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The rebound-competent viral reservoir (RCVR), comprised of virus that is able to persist during antiretroviral therapy (ART) and mediate reactivation of systemic viral replication and rebound viremia after antiretroviral therapy interruption (ATI), remains the biggest obstacle to the eradication of HIV infection. A better understanding of the cellular and tissue origins and the dynamics of viral populations that initiate rebound upon ATI could help develop targeted therapeutic strategies for reducing the RCVR. In this study, barcoded SIVmac239M was used to infect rhesus macaques to enable monitoring of viral barcode clonotypes contributing to virus detectable in plasma after ATI. Blood, lymphoid tissues (LTs, spleen, mesenteric and inguinal lymph nodes), and non-lymphoid tissues (NLTs, colon, ileum, lung, liver, and brain) were analyzed using viral barcode sequencing, intact proviral DNA assay, single-cell RNA sequencing, and combined CODEX/RNAscope/ in situ hybridization. Four of seven animals had viral barcodes detectable by deep sequencing of plasma at necropsy although plasma viral RNA remained < 22 copies/mL. Among the tissues studied, mesenteric and inguinal lymph nodes, and spleen contained viral barcodes detected in plasma, and trended to have higher cell-associated viral loads, higher intact provirus levels, and greater diversity of viral barcodes. CD4+ T cells were the main cell type harboring viral RNA (vRNA) after ATI. Further, T cell zones in LTs showed higher vRNA levels than B cell zones for most animals. These findings are consistent with LTs contributing to virus present in plasma early after ATI. ONE SENTENCE SUMMARY: The reemerging of SIV clonotypes at early post-ATI are likely from the secondary lymphoid tissues.

SUMMARY PARAGRAPHTreatment of people with HIV (PWH) with antiretroviral therapy (ART) results in sustained suppression of viremia, but HIV persists indefinitely as integrated provirus in CD4-expressing cells. Intact persistent provirus, the “rebound competent viral reservoir” (RCVR), is the primary obstacle to achieving a cure. Most variants of HIV enter CD4+T cells by binding to the chemokine receptor, CCR5. The RCVR has been successfully depleted only in a handful of PWH following cytotoxic chemotherapy and bone marrow transplantation from donors with a mutation inCCR5. Here we show that long-term SIV remission and apparent cure can be achieved for infant macaques via targeted depletion of potential reservoir cells that express CCR5. Neonatal rhesus macaques were infected with virulent SIVmac251, then treated with ART beginning one week after infection, followed by treatment with either a CCR5/CD3-bispecific or a CD4-specific antibody, both of which depleted target cells and increased the rate of plasma viremia decrease. Upon subsequent cessation of ART, three of seven animals treated with CCR5/CD3-bispecific antibody rebounded quickly and two rebounded 3 or 6 months later. Remarkably, the other two animals remained aviremic and efforts to detect replication-competent virus were unsuccessful. Our results show that bispecific antibody treatment can achieve meaningful SIV reservoir depletion and suggest that functional HIV cure might be achievable for recently infected individuals having a restricted reservoir.

Retention in care is a major challenge for global AIDS control, including sub-Saharan Africa. In a large Ethiopian region, we evaluated an intervention where HIV positive community support workers (CSWs) provided HIV health education, personal counseling and social support for HIV patients new to care. We enrolled 1,799 patients recently entering care from 32 hospitals and health centers, randomized to intervention or control sites. Dates of all clinic visits, plus deaths or transfers were abstracted from HIV medical records. Primary outcomes were gap in clinical care (90 days from a missed clinical or drug pickup appointment) and death. For 36 months of follow-up, and for the first 12 months after enrollment, weighted risk differences [RD] between treatment arms were modest and non-significant for gap in clinical care, death or either outcome. Through 36 months, 624 of 980 controls and 469 of 819 intervention participants had gaps in clinical care (RD = -5.5%, 95% confidence interval [CI] = -17.9%, 7.0%); 79 controls and 82 intervention participants died (RD = 2.5% 95% CI = -1.7%, 6.8%). Factors including HIV stigma and a volatile political climate may have attenuated the advantages we anticipated, demonstrating how benefits of CSW interventions may depend upon psychosocial, clinical and structural factors particular to specific community settings.

