A practical solution to improve the field of view in circular scanning-based photoacoustic tomography.

One of the primary challenges in ring single-element photoacoustic tomography systems is the low image quality in areas away from the center of the ring. This is mainly due to the limited field of view (FOV) of each transducer, which in turn reduces the imaging FOV. To address this shortcoming, we have put forward a practical and straightforward solution to enhance the FOV of circular scanning-based photoacoustic tomography (CS-PAT). This is accomplished by placing transducers at different angles instead of using a single transducer placed at a normal angle to the imaging target. We also modified the ring scanner inner wall surface to significantly reduce photoacoustic reverberation. By imaging several phantoms, we show a significant improvement in the images generated by our system imaging from 4.1 to over 7 for the signal-to-noise ratio and structural similarity index increased from 41% to 70%.

Qualitative descriptive research on the level of use of the digital workplace by local health managers in France / Recherche descriptive qualitative sur le niveau d'utilisation de l'environnement numérique de travail chez le cadre de santé de proximité en France

As society faces up to the digital age, healthcare professionals must also adapt to this shift in line with the digital ambitions of the healthcare field.On reviewing the literature on the notions of use, practice, and adoption of digital technology, it is apparent that in France, compared to other countries, little data is available on the managerial practice of local health managers.The objective of this study was to measure the level of use and adoption of the digital workplace (DW) among these managers and to identify the factors influencing this use.This qualitative descriptive research was based on thirty semi-structured interviews conducted in France, in Normandy.The results, based on a categorical analysis, revealed a basic use of digital tools. Likewise, the level of adoption and mastery of these tools remained at a basic training level. The main factors that impact this phenomenon are technological, strategic, and related to the training and support policy in place. Managers do not operate in a DW. They are engaged in a process of instrumentation and instead operate within a computerized workplace. This level of use does not depend solely on an ontosystemic analysis of the manager in question. Emphasis should be given to ecosystemic reflections, centered on strategies for the rapid implementation of a contemporary digital culture.

Si la société est confrontée à l'ère numérique, les professionnels de santé doivent aussi s'adapter à cette mutation dans un contexte d'ambition numérique en santé. La revue de la littérature sur les notions d'utilisation, d'usage, de pratique et d'appropriation du numérique apporte, en France et en comparaison à d'autre pays, peu de données sur les cadres de santé de proximité concernant leur pratique managériale. L'objectif de cette recherche est de mesurer le niveau d'utilisation et d'appropriation de l'environnement numérique de travail chez ces cadres, et d'identifier les dimensions influençant cette utilisation. Cette recherche descriptive qualitative est basée sur 30 entretiens semi-dirigés réalisés en France, en Normandie. Les résultats, issus d'une analyse catégorielle, démontrent une utilisation du numérique basique et un niveau d'appropriation correspondant à une phase d'application. Les principales dimensions qui impactent ce phénomène sont technologiques, stratégiques et liées à la politique de formation et d'accompagnement. Le cadre ne travaille pas dans un environnement numérique de travail. Il se trouve dans un processus d'instrumentation et serait plus dans un usage de l'environnement informatique de travail. Ce niveau d'utilisation ne dépend pas uniquement d'une analyse ontosystémique du cadre. Une réflexion écosystémique serait à privilégier, centrée sur les stratégies du déploiement rapide d'une culture numérique contemporaine.

Isotopic Imaging Using fsLA Single-Collector ICP-SFMS for Direct U/Th Dating of Small Archaeological Carbonates.

