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Bioprivileged molecules hold great promise for supplementing petrochemicals in sustainable organic synthesis of a diverse bioactive products library. Secologanin, a biorenewable monoterpenoid glucoside with unique structural elements, is the key precursor for thousands of natural monoterpenoid alkaloids. Inspired by its inherent highly congested functional groups, a secologanin-based diversity-oriented synthesis (DOS) strategy for novel pseudo-natural alkaloids was developed. All the reactive units of secologanin were involved in these operation simplicity protocols under mild reaction conditions, including the one-step enantioselective transformation of exocyclic C8, C8/C11, and C8/C9/C10 as well as the chemoenzymatic manipulation of endocyclic C2/C6 via the attack by various nucleophiles. A combinatory scenario of the aforementioned reactions further provided diverse polycyclic products with multiple chiral centers. Preliminary activity screening of these newly constructed molecules led to the discovery of antimalarial and highly potent neuroprotective skeletons. The application of green biorenewable secologanin in diversity-oriented pseudo-natural monoterpenoid alkaloid synthesis might encourage the pursuit of valuable bioactive frameworks.

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Mitophagy, the elimination of damaged mitochondria through autophagy, promotes neuronal survival in cerebral ischemia. Previous studies found deficient mitophagy in ischemic neurons, but the mechanisms are still largely unknown. We determined that BNIP3L/NIX, a mitophagy receptor, was degraded by proteasomes, which led to mitophagy deficiency in both ischemic neurons and brains. BNIP3L exists as a monomer and homodimer in mammalian cells, but the effects of homodimer and monomer on mitophagy are unclear. Site-specific mutations in the transmembrane domain of BNIP3L (S195A and G203A) only formed the BNIP3L monomer and failed to induce mitophagy. Moreover, overexpression of wild-type BNIP3L, in contrast to the monomeric BNIP3L, rescued the mitophagy deficiency and protected against cerebral ischemic injury. The macroautophagy/autophagy inhibitor 3-MA and the proteasome inhibitor MG132 were used in cerebral ischemic brains to identify how BNIP3L was reduced. We found that MG132 blocked the loss of BNIP3L and subsequently promoted mitophagy in ischemic brains. In addition, the dimeric form of BNIP3L was more prone to be degraded than its monomeric form. Carfilzomib, a drug for multiple myeloma therapy that inhibits proteasomes, reversed the BNIP3L degradation and restored mitophagy in ischemic brains. This treatment protected against either acute or chronic ischemic brain injury. Remarkably, these effects of carfilzomib were abolished in bnip3l(-/-) mice. Taken together, the present study linked BNIP3L degradation by proteasomes with mitophagy deficiency in cerebral ischemia. We propose carfilzomib as a novel therapy to rescue ischemic brain injury by preventing BNIP3L degradation. Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ATG7: autophagy related 7; BCL2L13: BCL2-like 13 (apoptosis facilitator); BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; CFZ: carfilzomib; COX4I1: cytochrome c oxidase subunit 4I1; CQ: chloroquine; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; I-R: ischemia-reperfusion; MAP1LC3A/LC3A: microtube-associated protein 1 light chain 3 alpha; MAP1LC3B/LC3B: microtube-associated protein 1 light chain 3 beta; O-R: oxygen and glucose deprivation-reperfusion; OGD: oxygen and glucose deprivation; PHB2: prohibitin 2; pMCAO: permanent middle cerebral artery occlusion; PRKN/PARK2: parkin RBR E3 ubiquitin protein ligase; PT: photothrombosis; SQSTM1: sequestosome 1; tMCAO: transient middle cerebral artery occlusion; TOMM20: translocase of outer mitochondrial membrane 20; TTC: 2,3,5-triphenyltetrazolium hydrochloride.

A preliminary enhanced oil recovery (EOR) screening was completed for the Ben Nevis Formation, Hebron Field, offshore Canada. Polymer flooding was determined to be the most viable methodology based...

