Heparin Oligosaccharides as Vasoactive Intestinal Peptide Inhibitors via their Binding Process Characterization.

BACKGROUND: It has been proven that vasoactive intestinal peptide (VIP) was involved in the pathogenesis of prostate cancer. Cardin et al. found that by an alanine scan, the heparin-binding site on VIP was exactly the same sequence in VIP and its receptor. Therefore, heparin could competitively block the binding of VIP and its receptor. However, the structure-activity relationship between heparin and VIP has not been reported, especially in terms of the sequence and sulfation patterns of heparin oligosaccharides upon binding to VIP. OBJECTIVE: The binding process between heparin oligosaccharides and VIPA variety of experiments was designed to study the structure-activity relationship between heparin oligosaccharides and VIP. METHODS: Heparin was enzymatically digested and purified to produce heparin oligosaccharides, and the structures were characterized by NMR. The binding capacity between heparin oligosaccharides and VIP was analyzed by GMSA and ITC experiments. The binding between heparin oligosaccharides and VIP was simulated using a molecular docking program to show the complex. ELISA assay was used to investigate the effect of non-anticoagulant heparin oligosaccharides on the VIP-mediated cAMP/PKA signaling pathway in vitro. RESULTS: The results indicated that both the length and the sulfation pattern of heparin oligosaccharides affected its binding to VIP. VIP could induce the expression of cAMP at a higher level in PC3 cells, which could be regulated by the interaction of heparin oligosaccharides and VIP. CONCLUSION: The binding between heparin oligosaccharides and VIP could block the binding between VIP and its receptor on tumor cells. Downloading the regulation of the expression level of cAMP could possibly further affect the subsequent activation of PKA. These non-anticoagulant heparin oligosaccharides may block the VIP-mediated cAMP/PKA signaling pathway and thus exert their antitumor activity.

Inosine enhances tumor mitochondrial respiration by inducing Rag GTPases and nascent protein synthesis under nutrient starvation.

Metabolic heterogeneity of tumor microenvironment (TME) is a hallmark of cancer and a big barrier to cancer treatment. Cancer cells display diverse capacities to utilize alternative carbon sources, including nucleotides, under poor nutrient circumstances. However, whether and how purine, especially inosine, regulates mitochondrial metabolism to buffer nutrient starvation has not been well-defined yet. Here, we identify the induction of 5'-nucleotidase, cytosolic II (NT5C2) gene expression promotes inosine accumulation and maintains cancer cell survival in the nutrient-poor region. Inosine elevation further induces Rag GTPases abundance and mTORC1 signaling pathway by enhancing transcription factor SP1 level in the starved tumor. Besides, inosine supplementary stimulates the synthesis of nascent TCA cycle enzymes, including citrate synthesis (CS) and aconitase 1 (ACO1), to further enhance oxidative phosphorylation of breast cancer cells under glucose starvation, leading to the accumulation of iso-citric acid. Inhibition of the CS activity or knockdown of ACO1 blocks the rescue effect of inosine on cancer survival under starvation. Collectively, our finding highlights the vital signal role of inosine linking mitochondrial respiration and buffering starvation, beyond serving as direct energy carriers or building blocks for genetic code in TME, shedding light on future cancer treatment by targeting inosine metabolism.

Cancer-cell-secreted miR-204-5p induces leptin signalling pathway in white adipose tissue to promote cancer-associated cachexia.

Cancer-associated cachexia is a multi-organ weight loss syndrome, especially with a wasting disorder of adipose tissue and skeletal muscle. Small extracellular vesicles (sEVs) serve as emerging messengers to connect primary tumour and metabolic organs to exert systemic regulation. However, whether and how tumour-derived sEVs regulate white adipose tissue (WAT) browning and fat loss is poorly defined. Here, we report breast cancer cell-secreted exosomal miR-204-5p induces hypoxia-inducible factor 1A (HIF1A) in WAT by targeting von Hippel-Lindau (VHL) gene. Elevated HIF1A protein induces the leptin signalling pathway and thereby enhances lipolysis in WAT. Additionally, exogenous VHL expression blocks the effect of exosomal miR-204-5p on WAT browning. Reduced plasma phosphatidyl ethanolamine level is detected in mice lack of cancer-derived miR-204-5p secretion in vivo. Collectively, our study reveals circulating miR-204-5p induces hypoxia-mediated leptin signalling pathway to promote lipolysis and WAT browning, shedding light on both preventive screenings and early intervention for cancer-associated cachexia.