We present a new methodology for the U/Th dating of carbonate materials using femtosecond laser ablation single-collector inductively coupled plasma sector field mass spectrometry (fsLA single-collector ICP-SFMS), isotopic mappings, and image processing. This approach allows working on samples at very low U levels (ng·g-1). One of the major advantages of this imaging method is that it allows us to exploit deteriorated samples that could not be analyzed by conventional bulk U/Th dating methods, thanks to the identification of contaminated or leached areas at the scale of a few tens of microns and the subsequent correction for detrital 230Th incorporation. Only a few milligrams of material are required for measurement, which allows us to work on small samples such as shell fragments. The parameters of the fsLA single-collector ICP-SFMS coupling have been carefully optimized to ensure very high sensitivity detection and ultralow background while preserving good plasma robustness and a spatial resolution of 30 × 50 µm2. The accuracy was evaluated from low-level U speleothems previously dated by a conventional U/Th dating technique involving digestion, resin purification, double spike, and detection by multicollector inductively coupled plasma mass spectrometry (MC-ICPMS). U/Th ages of two archaeological samples with U at low ng·g-1 levels, a giant terrestrial snail shell and a burned ostrich eggshell, were determined. The measured U/Th ages are consistent with the expected ages determined by luminescence dating methods.

Contrasting distribution of REE and yttrium among particulate, colloidal and dissolved fractions during low and high flows in peri-urban and agricultural river systems.

Understanding the possible consequences of anthropogenic activities on REY environmental fate and adverse effects on biota requires a detailed knowledge of their distribution between the particulate, colloidal and dissolved fractions. Such information is practically non-existent for peri-urban rivers having heavily populated basins and suffering from direct impacts from various human activities. The present study compared the distribution of REY among the particulate (>1000 nm), coarse colloidal (1000 nm - 220 nm), small colloidal (220 nm - 10 kDa) and dissolved (<10 kDa) water fractions in two peri-urban river basins having contrasted land uses (agricultural vs urban/industrial) under low and high flow conditions. Regardless of hydrological conditions, most of the REY were in the particulate fraction for both catchments. These results suggest erosion of soils as the main source of particulate REY in the two rivers, although a Nd anomaly of industrial origin occurred in the particulate and coarse colloidal fractions of the industrialized river basin. During low flow, the REY patterns of the dissolved fraction displayed marked Gd and Eu anomalies and a fractionation between Light REY and Heavy REY. Both characteristics reflect the influence of wastewater treatment plant effluents on the dissolved REY patterns in the two rivers. During high flow, the dissolved fraction acquired a less fractionated, more natural Light REY and Middle REY pattern, including much lower Gd and Eu positive anomalies. The REY fractionation of the coarse colloidal fraction was close to the particulate, while small colloids were depleted in Light REY and more similar to the dissolved fraction. These different patterns suggest a difference in the nature of REY bearing phases between the two colloidal fractions. The available results collectively show that a complete understanding of REY environmental fate and anomalies cannot be achieved from the sole study of filterable water fractions (typically <0.45 µm).

[The analysis of professional practices for the benefit of the "analytical knowledge"]. / L'analyse des pratiques professionnelles au bénéfice du "savoir analyser".

For more than ten years, the nursing repository has strongly emphasized the logic of an autonomous, responsible and reflexive professional. In this context, the analysis of professional practices is prescribed. It can provide added value, but requires differentiating certain aspects in order to be used effectively and to highlight the analytical knowledge of "its" practice.

[How digital technology is revolutionising apprenticeships]. / Comment le numérique révolutionne les apprentissages ?

Digital technology is now an integral part of health training, offering many possibilities to diversify teaching methods. The apprenticeship has changed in a few years. Its challenges, means and methods are evolving and adapting to objectives which remain the same: to train autonomous, reflective and adaptable caregivers to give excellent quality care.

Effect of natural organic matter on thallium and silver speciation.