BACKGROUND Despite the potential of artificial intelligence/machine learning (AI/ML)-based medical modeling software (MMS) to revolutionize healthcare, the anticipated benefits have yet to be realized due to acknowledged gaps in translation. These gaps stem partly from the fragmentation of processes and resources to support MMS transparent documentation. Consequently, the absence of transparent reporting hinders the provision of evidence to support the implementation of MMS in clinical practice, thereby serving as a significant barrier to the successful translation of software from research settings to clinical practice. OBJECTIVE This study aimed to scope the current landscape of AI/ML-based MMS documentation practices and elucidate the function of documentation in facilitating the translation of ethical and explainable MMS into clinical workflows. METHODS A scoping review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. PubMed was searched using MeSH key concepts of AI/ML, ethical considerations, and explainability to identify publications detailing AI/ML-based MMS documentation, in addition to snowball sampling of selected reference lists. To include the possibility of implicit documentation practices not explicitly labeled as such, we did not use “documentation” as a key concept but as an inclusion criterion. A two-stage screening process (title and abstract screening and full-text review) was conducted by an independent reviewer. A data extraction template was utilized to record publication-related information, barriers to developing ethical and explainable MMS, available standards, regulations, frameworks, or governance strategies related to documentation, and recommendations for documentation for papers that met inclusion criteria. RESULTS Of the total 115 papers retrieved, 21 (18%) articles met the requirements for inclusion. Ethics and explainability were investigated in the context of AI/ML-based MMS documentation and translation. Data detailing the current state and challenges and recommendations for future work were synthesized. Notable themes defining the current state and challenges that required thorough review included bias, accountability, governance, and interpretability. Recommendations identified within the literature to address present barriers call for a proactive evaluation of MMS, multidisciplinary collaboration, adherence to investigation and validation protocols, transparency and traceability requirements, and guiding standards and frameworks that enhance documentation efforts and support the translation of AI/ML-based MMS. CONCLUSIONS The ability of MMS to deliver on expectations is dependent on resolving barriers to translation, including those identified within this scoping review related to bias, accountability, governance, and interpretability. Our findings suggest that transparent strategic documentation, aligning translational science and regulatory science, will support the translation of MMS by coordinating communication and reporting and reducing translational barriers, thereby furthering the adoption of MMS. CLINICALTRIAL

BackgroundTranslation of artificial intelligence/machine learning (AI/ML)-based medical modeling software (MMS) into clinical settings requires rigorous evaluation by interdisciplinary teams and across the AI lifecycle. The fragmented nature of available resources to support MMS documentation limits the transparent reporting of scientific evidence to support MMS, creating barriers and impeding the translation of software from code to bedside.ObjectiveThe aim of this paper is to scope AI/ML-based MMS documentation practices and define the role of documentation in facilitating safe and ethical MMS translation into clinical workflows.MethodsA scoping review was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. MEDLINE (PubMed) was searched using MeSH key concepts of AI/ML, ethical considerations, and explainability to identify publications detailing AI/ML-based MMS documentation, in addition to snowball sampling of selected reference lists. To include the possibility of implicit documentation practices not explicitly labeled as such, we did not use “documentation “ as a key concept but rather as an inclusion criterion. A two-stage screening process (title and abstract screening and full-text review) was conducted by an independent reviewer. A data extraction template was utilized to record publication-related information, barriers to developing ethical and explainable MMS, available standards, regulations, frameworks, or governance strategies related to documentation, and recommendations for documentation for papers that met inclusion criteria.ResultsOf the total 115 papers, 21 (18%) articles met the requirements for inclusion. Data regarding the current state and challenges of AI/ML-based documentation was synthesized and themes including bias, accountability, governance, and interpretability were identified.ConclusionsOur findings suggest that AI/ML-based MMS documentation practice is siloed across the AI life cycle and there exists a gray area for tracking and reporting of non-regulated MMS. Recommendations from the literature call for proactive evaluation, standards, frameworks, and transparency and traceability requirements to address ethical and explainability barriers, enhance documentation efforts, provide support throughout the AI lifecycle, and promote translation of MMS. If prioritized across multidisciplinary teams and across the AI lifecycle, AI/ML-based MMS documentation may serve as a method of coordinated communication and reporting toward resolution of AI translation barriers related to bias, accountability, governance, and interpretability.

Private and public sector structures and norms refine how emerging technology is used in practice. In healthcare, despite a proliferation of AI adoption, the organizational governance surrounding its use and integration is often poorly understood. What the Health AI Partnership (HAIP) aims to do in this research is to better define the requirements for adequate organizational governance of AI systems in healthcare settings and support health system leaders to make more informed decisions around AI adoption. To work towards this understanding, we first identify how the standards for the AI adoption in healthcare may be designed to be used easily and efficiently. Then, we map out the precise decision points involved in the practical institutional adoption of AI technology within specific health systems. Practically, we achieve this through a multi-organizational collaboration with leaders from major health systems across the United States and key informants from related fields. Working with the consultancy IDEO [dot] org, we were able to conduct usability-testing sessions with healthcare and AI ethics professionals. Usability analysis revealed a prototype structured around mock key decision points that align with how organizational leaders approach technology adoption. Concurrently, we conducted semi-structured interviews with 89 professionals in healthcare and other relevant fields. Using a modified grounded theory approach, we were able to identify 8 key decision points and comprehensive procedures throughout the AI adoption lifecycle. This is one of the most detailed qualitative analyses to date of the current governance structures and processes involved in AI adoption by health systems in the United States. We hope these findings can inform future efforts to build capabilities to promote the safe, effective, and responsible adoption of emerging technologies in healthcare.

In a few recent papers we introduced the chirality-flow formalism, which was shown to make calculations of tree-level Feynman diagrams simple and transparent. Chirality flow, which is based on the spinor-helicity formalism, allows to often immediately analytically write down a tree-level Feynman diagram in terms of spinor inner products. In this paper, we argue that there is also a significant simplification of the Lorentz structure at the one-loop level, at least when using the four-dimensional formulation of the four-dimensional helicity scheme. Additionally, we find that the possible terms in a tensor decomposition of loop integrals are highly constrained, and therefore the tensor reduction procedure is simplified., Comment: 28 pages, 1 figure

Human immunodeficiency virus 1 (HIV-1) infection is initiated by binding of the viral envelope glycoprotein (Env) to the cell-surface receptor CD4. Although high resolution structures of Env complexed with soluble domains of CD4 have been determined, the binding process is less understood on native membranes. Here, we apply cryo-electron tomography (cryo-ET) to monitor Env-CD4 interactions at membrane-membrane interfaces formed between HIV-1 and CD4-presenting virus-like particles. Env-CD4 complexes organized into clusters and rings, bringing opposing membranes closer together. Additionally, Env-CD4 clustering was dependent on capsid maturation. Subtomogram averaging and classification revealed that Env bound one, two, and finally three CD4 molecules, upon which Env adopted a partially open state. Our data indicate that asymmetric HIV-1 Env trimers bound to one and two CD4 molecules are detectable intermediates during virus binding to host cell membranes, which likely has consequences for antibody-mediated immune responses and vaccine immunogen design.