Synthesis of Ni Nanosheets by Template-Free Method and Their Application in Conductive and Magnetic Flexible Electrons.

Two-dimensional Ni nanosheets are synthesized by the template-free method using Na3CA as an orientation agent in liquid phase, and then the conductive Ni nanosheet ink is prepared for conductive circuits on flexible electronics. The thickness of the Ni nanosheets is about 800 nm, and the diameter is about 100 µm. Na3CA plays a structural guiding role to form Ni nanocrystals, promoting the self-assembly of Ni nanocrystals into Ni nanosheets effectively. The laminar stackable patterns of the Ni nanosheet circuits increase the contact area of the Ni nanosheets and improve the stability of the conductors under stress. Ni nanosheets can bend with the folding of the structure, while the mutual constraints between their layers promote the circuit to remain stable during the bending state. Therefore, the Ni nanosheet circuits display excellent conductive performance during the tiled and bent stages. In addition, Ni nanosheet/Ag nanowire composites are prepared to enhance conductivity to meet higher demands. Moreover, the experimental results of its application in magnetic guided switch closure circuits show that Ni nanosheet/Ag nanowire composites have the potential to participate in both conductive and magnetic field applications simultaneously.

Study on Microwave Deicing Efficiency of Microwave-Absorbing Concrete Pavements and Its Influencing Factors.

Microwave deicing technology, as a new environmentally friendly deicing technology, can effectively solve the problem of the frequent icing of road surfaces in the winter, which affects the safety of traffic. To improve the efficiency of microwave deicing on cement concrete pavement, this study proposed the use of magnetite, iron sulfide slag, steel slag, lead-zinc slag, and graphite as microwave-absorbing materials, and conducted microwave deicing tests under the influence of five factors, namely the form of the pavement surface structure, the content of the microwave-absorbing material, microwave power, the shielding state, and dry and wet conditions. Layer by layer, we selected the combination of pavement surface structure, microwave-absorbing material content, microwave power, shielding state, and dry and wet conditions on the bottom surface of the concrete slab with the optimal deicing effect. The results showed that the 2 cm scattered microwave-absorbing surface concrete structure has the fastest heating rate; the higher the magnetite content and microwave power, the higher the deicing efficiency; the maximum heating rate can be increased by 17.6% when the shielding layer is set at the bottom of the cement concrete slab; and the heating rate of the microwave-absorbing concrete slab in the wet state is increased by 20.8% relative to the dry state. In summary, 7000 W of power, a magnetite content of 60 vol % in the scattered microwave-absorbing surface, a shielding layer set at the bottom surface, and wet conditions can greatly improve the efficiency of microwave deicing compared with the microwave ice melting effects of plain cement concrete and other microwave-absorbing materials mixed into the concrete. In addition, the temperature uniformity of the microwave-absorbing materials is essential to improve the deicing efficiency of microwave-absorbing concrete, so it is essential to explore it further.

Study on the relationship between 25-hydroxyvitamin D level and rehabilitation of stroke patients.

