in the control groups survived 24 hr after spinal cord injury, and none recovered function in paralyzed limbs. MRI analysis of injured untreated and treated animals showed that CM101 reduced the area of damage at the site of spinal cord compression, which was corroborated by histological analysis of spinal cord sections from treated and control animals. Electrophysiologic measurements on isolated central nervous system and neurons in culture showed that CM101 protected axons from Wallerian degeneration; reversed γ-aminobutyrate-mediated depolarization occurring in traumatized neurons; and improved recovery of neuronal conductivity of isolated central nervous system in culture.

Homodimerization of tumor-reactive monoclonal antibodies markedly increases their ability to induce growth arrest or apoptosis of tumor cells

Monoclonal antibodies (mAbs) that exert antitumor activity can do so by virtue of their effector function and/or their ability to signal growth arrest or cell death. In this study, we demonstrate that mAbs which have little or no signaling activity—i.e., anti-CD19, CD20, CD21, CD22 and Her-2—can become potent antitumor agents when they are converted into IgG–IgG homodimers. The homodimers exert antigrowth activity by signaling G0/G1 arrest or apoptosis, depending upon which cell surface molecule they bind. This activity is specific and, in the case of the anti-CD19 mAb, did not require an Fc portion. These results offer the possibility that homodimers of other tumor-reactive mAbs which have little antitumor activity as monomers might be potent, antitumor agents.

Mutations at Phosphorylation Sites of Xenopus Microtubule-associated Protein 4 Affect Its Microtubule-binding Ability and Chromosome Movement during Mitosis

Microtubule-associated proteins (MAPs) bind to and stabilize microtubules (MTs) both in vitro and in vivo and are thought to regulate MT dynamics during the cell cycle. It is known that p220, a major MAP of Xenopus, is phosphorylated by p34cdc2 kinase as well as MAP kinase in mitotic cells, and that the phosphorylated p220 loses its MT-binding and -stabilizing abilities in vitro. We cloned a full-length cDNA encoding p220, which identified p220 as a Xenopus homologue of MAP4 (XMAP4). To examine the physiological relevance of XMAP4 phosphorylation in vivo, Xenopus A6 cells were transfected with cDNAs encoding wild-type or various XMAP4 mutants fused with a green fluorescent protein. Mutations of serine and threonine residues at p34cdc2 kinase-specific phosphorylation sites to alanine interfered with mitosis-associated reduction in MT affinity of XMAP4, and their overexpression affected chromosome movement during anaphase A. These findings indicated that phosphorylation of XMAP4 (probably by p34cdc2 kinase) is responsible for the decrease in its MT-binding and -stabilizing abilities during mitosis, which are important for chromosome movement during anaphase A.

Direct interaction of flagellin termini essential for polymorphic ability of flagellar filament

We report the structures of flagellar filaments reconstituted from various flagellins with small terminal truncations. Flagellins from Salmonella typhimurium strains SJW1103 (wild type), SJW1660, and SJW1655 were used, which form a left-handed supercoil, the L- and R-type straight forms, respectively. Structure analyses were done by electron cryomicroscopy and helical image reconstruction with a help of x-ray fiber diffraction for determining precise helical symmetries. Truncation of either terminal region, irrespective of the original flagellin species, results in a straight filament having a helical symmetry distinct either from the L- or R-type. This filament structure is named Lt-type. Although the local subunit packing is similar in all three types, a close comparison shows that the Lt-type packing is almost identical to the R-type but distinct from the L-type, which demonstrates the strong two-state preference of the subunit interactions. The structure clearly suggests that both termini are located in the inner tube of the concentric double-tubular structure of the filament core, and their proper interaction is responsible for the correct folding of fairly large terminal regions that form the inner tube. The double tubular structure appears to be essential for the polymorphic ability of flagellar filaments, which is required for the swimming–tumbling of bacterial taxis.