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"Ma, Ming-Fu"
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The Integrated HIV-1 Provirus in Patient Sperm Chromosome and Its Transfer into the Early Embryo by Fertilization
Complete understanding of the route of HIV-1 transmission is an important prerequisite for curbing the HIV/AIDS pandemic. So far, the known routes of HIV-1 transmission include sexual contact, needle sharing, puncture, transfusion and mother-to-child transmission. Whether HIV can be vertically transmitted from human sperm to embryo by fertilization is largely undetermined. Direct research on embryo derived from infected human sperm and healthy human ova have been difficult because of ethical issues and problems in the collection of ova. However, the use of inter-specific in vitro fertilization (IVF) between human sperm and hamster ova can avoid both of these problems. Combined with molecular, cytogenetical and immunological techniques such as the preparation of human sperm chromosomes, fluorescent in situ hybridization (FISH), and immunofluorescence assay (IFA), this study mainly explored whether any integrated HIV provirus were present in the chromosomes of infected patients' sperm, and whether that provirus could be transferred into early embryos by fertilization and maintain its function of replication and expression. Evidence showed that HIV-1 nucleic acid was present in the spermatozoa of HIV/AIDS patients, that HIV-1 provirus is present on the patient sperm chromosome, that the integrated provirus could be transferred into early embryo chromosomally integrated by fertilization, and that it could replicate alongside the embryonic genome and subsequently express its protein in the embryo. These findings indicate the possibility of vertical transmission of HIV-1 from the sperm genome to the embryonic genome by fertilization. This study also offers a platform for the research into this new mode of transmission for other viruses, especially sexually transmitted viruses.
Journal Article
Allelic methylation status of CpG islands on chromosome 21q in patients with Trisomy 21
Trisomy 21 is a chromosomal condition caused by the presence of all or part of an extra 21st chromosome. There has been limited research into the DNA methylation status of CpG islands (CGIs) in trisomy 21, therefore, exploring the DNA methylation status of CGIs in 21q is essential for the development of a series of potential epigenetic biomarkers for prenatal screening of trisomy 21. First, DNA sequences of CGIs in 21q from the USCS database were obtained and 149 sequences and 148 pairs of primers in the BGI YH database were aligned. All 300 cases were analyzed by a heavy methyl-polymerase chain reaction (HM-PCR) assay and a comparison of the DNA methylation status of CGIs was made between trisomy 21 and the control. The HM-PCR assay results did not show a difference in the DNA methylation status between individuals with trisomy 21 and the control. In total, there were 11 CGIs that showed various DNA methylation statuses between Japanese and Chinese patients. Subsequently, bisulfite genomic sequencing found variations in the methylation status of CpG dinucleotides in CGIs (nos. 14, 75, 109, 134 and 146) between trisomy 21 and the control. The different DNA methylation status of CpG dinucleotides in CGIs may be a potential epigenetic marker for diagnosing trisomy 21. No difference was identified in the DNA methylation status of 21q CGIs among Chinese individuals with trisomy 21 and the control. The homogeneity of the DNA methylation status of 21q CGIs in Chinese patients indicates that DNA methylation is likely to be an epigenetic marker distinguishing ethnicities.
Journal Article
NUMERICAL COMPUTATION OF BOUNDED SOLUTIONS FOR A SEMILINEAR ELLIPTIC EQUATION ON AN INFINITE STRIP
In this paper, we consider the computation of bounded solutions of a semilinear elliptic equation on an infinite strip. The dynamical system approach and reduction on center manifold are used to overcome the difficulties in numerical procedure.