Natural organic matter (NOM) is known to play an important role in the transport and binding of trace metal elements in aquatic and soil systems. Thallium is a pollutant for which the extent of the role played by NOM is poorly known. Consequently, this study investigates thallium(I) and its complexation to a purified humic substance as proxy for NOM. Experiments were performed with the Donnan Membrane Technique to separate, for the first time, the free Tl+ ion from its complexed form in the bulk solution. Various pH and concentrations were investigated at constant ionic strength and constant NOM proxy concentrations in solution. Experimental results were described with NICA-Donnan model. Thallium complexation was compared to silver complexation using literature data and using the same NICA-Donnan formalism. Parameters for these two cations (Tl+ and Ag+) are reported in this article, for the first time. Results display low thallium complexation to the NOM proxy while silver competes with divalent cations for the NOM binding sites. Calculated speciation for dissolved thallium highlights the dominance of free thallium (Tl+) in solution whereas Tl-NOM complexes contribute roughly 15% to total Tl(I) species in river and lake type waters. Similar results are obtained for soil solutions, Tl-bound to NOM < 30% of total, from UK soils with different land use and geochemistry.

Evolution of the Envelope Glycoprotein of HIV-1 Clade B toward Higher Infectious Properties over the Course of the Epidemic.

We showed previously that during the HIV/AIDS epidemic, the envelope glycoprotein (Env) of HIV-1, and in particular, the gp120 subunit, evolved toward an increased resistance to neutralizing antibodies at a population level. Here, we considered whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. We tested the infectivity of a panel of Env-pseudotyped viruses derived from patients infected by subtype B viruses at three periods of the epidemic (1987 to 1991, 1996 to 2000, and 2006 to 2010). Pseudotyped viruses harboring Env from patients infected during the most recent period were approximately 10-fold more infectious in cell culture than those from patients infected at the beginning of the epidemic. This was associated with faster viral entry kinetics: contemporary viruses entered target cells approximately twice as fast as historical viruses. Contemporary viruses were also twice as resistant as historical viruses to the fusion inhibitor enfuvirtide. Resistance to enfuvirtide correlated with a resistance to CCR5 antagonists, suggesting that contemporary viruses expanded their CCR5 usage efficiency. Viruses were equally captured by DC-SIGN, but after binding to DC-SIGN, contemporary viruses infected target cells more efficiently than historical viruses. Thus, we report evidence that the infectious properties of the envelope glycoprotein of HIV-1 increased during the course of the epidemic. It is plausible that these changes affected viral fitness during the transmission process and might have contributed to an increasing virulence of HIV-1.IMPORTANCE Following primary infection by HIV-1, neutralizing antibodies (NAbs) exert selective pressure on the HIV-1 envelope glycoprotein (Env), driving the evolution of the viral population. Previous studies suggested that, as a consequence, Env has evolved at the HIV species level since the start of the epidemic so as to display greater resistance to NAbs. Here, we investigated whether the antigenic evolution of the HIV-1 Env is associated with modifications of its functional properties, focusing on cell entry efficacy and interactions with the receptor and coreceptors. Our data provide evidence that the infectious properties of the HIV-1 Env increased during the course of the epidemic. These changes may have contributed to increasing virulence of HIV-1 and an optimization of transmission between individuals.

Interdomain Stabilization Impairs CD4 Binding and Improves Immunogenicity of the HIV-1 Envelope Trimer.

The HIV-1 envelope (Env) spike is a trimer of gp120/gp41 heterodimers that mediates viral entry. Binding to CD4 on the host cell membrane is the first essential step for infection but disrupts the native antigenic state of Env, posing a key obstacle to vaccine development. We locked the HIV-1 Env trimer in a pre-fusion configuration, resulting in impaired CD4 binding and enhanced binding to broadly neutralizing antibodies. This design was achieved via structure-guided introduction of neo-disulfide bonds bridging the gp120 inner and outer domains and was successfully applied to soluble trimers and native gp160 from different HIV-1 clades. Crystallization illustrated the structural basis for CD4-binding impairment. Immunization of rabbits with locked trimers from two different clades elicited neutralizing antibodies against tier-2 viruses with a repaired glycan shield regardless of treatment with a functional CD4 mimic. Thus, interdomain stabilization provides a widely applicable template for the design of Env-based HIV-1 vaccines.

