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To determine the effects of SARS-CoV-2 infection on cellular metabolism, we conducted an exhaustive survey of the cellular metabolic pathways modulated by SARS-CoV-2 infection and confirmed their importance for SARS-CoV-2 propagation by cataloging the effects of specific pathway inhibitors. This revealed that SARS-CoV-2 strongly inhibits mitochondrial oxidative phosphorylation (OXPHOS) resulting in increased mitochondrial reactive oxygen species (mROS) production. The elevated mROS stabilizes HIF-1α which redirects carbon molecules from mitochondrial oxidation through glycolysis and the pentose phosphate pathway (PPP) to provide substrates for viral biogenesis. mROS also induces the release of mitochondrial DNA (mtDNA) which activates innate immunity. The restructuring of cellular energy metabolism is mediated in part by SARS-CoV-2 Orf8 and Orf10 whose expression restructures nuclear DNA (nDNA) and mtDNA OXPHOS gene expression. These viral proteins likely alter the epigenome, either by directly altering histone modifications or by modulating mitochondrial metabolite substrates of epigenome modification enzymes, potentially silencing OXPHOS gene expression and contributing to long-COVID.

A monoclinic Y0.7Er0.3Fe2D4.2 compound exhibits unusual magnetic properties with different field induced magnetic transitions. The deuteride is ferrimagnetic at low temperature, and the Er and Fe sublattices present magnetic transitions at different temperatures. The Er moments are ordered below TEr = 55 K, whereas the Fe moments remain ferromagnetically coupled up to TM0 = 66 K. At TM0, the Fe moments display a sharp ferromagnetic–antiferromagnetic transition (FM–AFM) through itinerant electron metamagnetic behavior very sensitive to any volume change. Y0.7Er0.3Fe2D4.2 becomes paramagnetic above TN = 125 K. The pressure dependence of TEr and TM0 has been extracted from magnetic measurements under hydrostatic pressure up to 0.49 GPa. Both temperatures decrease linearly upon applied pressure with dTEr/dP = −126 and dTM0/dP = −140 K GPa−1 for a field of B = 0.03 T. Both magnetic Er and ferromagnetic Fe orders disappear at P = 0.44(4) GPa. However, under a larger applied field B = 5 T, dTM0/dP = −156 K GPa−1, whereas dTEr/dP = −134 K GPa−1 showing weaker sensitivity to pressure and magnetic field. At 2 K, the decrease of the saturation magnetization under pressure can be attributed to a reduction of the mean Er moment due to canting and/or a crystal field effect. Above TM0, the magnetization curves display metamagnetic behavior from an AFM to FM state, which is also very sensitive to the applied pressure. The transition field Btrans, which increases linearly upon heating, is shifted to a lower temperature upon applied pressure with ΔT = −17 K between 0 and 0.11 GPa. These results show strong decoupling of the Er and Fe magnetic sublattices vs temperature, applied field, and pressure. [ABSTRACT FROM AUTHOR]

HIV anti-retrovirals (ARVs) have vastly improved the life expectancy of people living with HIV (PLWH). However, toxic effects attributed to long-term ARV use also contribute to HIV-related co-morbidities such as heart disease, bone loss and HIV-associated neurocognitive disorders (HAND). Unfortunately, mouse models used to study the effects of ARVs on viral suppression, toxicity and HIV latency/tissue reservoirs have not been widely established. Here, we demonstrate an effective mouse model utilizing immune-compromised mice, reconstituted with infected human peripheral blood mononuclear cell (PBMCs). ARVs areincorporated into mouse chow and administered daily with combination ARV regimens includingAtripla (efavirenz, tenofovir disoproxil fumarate, and emtricitabine) and Triumeq (abacavir, dolutegravir and lamivudine). This model measures HIV-infected human cell trafficking, and ARV penetration throughout most relevant HIV organs and plasma, with a large amount of trafficking to the secondary lymphoid organs. Furthermore, the HIV viral load within each organ and the plasma was reduced in ARV treated vs. untreated control. Overall, we have demonstrated a mouse model that is relatively easy and affordable to establish and utilize to study ARVs’ effect on various tissues, including the co-morbid conditions associated with PLWH, such as HAND, and other toxic effects.

