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The study was aimed at identifying endogenous proteins which assist or impede the permeabilized state in the cell membrane disrupted by nsEP (20 or 40 pulses, 300 ns width, 7 kV/cm). We employed a LentiArray CRISPR library to generate knockouts (KOs) of 316 genes encoding for membrane proteins in U937 human monocytes stably expressing Cas9 nuclease. The extent of membrane permeabilization by nsEP was measured by the uptake of Yo-Pro-1 (YP) dye and compared to sham-exposed KOs and control cells transduced with a non-targeting (scrambled) gRNA. Only two KOs, for SCNN1A and CLCA1 genes, showed a statistically significant reduction in YP uptake. The respective proteins could be part of electropermeabilization lesions or increase their lifespan. In contrast, as many as 39 genes were identified as likely hits for the increased YP uptake, meaning that the respective proteins contributed to membrane stability or repair after nsEP. The expression level of eight genes in different types of human cells showed strong correlation (R > 0.9, p < 0.02) with their LD50 for lethal nsEP treatments, and could potentially be used as a criterion for the selectivity and efficiency of hyperplasia ablations with nsEP.

Zika virus (ZIKV) is a mosquito-borne orthoflavivirus of global concern due to its ability to cause congenital neurological defects in infants. Natural killer (NK) cells are innate lymphocytes that can directly kill virus-infected cells. It is thought that NK cells are protective against ZIKV, although the mechanisms by which NK cells detect and respond to ZIKV are not well understood. Here, we evaluated NK cell receptor expression on isolated NK cells from a Panamanian cohort of ZIKV-infected participants, and corresponding NK receptor ligand expression on participant PBMCs and ZIKV-infected cells using mass cytometry. We found that during acute ZIKV infection, NK cells express high levels of activation markers, proliferative markers, and cytotoxic effector proteins, indicating that NK cells are mounting a response to ZIKV. Interestingly, many markers elevated during acute infection remain elevated post-acute infection, suggesting ZIKV infection may have potential long-term effects on NK cell function. Analysis of NK receptor ligand expression on ZIKV-infected participant PBMCs and ZIKV-infected cells did not identify a cellular source of NK cell activation, suggesting that either soluble or tissue-specific factors are responsible for modulating NK cell activity during ZIKV infection. Comparison of the NK cell receptor expression with a previously characterized cohort of dengue-infected participants revealed both common and virus-specific changes in NK cell phenotype during acute infection. This work improves our understanding of the NK cell response to orthoflavivirus infection, which will aid in the development of vaccines and therapeutics.

Long COVID is a heterogeneous condition characterized by a wide range of symptoms that persist for 90 days or more following SARS-CoV-2 infection. Now more than five years out from the onset of the SARS-CoV-2 pandemic, the mechanisms driving Long COVID are just beginning to be elucidated. Adipose tissue has been proposed as a potential reservoir for viral persistence and tissue dysfunction contributing to symptomology seen in Long COVID. To test this hypothesis, we analyzed subcutaneous adipose tissue (SAT) from two cohorts: participants with subacute COVID-19 (28-89 days post-infection) compared to pre-pandemic controls, and participants with Long COVID compared to those with those classified as \"indeterminate\" based on the RECOVER-Adult Long COVID Research Index (12-47 months post-infection). We found no evidence of persistent SARS-CoV-2 RNA in adipose tissue in any participant. SAT from participants with subacute COVID-19 displayed significant transcriptional remodeling, including depleted immune activation pathways and upregulated Hox genes and integrin interactions, suggesting resident immune cell exhaustion and perturbations in tissue function. However, no consistent changes in gene expression were observed between Long COVID samples and samples from indeterminant participants. Thus, SAT may contribute to inflammatory dysregulation following COVID-19, but does not appear to play a clear role in Long COVID pathophysiology. Further research is needed to clarify the role of adipose tissue in COVID-19 recovery.