In this paper, we present an extension of MadGraph5_aMC@NLO which is able to evaluate tree-level QCD matrix-elements up to $2\to 6$ (one more particle than before). To achieve this, we implemented Berends-Giele-like recursion, and re-implemented the way colour is computed such that we can now expand the colour matrix in powers of 1/Nc and truncate this expansion to a chosen order. For high multiplicity samples, even without truncating the colour matrix, the new implementation offers a speed gain compared to the previous MadGraph5_aMC@NLO code., Published version in EPJC. Minor changes to v1. 18 pages, 18 figures

In this paper, we present an extension of MadGraph5_aMC@NLO which is able to evaluate tree-level QCD matrix-elements up to $$2\rightarrow 6$$ 2 → 6 (one more particle than before). To achieve this, we implemented Berends–Giele-like recursion, and re-implemented the way colour is computed such that we can now expand the colour matrix in powers of $$1/N_c$$ 1 / N c and truncate this expansion to a chosen order. For high multiplicity samples, even without truncating the colour matrix, the new implementation offers a speed gain compared to the previous MadGraph5_aMC@NLO code.

AEROS aims to develop a nanosatellite as a precursor of a future system of systems, which will include assets and capabilities of both new and existing platforms operating in the Ocean and Space, equipped with state-of-the-art sensors and technologies, all connected through a communication network linked to a data gathering, processing and dissemination system. This constellation leverages scientific and economic synergies emerging from New Space and the opportunities in prospecting, monitoring, and valuing the Ocean in a sustainable manner, addressing the demand for improved spatial, temporal, and spectral coverage in areas such as coastal ecosystems management and climate change assessment and mitigation. Currently, novel sensors and systems, including a miniaturized hyperspectral imager and a flexible software-defined communication system, are being developed and integrated into a new versatile satellite structure, supported by an innovative on-board software. Additional sensors, like the LoRaWAN protocol and a wider field of view RGB camera, are under study. To cope with data needs, a Data Analysis Centre, including a cloud-based data and telemetry dashboard and a back-end layer, to receive and process acquired and ingested data, is being implemented to provide tailored-to-use remote sensing products for a wide range of applications for private and institutional stakeholders., 15 pages, 9 figures, Manuscript presented at the 4S Symposium 2022, Vilamoura, Portugal, 16 - 20 May 2022

AEROS is a 3U CubeSat pathfinder toward a future ocean-observing constellation, targeting the Portuguese Atlantic region. AEROS features a miniaturized, high-resolution Hyperspectral Imager (HSI), a 5MP RGB camera, and a Software Defined Radio (SDR). The sensor generated data will be processed and aggregated for end-users in a new web-based Data Analysis Center (DAC). The HSI has 150 spectrally contiguous bands covering visible to near-infrared with 10 nm bandwidth. The HSI collects ocean color data to support studies of oceanographic characteristics known to influence the spatio-temporal distribution and movement behavior of marine organisms. Usage of an SDR expands AEROS's operational and communication range and allows for remote reconfiguration. The SDR receives, demodulates, and retransmits short duration messages, from sources including tagged marine organisms, autonomous vehicles, subsurface floats, and buoys. The future DAC will collect, store, process, and analyze acquired data, taking advantage of its ability to disseminate data across the stakeholders and the scientific network. Correlation of animal-borne Argos platform locations and oceanographic data will advance fisheries management, ecosystem-based management, monitoring of marine protected areas, and bio-oceanographic research in the face of a rapidly changing environment. For example, correlation of oceanographic data collected by the HSI, geolocated with supplementary images from the RGB camera and fish locations, will provide researchers with near real-time estimates of essential oceanographic variables within areas selected by species of interest., 13 pages, 16 figures, Manuscript presented at the 73rd International Astronautical Congress, IAC 2022, Paris, France, 18 - 22 September 2022