Low salinity water injection (LSWI), an emerging Enhanced Oil Recovery (EOR) method, has proven to be effective in increasing oil recovery by wettability alteration. As low salinity water is injected into the reservoir, the pre-established equilibrium is disturbed. The chemical reactions among the oil/brine/rock system alters the existing wettability, resulting in enhanced oil recovery. Water-alternating-gas (WAG) injection is also a leading EOR flooding process in light to medium oil sandstone and carbonate reservoirs. A recently proposed hybrid EOR method, CO2 low salinity (LS) WAG injection, shows promise based on experimental and simulation studies, compared to LSWI or CO2 injection alone. Wettability alteration is considered as the dominant mechanism for CO2 LSWAG injection. In this study, a new displacement contact angle measurement which better mimics the actual displacement process taking place in a reservoir is used, aiming to investigate the effect of monovalent and divalent cations, CO2, and injection schemes. It is found that the injection of NaCl low salinity water alters the wettability towards slightly water-wet, and the injection of CaCl2 low salinity water alters the wettability towards slightly oil-wet. The injection of CO2 promotes water-wetness and geochemical reactions between oil and brine. Injection scheme of CO2 and NaCl low salinity water is more efficient than WAG cycle of CO2/NaCl in wettability alteration towards more water-wet. However, the opposite trend is observed with CaCl2 low salinity water, of which WAG cycle of CO2/CaCl2 is more efficient in altering wettability towards water-wet. The oil drop deformation process during LSWI resembles the process of oil removal using surfactant. As CO2 is introduced, due to the acidic effect of CO2 and ion exchange, it acts to wet the rock surface, leading to a more water-wet state. With introduction of CO2, the oil drop deformation resembles the “roll-up” oil removal process.

How mitochondria damaged in distal axons are cleared is not understood. Zheng et al. find that axonal mitochondria return to neuronal soma for mitophagy after ischemic insult. These spatial features of neuronal mitophagy provide insight into how neurons control mitochondrial quality under pathological conditions., Mitophagy protects against ischemic neuronal injury by eliminating damaged mitochondria, but it is unclear how mitochondria in distal axons are cleared. We find that oxygen and glucose deprivation-reperfusion reduces mitochondrial content in both cell bodies and axons. Axonal mitochondria elimination was not abolished in Atg7fl/fl;nes-Cre neurons, suggesting the absence of direct mitophagy in axons. Instead, axonal mitochondria were enwrapped by autophagosomes in soma and axon-derived mitochondria prioritized for elimination by autophagy. Intriguingly, axonal mitochondria showed prompt loss of anterograde motility but increased retrograde movement upon reperfusion. Anchoring of axonal mitochondria by syntaphilin blocked neuronal mitophagy and aggravated injury. Conversely, induced binding of mitochondria to dynein reinforced retrograde transport and enhanced mitophagy to prevent mitochondrial dysfunction and attenuate neuronal injury. Therefore, we reveal somatic autophagy of axonal mitochondria in ischemic neurons and establish a direct link of retrograde mitochondrial movement with mitophagy. Our findings may provide a new concept for reducing ischemic neuronal injury by correcting mitochondrial motility.

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment., Graphical abstract This review summarizes the current knowledge on natural compounds, focusing on the potential implication of stroke, acting as modulators of autophagy.Image 1

Enhanced oil recovery (EOR) and maximizing recovery from declining production fields remain a challenge in the offshore industry. The challenge is to find an EOR method that is both technically and economically feasible considering the high capital and operating costs in the offshore environment. The goal of this work was to conduct a simple cost-benefit analysis based on a technical, facility, and economical screening of chemical EOR methods applicable to the offshore. Offshore Newfoundland, Canada is used as a base case as it represents a challenging geographical environment. The reservoir properties are good, based on volumetrics and characteristics, but the fields are located over 300 km offshore in a harsh environment where operational costs are high. A data mining approach was used for the EOR screening process. Data from over one thousand core flooding experiments investigating various chemical EOR methods, including surfactant, polymer, alkaline-surfactant (AS), alkaline-surfactant-polymer (ASP), nanoparticle, and low salinity water injection (LSWI), were collected. Factors with the greatest influence on the performance of a given EOR method were statistically examined and discretized. The ranges of recovery factor, rock type, chemical concentrations, and the most commonly used chemicals are presented in this review paper. Economic factors examined included capital expenditures (CAPEX) and the operating cost of production (OPEX). Benefits are found to be strongly related to oil production and Brent crude oil forecasts. Sensitivity studies of the recovery factor ranges with the different chemical concentrations, net present values (NPV), and the influence of the inflation were all taken into consideration. Two different injection plans were considered: injection from day one of production, and injection after secondary production. The highest CAPEX and OPEX were calculated for the ASP method, whereas LSWI resulted in the lowest. The results indicate that most of the chemical EOR methods could be economically successful, however, the timing of implementation will affect the potential benefits. If high recovery and low chemical concentrations are considered, ASP flooding is the most successful chemical EOR method when injecting from day one. However, if the EOR method starts after a decline in production, surfactant flooding proves more beneficial, regardless of the scenario considered. This paper presents a systematic approach to chemical EOR screening, combining available technical data using a data analytics approach with economic and technical uncertainty.

