Abstract Despite its efficiency to prevent viral multiplication, antiretroviral therapy does not affect HIV-1 latently-infected cells. These cells do not produce significant amounts of viruses and constitute HIV-1 reservoir. To purge this long-lived viral reservoir, the "shock and kill" strategy relies on the use of latency reversing agents (LRAs) to induce activation of latent cells. All LRAs developed until now target cellular proteins and are therefore not specific for HIV-infected cells. Here we present a new LRA that binds and activates HIV-1 Tat which is the key regulator for viral transcription and latency reversal. This molecule termed D10 was designed to bind to the major groove of the Tat protein, and found to activate Tat transcriptional activity by stabilizing the HIV transcription complex. This LRA induces strong HIV production by latent cell lines and latent cells from people living with HIV-1. On latent cells from PBMCs, D10 is active at ∼50 nM, the concentration required to stabilize HIV transcription complex. D10 is the first Tat activator available and the first LRA that targets an HIV protein.
Soft robots were introduced in large part to enable safe, adaptive interaction with the environment, and this interaction relies fundamentally on contact. However, modeling and planning contact-rich interactions for soft robots remain challenging: dense contact candidates along the body create redundant constraints and rank-deficient linear complementarity problems (LCPs), while the disparity between high stiffness and low friction introduces severe ill-conditioning. Existing approaches rely on problem-specific approximations or penalty-based treatments. This letter presents a complementarity-based framework for soft-robot contact modeling and planning that uses a consistent contact formulation across forward simulation and trajectory optimization. We develop a robust LCP model tailored to discretized soft robots and address these challenges with a three-stage conditioning pipeline: inertial rank selection to remove redundant contacts, Ruiz equilibration to correct scale disparity and ill-conditioning, and lightweight Tikhonov regularization on normal blocks. Building on the same formulation, we introduce a kinematically guided warm-start strategy that enables dynamic trajectory optimization through contact using Mathematical Programs with Complementarity Constraints (MPCC) and demonstrate its effectiveness in simulation on contact-rich ball-manipulation tasks. In conclusion, the proposed framework provides a new foundation for contact modeling, simulation, and planning in soft robotics.
Numerous orthoflaviviruses transmitted through the bites of different mosquito species infect more than 500 million people annually. Bite-initiated skin infection represents a critical and conserved step in transmission and a deeper understanding of this process will promote the design of broad-spectrum interventions to address diverse orthoflavivirus health threats. Here, we identify and characterize a transmission-enhancing viral factor in mosquito saliva that is shared across orthoflaviviruses. Saliva of West Nile virus-infected Culex and Zika virus-infected Aedes contains a viral non-coding RNA, subgenomic orthoflaviviral RNA (sfRNA), within lipid vesicles distinct from virions. Higher concentration of sfRNA in infectious saliva positively correlates with infection intensity in human cells and skin explants. Early sfRNA delivery into transmission-relevant skin cell types and human skin explant demonstrate that sfRNA is responsible for the infection enhancement. Co-inoculation of sfRNA in a mouse model of transmission enhanced skin infection and worsened disease severity, evidencing the role of salivary sfRNA as a transmission-enhancer. Mechanistically, salivary sfRNA attenuates early interferon response in human skin cells and skin explants by altering MDA5-mediated signaling. Our results, derived from two distinct orthoflaviviruses and supported by prior studies, establish salivary sfRNA as a pan-orthoflavivirus transmission-enhancing factor driven by a conserved viral non-coding RNA. ### Competing Interest Statement The authors have declared no competing interest.
The article analyzes some aspects of the new existing framework in the Republic of Moldova regarding doctoral studies following the recent approval of a series of normative acts, including those related to the conferment and confirmation of the scientific title of doctor. These are compared with previously existing procedures, at national level, but also with good international practices. There are multiple contradictions in the approved acts, including in the procedures provided, but also lower quality standards compared to those in European countries. The new framework established in the field, corroborated with other trends in the field of higher education and research, raises new challenges in ensuring the quality of scientific activities in the Republic of Moldova. In this context, the authors submit a series of proposals to improve the regulatory framework and procedures to certify the scientific qualification of the staff involved in the doctoral studies process.