AIM OF THE STUDY: To analyse the relationship between 25-hydroxyvitamin D (25(OH)D) level and rehabilitation in stroke patients. MATERIAL AND METHODS: 100 stroke patients hospitalized in the Neurorehabilitation Department of China Rehabilitation Research Center from November 2019 to April 2020 were selected as the research subjects. And set up a case group. 50 subjects who underwent outpatient physical examination in China Rehabilitation Research Center in the same period were selected as the control group. The differences of biochemical and bone metabolism indexes such as serum 25(OH)D, blood lipid, liver and kidney function between the two groups were analysed. We took rehabilitation efficacy as the dependent variable, Pearson correlation analysis and multivariate logistic regression analysis were performed to analyse the indicators affecting rehabilitation efficacy. RESULTS: The average level of 25(OH)D in the case group was significantly lower than that in the control group ( p < 0.05). The rehabilitation efficacy was significantly positively correlated with 25(OH)D level ( p < 0.003) and significantly negatively correlated with duration of disease ( p < 0.01) and NIHSS score ( p < 0.05). CONCLUSIONS: The increase in 25(OH)D is a protective factor for non-occurrence of cerebral infarction, and the increase in the 25(OH)D level is conducive to the prognosis of cerebral infarction.

Numerical Demonstration of 800 Gbps WDM Silicon Photonic Transmitter with Sub-Decibel Surface-Normal Optical Interfaces.

We propose and numerically demonstrate an 800 Gbps silicon photonic transmitter with sub-decibel surface-normal optical interfaces. The silicon photonic transmitter is composed of eight silicon Mach-Zehnder optical modulators and an interleaved AMMI WDM device. This WDM device comprises two 1 × 4 angled MMI and a Mach-Zehnder interferometer (MZI) optical interleaver with an apodized bidirectional grating which has about -0.5 dB coupling loss. Both the Mach-Zehnder electro-optical modulators and MZI optical interleaver regard the bidirectional grating coupler as vertical optical coupler and 3-dB power splitter/combiner. By importing the S-parameter matrices of all the components which have been carefully designed in simulation software, the circuit-level model of the optical transmitter can be built up. On this basis, the static and dynamic performance characterization were carried out numerically. For NRZ modulation, the optical transmitter exhibits the overall optical loss of 4.86-6.72 dB for eight wavelength channels. For PAM4 modulation, the optical loss is about 0.5 dB larger than that of NRZ modulation, which varies between 5.38-7.27 dB. From the eye diagram test results, the WDM silicon photonic transmitter can achieve single channel data transmission at 100 Gb/s NRZ data or 50 GBaud/s PAM4 symbol rate with acceptable bit error rate.

Bidirectional grating based interleaved angled MMI for high-uniformity wavelength division (de)multiplexing and surface-normal fiber packaging.

We propose and experimentally demonstrate a vertical fiber interfacing interleaved angled multimode interference (MMI) coupler for wavelength-division multiplexing (WDM) applications. This four-channel WDM device comprises two 1×2 angled MMI couplers and a bidirectional grating-based Mach-Zehnder interferometer (MZI) structure. In the MZI optical interleaver, the uniform bidirectional grating functions as both the perfectly vertical grating coupler and the 3 dB power splitter. Benefitting from the flat-top coupling spectrum of the grating coupler, a high-uniformity wavelength-division (de)multiplexing can be achieved with a simulated insertion loss of 3.15-3.36 dB (the nonuniformity of 0.22 dB). The angled MMIs (AMMIs) are designed and optimized using the eigenmode expansion method. For wavelength matching between the MZI and AMMIs, the circuit simulation model of the interleaved AMMI is built by importing the S-parameter matrices of all the optical components extracted from the physical level simulations. The device was fabricated using standard CMOS technology and all the features were patterned with the 193-nm deep-UV lithography. Experimental results obtained without thermal tuning are in good agreement with the simulation results. The device exhibits an insertion loss of 4.5-4.65 dB (nonuniformity of 0.15 dB), channel spacing of 10 nm, and cross talk of -(21.62-26)dB.