Introduction Accurate and precise platelet (PLT) count is critical for the appropriate management of patients with thrombocytopenia. This study evaluated the performance of PLT counting with the Abbott Alinity hq hematology analyzer, which utilizes multi-dimensional optical technology. Methods Imprecision, linearity, and accuracy were assessed per CLSI guidelines. Alinity hq PLT results were compared to the international flow cytometry reference method (IRM) in the concentration range of 6.3 to 103.0 × 109 /L. Additional comparisons were made with Sysmex XN-3000 PLT counts: impedance (PLT-I), optical (PLT-O), and optical fluorescent (PLT-F) methods. Results The average within-run %CV was 4.7% on patient samples with PLT concentrations ranging from 13.1 to 41.7 × 109 /L, and the within-laboratory %CV was 3.6% at the level of 68.2 × 109 /L. Linearity evaluation indicated a maximum deviation of 3.1% from the linear fit in the range of 0.1 to 316.8 × 109 /L. Comparison between Alinity hq and the IRM PLT counts yielded a correlation coefficient of 0.99 and predicted bias of 0.0 and -0.5 × 109 /L at 10.0 and 20.0 × 109 /L transfusion thresholds, respectively. Alinity hq PLT counts also correlated well with Sysmex PLT counts, with strongest correlation obtained with PLT-F and PLT-O (r = .99) methods. Conclusion This study demonstrated excellent analytical performance of Alinity hq PLT counting in thrombocytopenic samples, equivalency with the IRM and strong agreement with Sysmex PLT-F and PLT-O methods. The Alinity hq multi-dimensional optical PLT count is available with every CBC without additional reagents and may help promote efficiency in clinical laboratories.

SIVmac239 infection of macaques is a favored model of human HIV infection. However, the SIVmac239 envelope (Env) trimer structure, glycan occupancy, and the targets and ability of neutralizing antibodies (nAbs) to protect against SIVmac239 remain unknown. Here, we report the isolation of SIVmac239 nAbs that recognize a glycan hole and the V1/V4 loop. A high-resolution structure of a SIVmac239 Env trimer-nAb complex shows many similarities to HIV and SIVcpz Envs, but with distinct V4 features and an extended V1 loop. Moreover, SIVmac239 Env has a higher glycan shield density than HIV Env that may contribute to poor or delayed nAb responses in SIVmac239-infected macaques. Passive transfer of a nAb protects macaques from repeated intravenous SIVmac239 challenge at serum titers comparable to those described for protection of humans against HIV infection. Our results provide structural insights for vaccine design and shed light on antibody-mediated protection in the SIV model.

Antiretroviral therapy (ART) is not curative due to the persistence of a reservoir of HIV-infected cells, particularly in tissues such as lymph nodes, with the potential to cause viral rebound after treatment cessation. In this study, fingolimod (FTY720), a lysophospholipid sphingosine-1-phosphate receptor modulator is administered to SIV-infected rhesus macaques at initiation of ART to block the egress from lymphoid tissues of natural killer and T-cells, thereby promoting proximity between cytolytic cells and infected CD4+ T-cells. When compared with the ART-only controls, FTY720 treatment during the initial weeks of ART induces a profound lymphopenia and increases frequencies of CD8+ T-cells expressing perforin in lymph nodes, but not their killing capacity; FTY720 also increases frequencies of cytolytic NK cells in lymph nodes. This increase of cytolytic cells, however, does not limit measures of viral persistence during ART, including intact proviral genomes. After ART interruption, a subset of animals that initially receives FTY720 displays a modest delay in viral rebound, with reduced plasma viremia and frequencies of infected T follicular helper cells. Further research is needed to optimize the potential utility of FTY720 when coupled with strategies that boost the antiviral function of T-cells in lymphoid tissues.

We described a novel HIV autologous isolation method based in coculturing macrophages and CD4

Current state of the art in Space Traffic Management (STM) relies on a handful of providers for surveillance and collision prediction, and manual coordination between operators. Neither is scalable to support the expected 10x increase in active spacecraft population in less than 10 years, nor does it support automated maneuver planning. We present a software prototype of an STM architecture based on open Application Programming Interfaces (APIs), and drawing on insights from NASA's architecture for low-altitude Unmanned Aerial System Traffic Management. The STM architecture is designed to provide structure to the interactions between spacecraft operators, various regulatory bodies, and STM service suppliers, while maintaining flexibility of these interactions and the ability for new market participants to enter easily. Autonomy will be an indispensable part of the proposed architecture in enabling efficient data sharing, coordination between STM participants and safe flight operations (e.g. select spacecraft maneuvers to prevent impending conjunctions between multiple spacecraft). The STM prototype is based on modern micro-service architecture adhering to OpenAPI standards and deployed in industry-standard virtualized containers, facilitating easy communication between different participants or services. The system architecture is designed to facilitate adding and replacing services with minimal disruption. We have implemented some example participant services (e.g. a space situational awareness/SSA provider, a conjunction assessment supplier/CAS, an automated maneuver advisor/AMA) within the prototype. Different services, with creative algorithms folded into them, can fulfill similar functional roles within the STM architecture by flexibly connecting to it using pre-defined APIs and data models, thereby lowering the barrier to entry of new players in the STM marketplace. We demonstrate the STM prototype on a multiple conjunction scenario with multiple maneuverable spacecraft, where an example CAS and AMA can recommend optimal maneuvers to the spacecraft operators, based on a pre-defined reward function. Such tools can intelligently search the space of potential collision avoidance maneuvers with varying parameters like lead time and propellant usage, to optimize a customized reward function, and be implemented as a scheduling service within the STM architecture. The case study shows an example of autonomous maneuver planning using the API-based framework. As satellite populations and predicted conjunctions increase, an STM architecture can facilitate seamless information exchange related to collision prediction and mitigation among various service applications on different platforms and servers. The availability of such an STM network also opens up new research topics on satellite maneuver planning, scheduling and negotiation across disjoint entities.