Journal Article
Clonidine, moxonidine, folic acid, and mecobalamin improve baroreflex function in stroke-prone, spontaneously hypertensive rats
Aim： To investigate the effect of clonidine, moxonidine, folic acid, and mecobalamin on arterial baroreflex （ABR） function in stroke-prone spontaneously hypertensive rats （SHR-SP） and the possible mechanisms involved. Methods： Eighty-one SHR-SP were divided into 7 groups. Four groups were designated for the intragastric （ig） administration of clonidine （1.0 and 10.0 μg/kg）, moxonidine （0.1 and 1.0 mg/kg）, folic acid （1.0 mg/kg）, and mecobalamin （1.0 mg/kg）. Three groups were for the intracerebroventricular （icv） injection of clonidine （4 μg/4 μL）, moxonidine （5 μg/4 μL）, and mecobalamin （20 μg/4 μL）. Blood pressure （BP） was recorded in the conscious state for 30 min and baroreflex sensitivity （BRS） was determined respectively before and after drug administration. Results： Clonidine and moxonidine significantly decreased BP, prolonged the heart period （HP）, and increased BRS when administered as either ig or icy injections. Both BP and HP were unchanged by ig folic acid or mecobalamin injection. However, BRS was significantly increased by both. Conclusion： Clonidine, moxonidine, folic acid, and mecobalamin improved impaired ABR function in SHR-SP. The central mechanism was involved in this effect of either clonidine or moxonidine. Mecobalamin improved ABR function through the peripheral mechanism.
Journal Article
Cryo-EM structure and biochemical analysis reveal the basis of the functional difference between human PI3KC3-C1 and-C2
Phosphatidylinositol 3-phosphate （PI3P） plays essential roles in vesicular trafficking, organelle biogenesis and autophagy. Two class III phosphatidylinositol 3-kinase （PI3KC3） complexes have been identified in mammals, the AT- G14L complex （PI3KC3-C1） and the UVRAG complex （PI3KC3-C2）. PI3KC3-C1 is crucial for autophagosome bio- genesis, and PI3KC3-C2 is involved in various membrane trafficking events. Here we report the cryo-EM structures of human PI3KC3-C1 and PI3KC3-C2 at sub-nanometer resolution. The two structures share a common L-shaped overall architecture with distinct features. EM examination revealed that PI3KC3-C1 ＂stands up＂ on lipid monolayers, with the ATG14L BATs domain and the VPS34 C-terminal domain （CTD） directly contacting the membrane. Biochemical dissection indicated that the ATG14L BATs domain is responsible for membrane anchoring, whereas the CTD of VPS34 determines the orientation. Furthermore, PI3KC3-C2 binds much more weakly than PI3KC3-C1 to both PI-containing liposomes and purified endoplasmic reticulum （ER） vesicles, a property that is specifically determined by the ATG14L BATs domain. The in vivo ER localization analysis indicated that the BATs domain was required for ER localization of PI3KC3. We propose that the different lipid binding capacity is the key factor that differentiates the functions of PI3KC3-C1 and PI3KC3-C2 in autophagy.
Journal Article
Direct observation of ultrafast hydrogen bond strengthening in liquid water
Water is one of the most important, yet least understood, liquids in nature. Many anomalous properties of liquid water originate from its well-connected hydrogen bond network
1
, including unusually efficient vibrational energy redistribution and relaxation
2
. An accurate description of the ultrafast vibrational motion of water molecules is essential for understanding the nature of hydrogen bonds and many solution-phase chemical reactions. Most existing knowledge of vibrational relaxation in water is built upon ultrafast spectroscopy experiments
2
–
7
. However, these experiments cannot directly resolve the motion of the atomic positions and require difficult translation of spectral dynamics into hydrogen bond dynamics. Here, we measure the ultrafast structural response to the excitation of the OH stretching vibration in liquid water with femtosecond temporal and atomic spatial resolution using liquid ultrafast electron scattering. We observed a transient hydrogen bond contraction of roughly 0.04 Å on a timescale of 80 femtoseconds, followed by a thermalization on a timescale of approximately 1 picosecond. Molecular dynamics simulations reveal the need to treat the distribution of the shared proton in the hydrogen bond quantum mechanically to capture the structural dynamics on femtosecond timescales. Our experiment and simulations unveil the intermolecular character of the water vibration preceding the relaxation of the OH stretch.
Liquid ultrafast electron scattering measures structural responses in liquid water with femtosecond temporal and atomic spatial resolution to reveal a transient hydrogen bond contraction then thermalization preceding relaxation of the OH stretch.