Targeting the Late Stage of HIV-1 Entry for Antibody-Dependent Cellular Cytotoxicity: Structural Basis for Env Epitopes in the C11 Region.

Antibodies can have an impact on HIV-1 infection in multiple ways, including antibody-dependent cellular cytotoxicity (ADCC), a correlate of protection observed in the RV144 vaccine trial. One of the most potent ADCC-inducing epitopes on HIV-1 Env is recognized by the C11 antibody. Here, we present the crystal structure, at 2.9 Å resolution, of the C11-like antibody N12-i3, in a quaternary complex with the HIV-1 gp120, a CD4-mimicking peptide M48U1, and an A32-like antibody, N5-i5. Antibody N12-i3 recognizes an epitope centered on the N-terminal "eighth strand" of a critical ß sandwich, which our analysis indicates to be emblematic of a late-entry state, after the gp120 detachment. In prior entry states, this sandwich comprises only seven strands, with the eighth strand instead pairing with a portion of the gp120 C terminus. The conformational gymnastics of HIV-1 gp120 thus includes altered ß-strand pairing, possibly to reduce immunogenicity, although nevertheless still recognized by the human immune system.

Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site.

Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4+ T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell (P < 0.001) response kinetics and superior ADCC (P < 0.014) in a group receiving the CD4bs-occluded vaccine compared to those of animals immunized with gp140. Of the cytokines examined, Ag-specific interleukin-4 (IL-4) T-helper enzyme-linked immunosorbent spot (ELISpot) assays of the CD4bs-occluded group increased earlier (P = 0.025) during the inductive phase. Importantly, CD4bs-occluded gp140 antigen induced superior B-cell and ADCC responses, and the elevated B-cell responses proved to be remarkably durable, lasting more than 60 weeks postimmunization.IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.

[Mobile learning in nurse training institutes, infinite pedagogical possibilities]. / L'apprentissage mobile en Ifsi, d'infinies possibilités pédagogiques.

Riding on the digital wave, the Rouen nurse training institute is developing mobile learning. Students and trainers are finding benefits in terms of learning methods and pedagogical innovations.

Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques.

Evaluation of the epitope specificities, locations (systemic or mucosal), and effector functions of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an array of humoral assays, we evaluated the magnitudes, epitope specificities, avidities, and functions of systemic and mucosal immune responses elicited by a vaccine regimen containing Env cross-linked to a CD4-mimetic miniprotein (gp140-M64U1) in rhesus macaques. Cross-linking of gp140 Env to M64U1 resulted in earlier increases of both the magnitude and avidity of the IgG binding response than those with Env protein alone. Notably, IgG binding responses at an early time point correlated with antibody-dependent cellular cytotoxicity (ADCC) function at the peak immunity time point, which was higher for the cross-linked Env group than for the Env group. In addition, the cross-linked Env group developed higher IgG responses against a linear epitope in the gp120 C1 region of the HIV-1 envelope glycoprotein. These data demonstrate that structural modification of the HIV-1 envelope immunogen by cross-linking of gp140 with the CD4-mimetic M64U1 elicited an earlier increase of binding antibody responses and altered the specificity of the IgG responses, correlating with the rise of subsequent antibody-mediated antiviral functions.IMPORTANCE The development of an efficacious HIV-1 vaccine remains a global priority to prevent new cases of HIV-1 infection. Of the six HIV-1 efficacy trials to date, only one has demonstrated partial efficacy, and immune correlate analysis of that trial revealed a role for binding antibodies and antibody Fc-mediated effector functions. New HIV-1 envelope immunogens are being engineered to selectively expose the most vulnerable and conserved sites on the HIV-1 envelope, with the goal of eliciting antiviral antibodies. Evaluation of the humoral responses elicited by these novel immunogen designs in nonhuman primates is critical for understanding how to improve upon immunogen design to inform further testing in human clinical trials. Our results demonstrate that structural modifications of Env that aim to mimic the CD4-bound conformation can result in earlier antibody elicitation, altered epitope specificity, and increased antiviral function postimmunization.