The strain 68-1 rhesus cytomegalovirus (RhCMV)–based vaccine for simian immunodeficiency virus (SIV) can stringently protect rhesus macaques (RMs) from SIV challenge by arresting viral replication early in primary infection. This vaccine elicits unconventional SIV-specific CD8 + T cells that recognize epitopes presented by major histocompatibility complex (MHC)–II and MHC-E instead of MHC-Ia. Although RhCMV/SIV vaccines based on strains that only elicit MHC-II– and/or MHC-Ia–restricted CD8 + T cells do not protect against SIV, it remains unclear whether MHC-E–restricted T cells are directly responsible for protection and whether these responses can be separated from the MHC-II–restricted component. Using host microRNA (miR)–mediated vector tropism restriction, we show that the priming of MHC-II and MHC-E epitope–targeted responses depended on vector infection of different nonoverlapping cell types in RMs. Selective inhibition of RhCMV infection in myeloid cells with miR-142–mediated tropism restriction eliminated MHC-E epitope–targeted CD8 + T cell priming, yielding an exclusively MHC-II epitope–targeted response. Inhibition with the endothelial cell–selective miR-126 eliminated MHC-II epitope–targeted CD8 + T cell priming, yielding an exclusively MHC-E epitope–targeted response. Dual miR-142 + miR-126–mediated tropism restriction reverted CD8 + T cell responses back to conventional MHC-Ia epitope targeting. Although the magnitude and differentiation state of these CD8 + T cell responses were generally similar, only the vectors programmed to elicit MHC-E–restricted CD8 + T cell responses provided protection against SIV challenge, directly demonstrating the essential role of these responses in RhCMV/SIV vaccine efficacy.

Scattering amplitudes are often split up into their color (su(N)) and kinematic components. Since the su(N) gauge part can be described using flows of color, one may anticipate that the double su(2) kinematic part can be described in terms of flows of chirality. In two recent papers we showed that this is indeed the case, introducing the chirality-flow formalism for standard model calculations. Using the chirality-flow method -- which builds on and further simplifies the spinor-helicity formalism -- Feynman diagrams can be directly written down in terms of Lorentz-invariant spinor inner products, allowing the simplest and most direct path from a Feynman diagram to a complex number. In this presentation, we introduce this method and show some examples., Invited talk presented at the 14th international workshop "Lie Theory and its Applications in Physics" (LT-14), 21-25 June 2021, Sofia, Bulgaria (online); 7 pages, no figures

We described a novel HIV autologous isolation method based in coculturing macrophages and CD4+T-cell-enriched fractions from peripheral blood collected from antiretroviral-treated (ART) HIV patients. This method allows the isolation of high viral titers of autologous viruses, over 1010HIV RNA copies/ml, and reduces the time required to produce necessary amounts for virus for use as antigens presented by monocyte-derived myeloid cells in HIV therapeutic vaccine approaches. By applying these high titer and autologous virus produced in the patient-derived cells, we intended to elicit a boost of the immunological system response in HIV therapeutic vaccines in clinical trials. This study was partially supported by grants from the Spanish Ministry of Economy (MINECO) (grants: SAF2015-66193-R, SAF-2017-88089-R, RTI2018-096309-B-I00); the Fondo Europeo para el Desarrollo Regional (FEDER); the SPANISH AIDS Research Network RD16/0025/0002 and RD16/0025/0014-ISCIII-FEDER (RIS); the Fondo de Investigación Sanitaria (FIS) PI12/01247 and PI20/00676; and HIVACAT program and the CERCA Programme/Generalitat de Catalunya SGR 615 and SGR 653. The project leading to these results has received funding from “la Caixa” Foundation under agreement. This study was also supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract Nos. HHSN261200800001E and 75N91019D00024. Sí

The article is devoted to the institution of challenging the normative legal acts of Rospatent in the Court on Intellectual Rights on the example of several cases examined by the Court. The authors highlight a number of problems in this area. Since the consideration of a public objection to a patent for a controversial utility model or invention and the decision on the results of the consideration of such an objection is within the competence of Rospatent, and the PIS performs only a supervisory function, it is difficult to solve this problem within a reasonable time. The authors propose: all disputes related to intellectual property after issuing a security document should be resolved not in an administrative - judicial manner, but only in a judicial one, by analogy with the violation of the patent of the Russian Federation for intellectual property objects.

The primary human immunodeficiency virus (HIV) reservoir is composed of resting memory CD4+ T cells, which often express the immune checkpoint receptors programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which limit T cell activation via synergistic mechanisms. Using simian immunodeficiency virus (SIV)-infected, long-term antiretroviral therapy (ART)-treated rhesus macaques, we demonstrate that PD-1, CTLA-4 and dual CTLA-4/PD-1 immune checkpoint blockade using monoclonal antibodies is well tolerated, with evidence of bioactivity in blood and lymph nodes. Dual blockade was remarkably more effective than PD-1 blockade alone in enhancing T cell cycling and differentiation, expanding effector-memory T cells and inducing robust viral reactivation in plasma and peripheral blood mononuclear cells. In lymph nodes, dual CTLA-4/PD-1 blockade, but not PD-1 alone, decreased the total and intact SIV-DNA in CD4+ T cells, and SIV-DNA and SIV-RNA in B cell follicles, a major site of viral persistence during ART. None of the tested interventions enhanced SIV-specific CD8+ T cell responses during ART or viral control after ART interruption. Thus, despite CTLA-4/PD-1 blockade inducing robust latency reversal and reducing total levels of integrated virus, the degree of reservoir clearance was still insufficient to achieve viral control. These results suggest that immune checkpoint blockade regimens targeting PD-1 and/or CTLA-4, if performed in people living with HIV with sustained aviremia, are unlikely to induce HIV remission in the absence of additional interventions.