Bone mineral density (BMD) loss in people living with HIV occurs with the initiation of combined antiretroviral therapy (cART), particularly with tenofovir disoproxil fumarate (TDF) containing cART. Switching from TDF to abacavir (ABC) or dolutegravir (DTG) leads to increased BMD. Whether BMD gains are due to cessation of TDF or anabolic effects of ABC or DTG is unclear. We investigated the effects of ABC and DTG on osteoblast lineage cells in vitro and in vivo. Primary human osteoblasts and male C57BL/6 mice were treated with individual antiretrovirals (ARVs) or a combination of ABC/DTG/lamivudine (3TC). Nearly all ARVs and cART inhibited osteogenic activity in vitro. Due to the importance of Wnt/β-catenin in bone formation, we further investigated ARV effects on the Wnt/β-catenin pathway. ABC, alone and as part of ABC/DTG/3TC, increased osteoblastic β-catenin activity as indicated by increased TOPFlash activity, hypo-phosphorylated (active) β-catenin staining, and β-catenin targeted gene expression. Mice treated with TDF had decreased lumbar spine BMD and trabecular connectivity density in the vertebrae, while those treated with ABC/DTG/3TC reduced cortical area and thickness in the femur. Mice treated with ABC alone had no bone structural changes, increased circulating levels of the bone formation marker, P1NP, and elevated expression of the Wnt/β-catenin target gene, Lef1, in osteocyte enriched samples. Further, bones from ARV-treated mice were isolated to evaluate ARV distribution. All ARVs were detected in the bone tissue, which was inclusive of bone marrow, but when bone marrow was removed, only TDF, ABC, and DTG were detected at ~0.1% of the circulating levels. Overall, our findings demonstrate that ABC activates Wnt/β-catenin signaling, but whether this leads to increased bone formation requires further study. Assessing the impact of ARVs on bone is critical to informing ARV selection and/or discovery of regimens that do not negatively impact the skeleton. [ABSTRACT FROM AUTHOR]

HIV anti-retrovirals (ARVs) have vastly improved the life expectancy of people living with HIV (PLWH). However, toxic effects attributed to long-term ARV use also contribute to HIV-related co-morbidities such as heart disease, bone loss and HIV-associated neurocognitive disorders (HAND). Unfortunately, mouse models used to study the effects of ARVs on viral suppression, toxicity and HIV latency/tissue reservoirs have not been widely established. Here, we demonstrate an effective mouse model utilizing immune-compromised mice, reconstituted with infected human peripheral blood mononuclear cell (PBMCs). ARVs areincorporated into mouse chow and administered daily with combination ARV regimens includingAtripla (efavirenz, tenofovir disoproxil fumarate, and emtricitabine) and Triumeq (abacavir, dolutegravir and lamivudine). This model measures HIV-infected human cell trafficking, and ARV penetration throughout most relevant HIV organs and plasma, with a large amount of trafficking to the secondary lymphoid organs. Furthermore, the HIV viral load within each organ and the plasma was reduced in ARV treated vs. untreated control. Overall, we have demonstrated a mouse model that is relatively easy and affordable to establish and utilize to study ARVs' effect on various tissues, including the co-morbid conditions associated with PLWH, such as HAND, and other toxic effects. [ABSTRACT FROM AUTHOR]

A versatile type of non-magnetic uniaxial pressure cell has been designed for magnetic measurements in SQUID magnetometer. An advanced technology of machining of miniature parts of the cell was used to make new type of an internal squeezer module, where a sample can be compressed by force up to 3 kN in direction perpendicular to external magnetic field. A correct operation of the cell was tested by study of magnetic behaviour of the Heusler off-stoichiometric Ni2MnSn alloy under uniaxial compression. An unexpected significant difference between reversible effects of uniaxial compression on magnetization of the austenite and martensite phases of the alloy is discussed. The uniaxial compression effects are compared with the effects of hydrostatic pressure on a coupling between magnetization and structural transformation of the alloy. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Introduction: Bone loss and cognitive impairment are common in women living with HIV (WLWH) and are exacerbated by menopause. Bone-derived undercarboxylated osteocalcin (ucOCN) and sclerostin appear to influence cognition. The current study investigated whether the circulating levels of these 2 proteins are associated with cognition in midlife WLWH and demographically similar HIV seronegative women. Methods: Plasma samples from women enrolled in a musculoskeletal substudy within the Women's Interagency HIV Study were used to measure ucOCN and sclerostin. A neuropsychological (NP) test battery assessing executive function, processing speed, attention/working memory, learning, memory, verbal fluency, and motor function was administered within 6 months of musculoskeletal enrollment and every 2 years after (1–4 follow-up visits per participant). A series of generalized estimating equations were conducted to examine the association between biomarkers and NP performance at the initial assessment and over time in the total sample and in WLWH only. Primary predictors included biomarkers, time, and biomarker by time interactions. If the interaction terms were not significant, models were re-run without interactions. Results: Neither biomarker predicted changes in NP performance over time in the total sample or in WLWH. ucOCN was positively associated with executive function in the total sample and in WLWH and with motor skills in WLWH. ucOCN was negatively associated with attention/working memory in the total sample. There were no significant associations between sclerostin and NP performance. Conclusion: The current study suggests an association between bone-derived ucOCN and cognition in women with and without HIV infection. [ABSTRACT FROM AUTHOR]

The magnetic properties of the ThFe(sub 11)C(sub x) (x=1.5 and 1.8) compounds was investigated at ambient and high pressures. These compounds exhibited reorientation of their easy magnetization axis, which results from competing magnetic isotropy of inequivalent iron sites where the spin orientation transition was found to decrease significantly upon increasing pressure.