M48U1 and Tenofovir combination synergistically inhibits HIV infection in activated PBMCs and human cervicovaginal histocultures.

Microbicides are considered a promising strategy for preventing human immunodeficiency virus (HIV-1) transmission and disease. In this report, we first analyzed the antiviral activity of the miniCD4 M48U1 peptide formulated in hydroxyethylcellulose (HEC) hydrogel in activated peripheral blood mononuclear cells (PBMCs) infected with R5- and X4-tropic HIV-1 strains. The results demonstrate that M48U1 prevented infection by several HIV-1 strains including laboratory strains, and HIV-1 subtype B and C strains isolated from the activated PBMCs of patients. M48U1 also inhibited infection by two HIV-1 transmitted/founder infectious molecular clones (pREJO.c/2864 and pTHRO.c/2626). In addition, M48U1 was administered in association with tenofovir, and these two antiretroviral drugs synergistically inhibited HIV-1 infection. In the next series of experiments, we tested M48U1 alone or in combination with tenofovir in HEC hydrogel with an organ-like structure mimicking human cervicovaginal tissue. We demonstrated a strong antiviral effect in absence of significant tissue toxicity. Together, these results indicate that co-treatment with M48U1 plus tenofovir is an effective antiviral strategy that may be used as a new topical microbicide to prevent HIV-1 transmission.

Across the Gap: Geochronological and Sedimentological Analyses from the Late Pleistocene-Holocene Sequence of Goda Buticha, Southeastern Ethiopia.

Goda Buticha is a cave site near Dire Dawa in southeastern Ethiopia that contains an archaeological sequence sampling the late Pleistocene and Holocene of the region. The sedimentary sequence displays complex cultural, chronological and sedimentological histories that seem incongruent with one another. A first set of radiocarbon ages suggested a long sedimentological gap from the end of Marine Isotopic Stage (MIS) 3 to the mid-Holocene. Macroscopic observations suggest that the main sedimentological change does not coincide with the chronostratigraphic hiatus. The cultural sequence shows technological continuity with a late persistence of artifacts that are usually attributed to the Middle Stone Age into the younger parts of the stratigraphic sequence, yet become increasingly associated with lithic artifacts typically related to the Later Stone Age. While not a unique case, this combination of features is unusual in the Horn of Africa. In order to evaluate the possible implications of these observations, sedimentological analyses combined with optically stimulated luminescence (OSL) were conducted. The OSL data now extend the radiocarbon chronology up to 63 ± 7 ka; they also confirm the existence of the chronological gap between 24.8 ± 2.6 ka and 7.5 ± 0.3 ka. The sedimentological analyses suggest that the origin and mode of deposition were largely similar throughout the whole sequence, although the anthropic and faunal activities increased in the younger levels. Regional climatic records are used to support the sedimentological observations and interpretations. We discuss the implications of the sedimentological and dating analyses for understanding cultural processes in the region.

Co-receptor Binding Site Antibodies Enable CD4-Mimetics to Expose Conserved Anti-cluster A ADCC Epitopes on HIV-1 Envelope Glycoproteins.

Human immunodeficiency virus type 1 (HIV-1) has evolved a sophisticated strategy to conceal conserved epitopes of its envelope glycoproteins (Env) recognized by antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. These antibodies, which are present in the sera of most HIV-1-infected individuals, preferentially recognize Env in its CD4-bound conformation. Accordingly, recent studies showed that small CD4-mimetics (CD4mc) able to "push" Env into this conformation sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. Here we test whether CD4mc also expose epitopes recognized by anti-cluster A monoclonal antibodies such as A32, thought to be responsible for the majority of ADCC activity present in HIV+ sera and linked to decreased HIV-1 transmission in the RV144 trial. We made the surprising observation that CD4mc are unable to enhance recognition of HIV-1-infected cells by this family of antibodies in the absence of antibodies such as 17b, which binds a highly conserved CD4-induced epitope overlapping the co-receptor binding site (CoRBS). Our results indicate that CD4mc initially open the trimeric Env enough to allow the binding of CoRBS antibodies but not anti-cluster A antibodies. CoRBS antibody binding further opens the trimeric Env, allowing anti-cluster A antibody interaction and sensitization of infected cells to ADCC. Therefore, ADCC responses mediated by cluster A antibodies in HIV-positive sera involve a sequential opening of the Env trimer on the surface of HIV-1-infected cells. The understanding of the conformational changes required to expose these vulnerable Env epitopes might be important in the design of new strategies aimed at fighting HIV-1.