Structural characterization of the HIV-1 Envelope (Env) glycoprotein has facilitated the development of Env probes to isolate HIV-specific monoclonal antibodies (mAbs). However, preclinical studies have largely evaluated these virus-specific mAbs against chimeric viruses, which do not naturally infect non-human primates, in contrast to the unconstrained simian immunodeficiency virus (SIV)mac239 clone. Given the paucity of native-like reagents for the isolation of SIV-specific B cells, we examined a method to isolate SIVmac239-specific mAbs without using Env probes. We first activated virus-specific B cells by inducing viral replication after the infusion of a CD8β-depleting mAb or withdrawal of antiretroviral therapy in SIVmac239-infected rhesus macaques. Following the rise in viremia, we observed 2- to 4-fold increases in the number of SIVmac239 Env-reactive plasmablasts in circulation. We then sorted these activated B cells and obtained 206 paired Ab sequences. After expressing 122 mAbs, we identified 14 Env-specific mAbs. While these Env-specific mAbs bound to both the SIVmac239 SOSIP.664 trimer and to infected primary rhesus CD4+ T cells, five also neutralized SIVmac316. Unfortunately, none of these mAbs neutralized SIVmac239. Our data show that this method can be used to isolate virus-specific mAbs without antigenic probes by inducing bursts of contemporary replicating viruses in vivo. Keywords: SIV, monoclonal antibodies, rhesus macaques, CD8b depletion, antiretroviral therapy interruption

In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4 + T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti–PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4 + T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4 + T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti–PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti–PD-1 with other interventions to reduce the HIV reservoir.

Recently we introduced the chirality-flow formalism, a method which builds on the spinor-helicity formalism and is inspired by the color-flow idea in QCD. With this formalism, Feynman rules and diagrams are simplified to the extent that it is often possible to immediately, by hand, write down a helicity amplitude given a Feynman diagram. In this paper we show that the method can also speed up numerical evaluation of scattering amplitudes by considering $e^+ e^-$ going to $n$ photons in a MadGraph-based tree-level implementation. We find that the computation time is reduced by roughly a factor ten for six photons, and that it scales better with the number of external particles than the default MadGraph5_aMC@NLO implementation. This performance gain is in part attributed to the more compact Lorentz structures involved, and in part due to a transparent choice of gauge reference vectors which reduces the number of Feynman diagrams considered., Comment: 6 pages, 1 figure

The increasing number of Anthropogenic Space Objects (ASOs) in Low Earth Orbit (LEO) poses a threat to the safety and sustainability of the space environment. Multiple companies are planning to launch large constellations of hundreds or thousands of satellites in the near future, increasing congestion in LEO and the risk of collisions and debris generation. This paper employs a new multi-shell multi-species evolutionary source-sink model, called MOCAT-3, to estimate LEO orbital capacity. In particular, a new definition of orbital capacity based on the stable equilibrium points of the system is provided. Moreover, an optimization approach is used to compute the maximum orbital capacity of the low region of LEO (200-900 km of altitude), considering the equilibrium solutions and the failure rate of satellites as a constraint. Hence, an estimate for the maximum number of satellites that it is possible to fit in LEO, considering the stability of the space environment, is obtained. As a result, considering 7% of failure rate, the maximum orbital capacity of LEO is estimated to be about 12.6 million satellites. Compatibility of future traffic launch, especially in terms of satellite constellations, is also analyzed and a strategy to accommodate for future traffic needs is proposed.

Activation of the NF-κB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro. However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP). CD4+ T cells from people living with HIV and from SIV+ rhesus macaques (RM) on antiretroviral therapy (ART) exposed in vitro to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA/Ionomycin, indicating that GSK445A can potently reverse HIV/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8+ T cells, but instead, increased their numbers and enhanced IFN-γ production in response to HIV peptides. In vivo, GSK445A tolerability was established in SIV-naïve RM at 15 μg/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription in vivo. Collectively, these results indicate that GSK445A is a potent HIV/SIV LRA in vitro and has a tolerable safety profile amenable for further evaluation in vivo in NHP models of HIV cure/remission., Author summary Antiretroviral therapy (ART) is not a definitive cure for HIV infection, in part, because the virus is able to integrate its genetic material in the host cell and remain in a dormant but fully replication-competent form during ART. These latently-infected cells can persist for long periods of time and remain hidden from the host’s immune system. If ART is stopped, the virus can reactivate from this pool of infected cells and resume HIV replication and disease progression. As such, finding and eliminating cells with latent HIV infection is priority for HIV cure research. One approach is to use compounds referred to as latency-reversing agents, that can induce HIV reactivation during ART. The goal of this approach is to facilitate elimination of infected cells by the virus itself once it reactivates or by the host’s immune system, once virus induction renders the cells detectable by the immune system, while also preventing the virus from infecting new cells due to the continued presence of ART. In this study we report on the activity of a novel latency-reversing agent called GSK445A, a potent activator of the enzyme protein kinase C (PKC). We show that GSK445A can induce HIV and simian immunodeficiency virus (SIV) latency reversal in vitro and has a tolerable saftey profile in nonhuman primates that should permit further testing of this PKC-agonist in strategies to cure HIV.