Degradation versus Inhibition: Development of Proteolysis-Targeting Chimeras for Overcoming Statin-Induced Compensatory Upregulation of 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an eight-pass transmembrane protein in the endoplasmic reticulum (ER) and a classical drug target to treat dyslipidemia. Statins including the well-known atorvastatin (Lipitor; Pfizer) have been widely used for the prevention and treatment of cardiovascular disease for decades. However, statins can elicit a compensatory upregulation of HMGCR protein and cause adverse effects including skeletal muscle damage. They are ineffective for patients with statin intolerance. Inspired by the recently emerging proteolysis-targeting chimeras (PROTACs), we set out to eliminate HMGCR protein using PROTAC-mediated degradation. One PROTAC designated as P22A was found to reduce HMGCR protein level and block cholesterol biosynthesis potently with less compensatory upregulation of HMGCR. To the best of our knowledge, HMGCR is the first ER-localized, polytopic transmembrane protein successfully degraded by the PROTAC technique. This finding may provide a new strategy to lower cholesterol levels and treat the associated diseases.

Effects of Exercise on Blood Glucose and Glycemic Variability in Type 2 Diabetic Patients with Dawn Phenomenon.

BACKGROUND: The dawn phenomenon (DP) is the primary cause of difficulty in blood glucose management in type 2 diabetic (T2D) patients, and the use of oral hypoglycemic agents has shown weak efficacy in controlling DP. Thus, this study is aimed at investigating the effect of moderate-intensity aerobic exercise before breakfast on the blood glucose level and glycemic variability in T2D patients with DP. METHODS: A total of 20 T2D patients with DP confirmed via continuous glucose monitoring (CGM) participated in the current study. After collecting baseline measurements by CGM as a control, CGM was reinstalled and 30 minutes of moderate-intensity aerobic exercise was performed prior to breakfast. Dawn blood glucose increase, blood glucose levels, and glycemic variability were measured before and after exercise. RESULTS: Dawn blood glucose increase (ΔGlu, 1.25 ± 0.84vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs. 8.78 ± 1.09, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16vs.2.15 ± 1.07, P = 0.005), highest blood glucose value before breakfast (Gmax, 8.01 ± 1.16. CONCLUSIONS: Acute moderate-intensity aerobic exercise before breakfast reduced the morning rise of blood glucose in T2D patients, partially counteracting DP. Furthermore, exercise significantly reduced blood glucose fluctuations and improved blood glucose control throughout the day. We recommend that T2D patients with DP take moderate-intensity aerobic exercise before breakfast to improve DP and glycemic control.

Envelope stress responses defend against type six secretion system attacks independently of immunity proteins.

The arms race among microorganisms is a key driver in the evolution of not only the weapons but also defence mechanisms. Many Gram-negative bacteria use the type six secretion system (T6SS) to deliver toxic effectors directly into neighbouring cells. Defence against effectors requires cognate immunity proteins. However, here we show immunity-independent protection mediated by envelope stress responses in Escherichia coli and Vibrio cholerae against a V. cholerae T6SS effector, TseH. We demonstrate that TseH is a PAAR-dependent species-specific effector highly potent against Aeromonas species but not against its V. cholerae immunity mutant or E. coli. A structural analysis reveals TseH is probably a NlpC/P60-family cysteine endopeptidase. We determine that two envelope stress-response pathways, Rcs and BaeSR, protect E. coli from TseH toxicity by mechanisms including capsule synthesis. The two-component system WigKR (VxrAB) is critical for protecting V. cholerae from its own T6SS despite expressing immunity genes. WigR also regulates T6SS expression, suggesting a dual role in attack and defence. This deepens our understanding of how bacteria survive T6SS attacks and suggests that defence against the T6SS represents a major selective pressure driving the evolution of species-specific effectors and protective mechanisms mediated by envelope stress responses and capsule synthesis.

Competitive oxidation and ubiquitylation on the evolutionarily conserved cysteine confer tissue-specific stabilization of Insig-2.