Targeting the HIV-infected reservoir in lymphoid tissues (LT) will be critical to developing a cure for people living with HIV (PLWH). LT explants used to study HIV infection enable the evaluation of human-specific disease progression and treatment response; however, their short lifespan makes it challenging to assess long-term treatment interventions. We therefore established an immune organoid model of HIV infection using human tonsil or spleen cells, demonstrating productive HIV infection and viral integration into CD4+ T cells. Treatment with a protease inhibitor fully suppressed ongoing viral production, with virologic rebound occurring within days of treatment interruption. The transfer of healthy allogeneic NK cells to target the reservoir upon treatment interruption reduced the number of infected cells, intact viral genomes, and production of de novo infectious viral particles. Adoption of this immune organoid platform will accelerate the evaluation of cure-based strategies to eliminate the HIV reservoir in tissues for PLWH.Competing Interest StatementJ.A.Z is a co-founder of CDR3 Therapeutics. C.A.B is a member of the Scientific Advisory Boards of ImmuneBridge and DeepCell, Inc. on topics unrelated to this project.Funder Information DeclaredNIH, R01 AI161803, R01 AI183381, T32AI007290, T32 AI007502NCRR, 1S10OD032300-01

Purpose Structures play a very important role in developing pressure sensors with good sensitivity and linearity, as they undergo deformation to the input pressure and function as the primary sensing element of the sensor. To achieve high sensitivity, thinner diaphragms are required; however, excessively thin diaphragms may induce large deflection and instability, leading to the unfavorable performances of a sensor in terms of linearity and repeatability. Thereby, importance is given to the development of innovative structures that offer good linearity and sensitivity. This paper aims to investigate the sensitivity of a bossed diaphragm coupled fixed guided beam three-dimensional (3D) structure for pressure sensor applications. Design/methodology/approach The proposed sensor comprises of mainly two sensing elements: the first being the 3D mechanical structure made of bulk silicon consisting of boss square diaphragm along with a fixed guided beam landing on to its center, forming the primary sensing element, and the diffused piezoresistors, which form the secondary sensing element, are embedded in the tensile and compression regions of the fixed guided beam. This micro mechanical 3 D structure is packaged for applying input pressure to the bottom of boss diaphragm. The sensor without pressure load has no deflection of the diaphragm; hence, no strain is observed on the fixed guided beam and also there is no change in the output voltage. When an input pressure P is applied through the pressure port, there is a deformation in the diaphragm causing a deflection, which displaces the mass and the fixed guided beam vertically, causing strain on the fixed guided beam, with tensile strain toward the guided end and compressive strain toward the fixed end of the close magnitudes. The geometrical dimensions of the structure, such as the diaphragm, boss and fixed guided beam, are optimized for linearity and maximum strain for an applied input pressure range of 0 to 10 bar. The structure is also analyzed analytically, numerically and experimentally, and the results are compared. Findings The structure offers equal magnitudes of tensile and compressive stresses on the surface of the fixed guided beam. It also offers good linearity and sensitivity. The analytical, simulation and experimental studies of this sensor are introduced and the results correlate with each other. Customized process steps are followed wherein two silicon-on-insulator (SOI) wafers are fusion bonded together, with SOI-1 wafer used to realize the diaphragm along with the boss and SOI-2 wafer to realize the fixed guided beam, leading to formation of a 3D structure. The geometrical dimensions of the structure, such as the diaphragm, boss and fixed guided beam, are optimized for linearity and maximum strain for an applied input pressure range of 0 to10 bar. Originality/value This paper presents a unique and compact 3D micro-mechanical structure pressure sensor with a rigid center square diaphragm (boss diaphragm) and a fixed guided beam landing at its center, with diffused piezoresistors embedded in the tensile and compression regions of the fixed guided beam. A total of six masks were involved to realize and fabricate the 3D structure and the sensor, which is presumed to be the first of its kind in the fabrication of MEMS-based piezoresistive pressure sensor.