SUMMARYSIVmac239 infection of macaques is a favored model of human HIV infection. However, the SIVmac239 envelope (Env) trimer structure, glycan occupancy, and the targets and ability of neutralizing antibodies (nAbs) to protect against SIVmac239 remain unknown. Here, we report the isolation of SIVmac239 nAbs that recognize a glycan hole and the V1/V4 loop. A high-resolution structure of a SIVmac239 Env trimer-nAb complex shows many similarities to HIV and SIVcpz Envs, but with distinct V4 features and an extended V1 loop. Moreover, SIVmac239 Env has a higher glycan shield density than HIV Env that may contribute to poor or delayed nAb responses in SIVmac239-infected macaques. Passive transfer of a nAb protects macaques from repeated low dose intraveneous SIVmac239 challenge at serum titers comparable to those described for protection of humans against HIV infection. Our results provide structural insights for vaccine design and shed light on antibody-mediated protection in the SIV model.

Central retinal artery occlusion (CRAO) is a condition that causes sudden vision loss due to obstruction of the retinal artery, typically from a thrombotic or embolic source. It is often associated with atherosclerotic risk factors, including cardiovascular disease, diabetes, hyperlipidemia, and a history of cerebrovascular disease. CRAO often leads to a poor visual outcome as well as neovascularization of the iris, retina, and optic disc, which can exacerbate vision loss and cause pain. While there are several treatment modalities for CRAO, few have been proven to be effective in decreasing the effects of neovascularization. The use of hyperbaric oxygen (HBO2) therapy is often used in the treatment of CRAO due to its ease of use and relatively benign side effect profile. This study aims to assess the degree of improvement in visual acuity (VA) and neovascularization following HBO2. Our data ultimately shows that 20% of patients developed neovascularization after HBO2 compared to 29.8% of those who did not undergo HBO2 (p.05). Our findings suggest that HBO2 has a statistically significant protective effect against neovascularization and may improve long-term visual acuity.

BackgroundThe SARS-CoV-2 Beta variant, associated with immune escape and higher transmissibility, drove a more severe second COVID-19 wave in South Africa. Individual patient level characteristics and outcomes with the Beta variant are not well characterized.MethodsWe performed a retrospective cohort study comparing disease severity and inpatient mortality of COVID-19 pneumonia between the first and second wave periods at a referral hospital in Cape Town, South Africa. Beta variant infection was confirmed by genomic sequencing. Outcomes were analyzed with logistic regression and accelerated failure time models.Results1,182 patients were included: 571 during the first wave period and 611 from the second wave. Beta variant accounted for 97% of infections in the second wave. There was no difference in crude in-hospital mortality between wave periods (first wave 22.2%, second wave 22.1%; p = 0.9). Time to death was decreased with higher weekly hospital admissions (16%; 95% CI, 8 to 24 for every 50-patient increase), age (18%; 95% CI, 12 to 24 for every 10-year increase) and hypertension (31%; 95% CI, 12 to 46). Corticosteroid use delayed time to death by 2-fold (95% CI, 1.5 to 3.0). Admission during the second wave decreased time to death after adjustment for other predictors, but this did not reach statistical significance (24%; 95% CI, 47 to -2). There was no effect of HIV on survival.ConclusionsThere was a trend towards earlier mortality during the second COVID-19 wave driven by the Beta variant, suggesting a possible biological basis. Use of oral prednisone was strongly protective.Key pointsIn Cape Town, South Africa, the second wave of COVID-19, dominated by the Beta variant, was associated with decreased time to inpatient death after adjustment for age, comorbidities, steroid use, and admission numbers. Use of oral prednisone was strongly protective.

Simian immunodeficiency viruses (SIVs) are lentiviruses that naturally infect non-human primates of African origin and seeded cross-species transmissions of HIV-1 and HIV-2. Here we report prefusion stabilization and cryo-EM structures of soluble envelope (Env) trimers from rhesus macaque SIV (SIV

Inspired by the flow description of su(N) colour calculations, we recently showed how to simplify the spinor-helicity formalism (at the algebra level two copies of complexified su(2)) by treating each Weyl spinor as part of a flow line with definite chirality and momentum. This formalism, dubbed the chirality-flow formalism, eliminates all non-trivial algebra from tree-level spinor-helicity calculations, thus allowing the shortest possible route from Feynman diagrams to complex numbers (spinor inner products). In this presentation, we briefly introduce the main features of this method and show some examples., 7 pages. LHCP conference proceeding. Version accepted for publication in Proceedings of Science