Cocrystal Structures of Antibody N60-i3 and Antibody JR4 in Complex with gp120 Define More Cluster A Epitopes Involved in Effective Antibody-Dependent Effector Function against HIV-1.

UNLABELLED: Accumulating evidence indicates a role for Fc receptor (FcR)-mediated effector functions of antibodies, including antibody-dependent cell-mediated cytotoxicity (ADCC), in prevention of human immunodeficiency virus type 1 (HIV-1) acquisition and in postinfection control of viremia. Consequently, an understanding of the molecular basis for Env epitopes that constitute effective ADCC targets is of fundamental interest for humoral anti-HIV-1 immunity and for HIV-1 vaccine design. A substantial portion of FcR effector function of potentially protective anti-HIV-1 antibodies is directed toward nonneutralizing, transitional, CD4-inducible (CD4i) epitopes associated with the gp41-reactive region of gp120 (cluster A epitopes). Our previous studies defined the A32-like epitope within the cluster A region and mapped it to the highly conserved and mobile layers 1 and 2 of the gp120 inner domain within the C1-C2 regions of gp120. Here, we elucidate additional cluster A epitope structures, including an A32-like epitope, recognized by human monoclonal antibody (MAb) N60-i3, and a hybrid A32-C11-like epitope, recognized by rhesus macaque MAb JR4. These studies define for the first time a hybrid A32-C11-like epitope and map it to elements of both the A32-like subregion and the seven-layered ß-sheet of the gp41-interactive region of gp120. These studies provide additional evidence that effective antibody-dependent effector function in the cluster A region depends on precise epitope targeting--a combination of epitope footprint and mode of antibody attachment. All together these findings help further an understanding of how cluster A epitopes are targeted by humoral responses. IMPORTANCE: HIV/AIDS has claimed the lives of over 30 million people. Although antiretroviral drugs can control viral replication, no vaccine has yet been developed to prevent the spread of the disease. Studies of natural HIV-1 infection, simian immunodeficiency virus (SIV)- or simian-human immunodeficiency virus (SHIV)-infected nonhuman primates (NHPs), and HIV-1-infected humanized mouse models, passive transfer studies in infants born to HIV-infected mothers, and the RV144 clinical trial have linked FcR-mediated effector functions of anti-HIV-1 antibodies with postinfection control of viremia and/or blocking viral acquisition. With this report we provide additional definition of the molecular determinants for Env antigen engagement which lead to effective antibody-dependent effector function directed to the nonneutralizing CD4-dependent epitopes in the gp41-reactive region of gp120. These findings have important implications for the development of an effective HIV-1 vaccine.

CD4 mimetics sensitize HIV-1-infected cells to ADCC.

HIV-1-infected cells presenting envelope glycoproteins (Env) in the CD4-bound conformation on their surface are preferentially targeted by antibody-dependent cell-mediated cytotoxicity (ADCC). HIV-1 has evolved a sophisticated mechanism to avoid exposure of ADCC-mediating Env epitopes by down-regulating CD4 and by limiting the overall amount of Env at the cell surface. Here we report that small-molecule CD4-mimetic compounds induce the CD4-bound conformation of Env, and thereby sensitize cells infected with primary HIV-1 isolates to ADCC mediated by antibodies present in sera, cervicovaginal lavages, and breast milk from HIV-1-infected individuals. Importantly, we identified one CD4 mimetic with the capacity to sensitize endogenously infected ex vivo-amplified primary CD4 T cells to ADCC killing mediated by autologous sera and effector cells. Thus, CD4 mimetics hold the promise of therapeutic utility in preventing and controlling HIV-1 infection.