Aim Mitochondrial autophagy (mitophagy) clears damaged mitochondria and attenuates ischemic neuronal injury. Urolithin A (Uro‐A) activates mitophagy in mammal cells and Caenorhabditis elegans. We explored neuroprotection of Uro‐A against ischemic neuronal injury. Methods Mice were subjected to middle cerebral artery occlusion. The brain infarct and neurological deficit scores were measured. The N2a cells and primary cultured mice cortical neurons were subjected to oxygen‐glucose deprivation and reperfusion (OGD/R). Uro‐A was incubated during OGD/R, and cell injury was determined by MTT and LDH. Autophagosomes were visualized by transfecting mCherry‐microtubule‐associated protein 1 light chain 3 (LC3). The protein levels of LC3‐II, p62, Translocase Of Inner Mitochondrial Membrane 23 (TIMM23), and cytochrome c oxidase subunit 4 isoform 1 (COX4I1) were detected by Western blot. The ER stress markers, activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP), were determined by reverse transcription‐polymerase chain reaction (RT‐PCR). Results Urolithin A alleviated OGD/R‐induced injury in N2a cells and neurons and reduced ischemic brain injury in mice. Uro‐A reinforced ischemia‐induced autophagy. Furthermore, Uro‐A‐conferred protection was abolished by 3‐methyladenine, suggesting the requirement of autophagy for neuroprotection. However, mitophagy was not further activated by Uro‐A. Instead, Uro‐A attenuated OGD/R‐induced ER stress, which was abolished by 3‐methyladenosine. Additionally, neuroprotection was reversed by ER stress inducer. Conclusion Urolithin A protected against ischemic neuronal injury by reinforcing autophagy rather than mitophagy. Autophagy activation by Uro‐A attenuated ischemic neuronal death by suppressing ER stress.

Cerebral ischemia is a severe neurological disorder with limited therapy. Autophagy refers to the intracellular degradation process via an autophagosome-lysosome pathway. Emerging studies indicated the neuroprotective effects of autophagy against ischemic neuronal injury, suggesting the potential neuroprotection of autophagy-inducing compounds. Tomatidine is a gut microbiota-derived metabolite from unripe tomatoes. Tomatidine activates autophagy either in mammal cells or C elegans. However, potential neuroprotection of tomatidine against ischemic neuronal injury has not been determined. In the present investigation, N2a cells and primary cultured mice cortical neurons were subjected to oxygen-glucose deprivation followed by reperfusion (OGD/R). Cell injury was determined by MTT and lactate dehydrogenase release. Autophagosomes and autolysosomes were visualized by transfecting mCherry-GFP-tandem fluorescent LC3. The protein levels of LC3, Cathepsin D, Cathepsin B, and transcription factor EB (TFEB) were detected by Western blot. Lysosomes were stained with LysoTracker Red and dequenched-bovine serum albumin (DQ-BSA red). Tomatidine alleviated OGD/R-induced injury in N2a cells and neurons. Interestingly, tomatidine treatment attenuated, rather than reinforced, the OGD/R-elevated LC3-II, which can be reversed by lysosome inhibitor. These results indicated enhanced lysosomal activity rather than autophagosome generation with tomatidine treatment in our models. Indeed, tomatidine increased the lysosome number, proteolytic activities, as well as the expression of Cathepsin D and Cathepsin B. In addition, tomatidine increased the expression and nucleus translocation of (TFEB). Besides, lysosomal inhibitors chloroquine and bafilomycin, but not wortmannin, abolished the protection of tomatidine. In conclusion, the present study revealed the neuroprotection of tomatidine against ischemic injury by promoting lysosomal activity, possibly with the involvement of TFEB-related mechanisms.