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spreads rapidly amongst residents of skilled nursing facilities (SNFs). The rapid transmission dynamics and high morbidity and mortality that occur in SNFs emphasize the need for early detection of cases. We hypothesized that residents of SNFs infected with SARS-CoV-2 would demonstrate an acute change in either temperature or oxygen saturation (SpO2 ) prior to symptom onset. The Minnesota Department of Health (MDH) conducted a retrospective analysis of both temperature and SpO2 at two separate SNFs to assess the utility of these quantitative markers to identify SARS-CoV-2 infection prior to the development of symptoms. METHODS: A retrospective analysis was conducted of 165 individuals positive for SARS-CoV-2 who were residents of SNFs that experienced coronavirus disease 2019 (COVID-19) outbreaks during April-June 2020 in a metropolitan area of Minnesota. Age, sex, symptomology, temperature and SpO2 values, date of symptom onset, and date of positive SARS-CoV-2 test were analyzed. Temperature and SpO2 values for the period 14 days before and after the date of initial positive test were included. Descriptive analyses evaluated changes in temperature and SpO2 , defined as either exceeding a set threshold or demonstrating an acute change between consecutive measurements. RESULTS: Two (1%) residents had a temperature value ≥100°F, and 30 (18%) had at least one value ≥99°F within 14 days before symptom development. One hundred and sixteen residents (70%) had at least one SpO2 value ≤94%, while 131 (80%) had an acute decrease in SpO2 of ≥3% between consecutive values in the 14 days prior to symptom onset. CONCLUSIONS: Our results suggest that acute change in SpO2 might be useful in the identification of SARS-CoV-2 infection prior to the development of symptoms among residents living in SNFs. Facilities may consider adding SpO2 to daily temperature and symptom screening checklists to improve early detection of residents of SNFs infected with SARS-CoV-2.

Ultralow-k materials used in high voltage devices require mechanical resilience and electrical and dielectric stability even when subjected to mechanical loads. Existing devices with organic polymers suffer from low thermal and mechanical stability while those with inorganic porous structures struggle with poor mechanical integrity. Recently, three-dimensional hollow-beam nanolattices have emerged as promising candidates that satisfy these requirements. However, their properties are maintained for only five stress cycles at strains below 25%. Here, we demonstrate that alumina nanolattices with different relative density distributions across their height elicit a deterministic mechanical response concomitant with a 1.5∼3.3 times higher electrical breakdown strength than nanolattices with uniform density. These density-variant nanolattices exhibit an ultralow-k of ∼ 1.2, accompanied by complete electric and dielectric stability and mechanical recoverability over 100 cyclic compressions to 62.5% strain. We explain the enhanced insulation and long-term cyclical stability by the bi-phase deformation where the lower-density region protects the higher-density region as it is compresses before the higher-density region, allowing to simultaneously possess high strength and ductility like composites. This study highlights the superior electrical performance of the bi-phase nanolattice with a single interface in providing stable conduction and maximum breakdown strength. This article is protected by copyright. All rights reserved.

Primary HIV-1 infection can be classified into six Fiebig stages based on virological and serological laboratory testing, whereas simian-HIV (SHIV) infection in nonhuman primates (NHPs) is defined in time post-infection, making it difficult to extrapolate NHP experiments to the clinics. We identified and extensively characterized the Fiebig-equivalent stages in NHPs challenged intrarectally or intravenously with SHIV(AD8-EO). During the first month post-challenge, intrarectally challenged monkeys were up to 1 week delayed in progression through stages. However, regardless of the challenge route, stages I–II predominated before, and stages V–VI predominated after, peak viremia. Decrease in lymph node (LN) CD4(+) T cell frequency and rise in CD8(+) T cells occurred at stage V. LN virus-specific CD8(+) T cell responses, dominated by degranulation and TNF, were first detected at stage V and increased at stage VI. A similar late elevation in follicular CXCR5(+) CD8(+) T cells occurred, consistent with higher plasma CXCL13 levels at these stages. LN SHIV(AD8-EO) RNA(+) cells were present at stage II, but appeared to decline at stage VI when virions accumulated in follicles. Fiebig-equivalent staging of SHIV(AD8-EO) infection revealed concordance of immunological events between intrarectal and intravenous infection despite different infection progressions, and can inform comparisons of NHP studies with clinical data.

In order to design effective strategies to eradicate the HIV, an understanding of persistent viral reservoirs is needed. Many studies have demonstrated HIV residual viremia prevalence in high income countries, data from low- and middle-income countries (LMIC) are limited. We assessed the prevalence, and factors associated with residual viremia in people with HIV (PWH), who were virally-suppressed on antiretroviral therapy (ART) in LMIC. We also compared residual viremia prevalence between the LMIC and US. This is a cross-sectional, retrospective study that utilized stored specimen samples from the AIDS clinical trials group (ACTG) studies A5175 and A5208. The last available sample among participants with plasma HIV RNA

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68–1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68–1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68–1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge., Author summary SIV insert-expressing vaccine vectors based on strain 68–1 RhCMV elicit robust, highly effector-memory-biased, unconventionally restricted T cell responses that are associated with an unprecedented level of SIV control after challenge (replication arrest leading to clearance) in slightly over half of vaccinated monkeys. Since efficacy among monkeys vaccinated with the effective 68–1 vaccine is not predicted by standard measures of immunogenicity, we used functional genomics analysis of RhCMV/SIV vaccinated monkeys with known challenge outcomes to identify immune correlates of protection. We found that vaccine efficacy significantly correlates with a vaccine-induced response to IL-15 that includes modulation of immune cell, inflammation, TLR signaling, and cell death programming response pathways. These data suggest that RhCMV/SIV efficacy results from a coordinated and sustained vaccine-mediated induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ effector-memory T cell function, that cooperates with vaccine-elicited CD8+ T cells to mediate efficacy.