Analysis of experimental depolarizing Mueller matrices through a hybrid decomposition.

We propose a new decomposition for depolarizing Mueller matrices. This decomposition, which consists of a product of four basic optical devices (two diattenuators, a retarder, and a depolarizer) is derived from a previous one known as "symmetric decomposition" [J. Opt. Soc. Am. A26, 1109 (2009)10.1364/JOSAA.26.001109JOAOD61084-7529] and makes it easier to interpret polarization properties of Mueller matrices and improves estimation of the extracted parameters. Its application is illustrated by several theoretical and experimental examples.

Neutralization properties of simian immunodeficiency viruses infecting chimpanzees and gorillas.

UNLABELLED: Broadly cross-reactive neutralizing antibodies (bNabs) represent powerful tools to combat human immunodeficiency virus type 1 (HIV-1) infection. Here, we examined whether HIV-1-specific bNabs are capable of cross-neutralizing distantly related simian immunodeficiency viruses (SIVs) infecting central (Pan troglodytes troglodytes) (SIVcpzPtt) and eastern (Pan troglodytes schweinfurthii) (SIVcpzPts) chimpanzees (n = 11) as well as western gorillas (Gorilla gorilla gorilla) (SIVgor) (n = 1). We found that bNabs directed against the CD4 binding site (n = 10), peptidoglycans at the base of variable loop 3 (V3) (n = 5), and epitopes at the interface of surface (gp120) and membrane-bound (gp41) envelope glycoproteins (n = 5) failed to neutralize SIVcpz and SIVgor strains. In addition, apex V2-directed bNabs (n = 3) as well as llama-derived (heavy chain only) antibodies (n = 6) recognizing both the CD4 binding site and gp41 epitopes were either completely inactive or neutralized only a fraction of SIVcpzPtt strains. In contrast, one antibody targeting the membrane-proximal external region (MPER) of gp41 (10E8), functional CD4 and CCR5 receptor mimetics (eCD4-Ig, eCD4-Ig(mim2), CD4-218.3-E51, and CD4-218.3-E51-mim2), as well as mono- and bispecific anti-human CD4 (iMab and LM52) and CCR5 (PRO140, PRO140-10E8) receptor antibodies neutralized >90% of SIVcpz and SIVgor strains with low-nanomolar (0.13 to 8.4 nM) potency. Importantly, the latter antibodies blocked virus entry not only in TZM-bl cells but also in Cf2Th cells expressing chimpanzee CD4 and CCR5 and neutralized SIVcpz in chimpanzee CD4(+) T cells, with 50% inhibitory concentrations (IC50s) ranging from 3.6 to 40.5 nM. These findings provide new insight into the protective capacity of anti-HIV-1 bNabs and identify candidates for further development to combat SIVcpz infection. IMPORTANCE: SIVcpz is widespread in wild-living chimpanzees and can cause AIDS-like immunopathology and clinical disease. HIV-1 infection of humans can be controlled by antiretroviral therapy; however, treatment of wild-living African apes with current drug regimens is not feasible. Nonetheless, it may be possible to curb the spread of SIVcpz in select ape communities using vectored immunoprophylaxis and/or therapy. Here, we show that antibodies and antibody-like inhibitors developed to combat HIV-1 infection in humans are capable of neutralizing genetically diverse SIVcpz and SIVgor strains with considerable breadth and potency, including in primary chimpanzee CD4(+) T cells. These reagents provide an important first step toward translating intervention strategies currently developed to treat and prevent AIDS in humans to SIV-infected apes.