Journal Article
Influence of bias voltage on structure,mechanical and corrosion properties of reactively sputtered nanocrystalline TiN films
Nanocrystalline TiN films were prepared by DC reactive magnetron sputtering.The influence of substrate biases on structure,mechanical and corrosion properties of the deposited films was studied using X-ray diffraction,field emission scanning electron microscopy,nanoindentation and electrochemical techniques.The deposited films have a columnar structure,and their preferential orientation strongly depends on bias voltage.The preferential orientations change from(200)plane at low bias to(111)plane at moderate bias and then to(220)plane at relatively high bias.Nanohardness H,elastic modulus E,H/E*and H3/E*2 ratios,and corrosion resistance of the deposited films increase first and then decrease with the increase in bias voltage.All the best values appear at bias of-120 V,attributing to the film with a fine,compact and less defective structure.This demonstrates that there is a close relation among microstructure,mechanical and corrosion properties of the TiN films,and the film with the best mechanical property can also provide the most effective corrosion protection.
Journal Article
NAD + -boosting therapy alleviates nonalcoholic fatty liver disease via stimulating a novel exerkine Fndc5/irisin
Nicotinamide adenine dinucleotide
(NAD
)-boosting therapy has emerged as a promising strategy to treat various health disorders, while the underlying molecular mechanisms are not fully understood. Here, we investigated the involvement of fibronectin type III domain containing 5 (Fndc5) or irisin, which is a novel exercise-linked hormone, in the development and progression of nonalcoholic fatty liver disease (NAFLD).
NAD
-boosting therapy was achieved by administrating of nicotinamide riboside (NR) in human and mice. The Fndc5/irisin levels in tissues and blood were measured in NR-treated mice or human volunteers. The therapeutic action of NR against NAFLD pathologies induced by high-fat diet (HFD) or methionine/choline-deficient diet (MCD) were compared between wild-type (WT) and
mice. Recombinant Fndc5/irisin was infused to NALFD mice via osmotic minipump to test the therapeutic action of Fndc5/irisin. Various biomedical experiments were conducted
and
to know the molecular mechanisms underlying the stimulation of Fndc5/irisin by NR treatment.
NR treatment elevated plasma level of Fndc5/irisin in mice and human volunteers. NR treatment also increased Fndc5 expression in skeletal muscle, adipose and liver tissues in mice. In HFD-induced NAFLD mice model, NR displayed remarkable therapeutic effects on body weight gain, hepatic steatosis, steatohepatitis, insulin resistance, mitochondrial dysfunction, apoptosis and fibrosis; however, these actions of NR were compromised in
mice. Chronic infusion of recombinant Fndc5/irisin alleviated the NAFLD pathological phenotypes in MCD-induced NAFLD mice model. Mechanistically, NR reduced the lipid stress-triggered ubiquitination of Fndc5, which increased Fndc5 protein stability and thus enhanced Fndc5 protein level. Using shRNA-mediated knockdown screening, we found that NAD
-dependent deacetylase SIRT2, rather than other sirtuins, interacts with Fndc5 to decrease Fndc5 acetylation, which reduces Fndc5 ubiquitination and stabilize it. Treatment of AGK2, a selective inhibitor of SIRT2, blocked the therapeutic action of NR against NAFLD pathologies and NR-induced Fndc5 deubiquitination/deacetylation. At last, we identified that the lysine sites K127/131 and K185/187/189 of Fndc5 may contribute to the SIRT2-dependent deacetylation and deubiquitination of Fndc5.
The findings from this research for the first time demonstrate that NAD
-boosting therapy reverses NAFLD by regulating SIRT2-deppendent Fndc5 deacetylation and deubiquitination, which results in a stimulation of Fndc5/irisin, a novel exerkine. These results suggest that Fndc5/irisin may be a potential nexus between physical exercise and NAD
-boosting therapy in metabolic pathophysiology.
Journal Article
Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury
Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated
OTUD5
delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
Understanding the role of GPX4 in cell ferroptosis at the interface of the inner cortex and medulla is crucial in the context of renal injury. Here, the authors demonstrate that the OTUD5 interaction with GPX4 is key in resisting ischemia/reperfusion-induced ferroptosis in renal cells, offering a new strategy for treating acute kidney injury.
Journal Article