Insig-2 is an ER membrane protein negatively controlling lipid biosynthesis. Here, we find that Insig-2 is increased in the tissues, including liver, but unaltered in the muscle of gp78-deficient mice. In hepatocytes and undifferentiated C2C12 myoblasts, Insig-2 is ubiquitylated on Cys215 by gp78 and degraded. However, the C215 residue is oxidized by elevated reactive oxygen species (ROS) during C2C12 myoblasts differentiating into myotubes, preventing Insig-2 from ubiquitylation and degradation. The stabilized Insig-2 downregulates lipogenesis through inhibiting the SREBP pathway, helping to channel the carbon flux to ATP generation and protecting myotubes from lipid over-accumulation. Evolutionary analysis shows that the YECK (in which C represents Cys215 in human Insig-2) tetrapeptide sequence in Insig-2 is highly conserved in amniotes but not in aquatic amphibians and fishes, suggesting it may have been shaped by differential selection. Together, this study suggests that competitive oxidation-ubiquitylation on Cys215 of Insig-2 senses ROS and prevents muscle cells from lipid accumulation.

Mild encephalitis/encephalopathy with a reversible splenial lesion secondary to encephalitis complicated by hyponatremia: A case report and literature review.

RATIONALE: Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is an infection-associated encephalitis/encephalopathy syndrome that is predominately caused by a virus. MERS has no direct association with central nervous system (CNS) infections or inflammation. Non-CNS infections may cause reversible lesion in the splenium of corpus callosum. Recently, there have been reports of many patients with hyponatremia related MERS. Interleukin-6 (IL-6) was also found elevated in serum and in cerebrospinal fluid (CSF) in patients with MERS. The role of IL-6 in the non-osmotic release of vasopressin is crucial. Persistent hyponatremia may be linked to this effect. The following is a case report of MERS secondary to encephalitis, complicated by hyponatremia. We will summarize the latest research and progress regarding MERS. PATIENT CONCERNS: A 31-year-old man was admitted to our department with a 5-day history of fever and headache. His initial diagnosis was encephalitis and hyponatremia; during this period the patient also developed MERS secondary to the encephalitis. DIAGNOSES: Encephalitis was diagnosed by reviewing the history of fever, headache, neck rigidity and Kerning sign (+) on clinical examination. Lab tests revealed: serum VCA IgG (+), EBNA-1 IgG (-), EBV IgM (-), and inflammation in the analysis of CSF. Cranial MRI+C showed that the blood vessels on the surface of the brain were obviously increasing and thickening and diffuse slow waves were detected on the electroencephalogram (EEG). The patient's hyponatremia aggravated on the third day of hospitalization. On the fourth day of hospitalization, the patient was somnolent, apathetic, and slow. Magnetic resonance imaging (MRI) of the brain, with a T2-weighted fluid attenuated inversion recovery image, showed high-signal intensity in the splenium of the corpus callosum (SCC) on the fifth day of hospitalization. Diffusion-weighted imaging (DWI) showed splenial hyperintensity as a "boomerang sign" and reduced diffusion on apparent diffusion coefficient (ADC) maps. Cranial MRI findings returned to normal after 1 month. The diagnosis of MERS was confirmed. INTERVENTIONS: We administered an intravenous drip infusion of acyclovir and prescribed oral sodium supplementation. OUTCOMES: The patient's neurological symptoms gradually improved. The MRI lesion in the SCC disappeared on the 30th day. LESSONS: In patients with encephalitis accompanied by hyponatremia, elevated IL-6 or urinary ß2-microglobulin (ß2MG), and exacerbations such as sudden somnolence, delirium, confusion, and seizures, the possibility of secondary MERS should be investigated, in addition to the progression of encephalitis.

Cholesterol transport through the peroxisome-ER membrane contacts tethered by PI(4,5)P2 and extended synaptotagmins.

Most mammalian cells take up cholesterol from low-density lipoproteins (LDLs) via receptor-mediated endocytosis. After reaching lysosomes, LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs. Peroxisomes are recently found to receive cholesterol from lysosomes through lysosome-peroxisome membrane contacts. However, whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown. Here, by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes, we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1, 2 and 3 (E-Syts). Depletion of peroxisomal PI(4,5)P2 or E-Syts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes. Furthermore, we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro, and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER. Together, our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.