In this article we discuss the design of a new fronthaul interface for future 5G networks. The major shortcomings of current fronthaul solutions are first analyzed, and then a new fronthaul interface called next-generation fronthaul interface (NGFI) is proposed. The design principles for NGFI are presented, including decoupling the fronthaul bandwidth from the number of antennas, decoupling cell and user equipment processing, and focusing on high-performancegain collaborative technologies. NGFI aims to better support key 5G technologies, in particular cloud RAN, network functions virtualization, and large-scale antenna systems. NGFI claims the advantages of reduced bandwidth as well as improved transmission efficiency by exploiting the tidal wave effect on mobile network traffic. The transmission of NGFI is based on Ethernet to enjoy the benefits of flexibility and reliability. The major impact, challenges, and potential solutions of Ethernet-based fronthaul networks are also analyzed. Jitter, latency, and time and frequency synchronization are the major issues to overcome.

A first-principles study has been performed to calculate the electronic and optical properties of the SbxSn1−xO system. The simulations are based upon the method of generalized gradient approximations with the Perdew—Burke—Ernzerhof form in the framework of density functional theory. The supercell structure shows a trend from expanding to shrinking with the increasing Sb concentration. The increasing Sb concentration induces the band gap narrowing. Optical transition has shifted to the low energy range with increasing Sb concentration. Other important optical constants such as the dielectric function, reflectivity, refractive index, and electron energy loss function for Sb-doped SnO2 are discussed. The optical absorption edge of SnO2 doped with Sb also shows a redshift.

IL-22-producing CD4(+) T helper cells (Th22 cells) have been identified as major inducers of tissue inflammation and immune responses. Currently, no previous study explored the role of Th22 cells in the pathogenesis of hepatocellular carcinoma (HCC). The study aimed to determine the biological function of Th22 cells and its effector IL-22 in HCC patients.Forty-five HCC patients and 19 healthy controls were recruited and their peripheral blood was collected. The fresh HCC tissues, adjacent HCC tissues and ten normal liver tissues were also collected. Flow cytometry analysis was used to determine the frequencies of circulating Th22 cells and Th17 cells. Serum IL-22 levels were tested by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining and real-time polymerase chain reaction (PCR) were used to detect IL-22 protein and mRNA in tissues specimens, respectively.Circulating Th22 cells, Th17 cells and serum IL-22 levels were significantly elevated in HCC patients compared with those of healthy controls (P0.001). Th22 cells were showed to be positively correlated with IL-22 in HCC patients (P0.05), but not in healthy controls. No significant differences were found in HCC patients with HBeAg positivity or negativity in term of Th22 cells and serum IL-22 levels. The expression of IL-22 protein and mRNA was highest in HCC tissues, followed by adjacent HCC tissues and normal liver tissues. Furthermore, Th22 cells, serum IL-22 levels and IL-22 mRNA were elevated at stage III-IV compared with stage I-II of HCC (P0.05).Elevation of circulating Th22 cells and IL-22 may be implicated in the pathogenesis of HCC, and potentially be cellular targets for therapeutic intervention.

In this paper, the utility-based resource allocation algorithms for the secondary users (SU) supporting heterogeneous services in orthogonal frequency division multiplexing (OFDM)-based cognitive radio cellular networks (CogCells) are studied. Two kinds of users are considered: best-effort-only service users and multiple services users. According to the convex optimization theory, the Lagrangian dual method is proposed, in which the joint subcarrier assignment and power allocation are performed to achieve the optimal solution. To simplify the computation complexity, a low complexity dynamic subcarrier allocation algorithm, named Max Utility for Multiple Services on Cognitive Radio (CR-MUMS), is formulated to extend the non-linear integer optimization to a continuous convex optimization. Final simulation results illustrate that the proposed algorithm with low computational complexity provides better optimal performance than Modified Largest Weighted Delay First (M-LWDF) and Proportional Fair (PF) algorithms.

The magnetic properties of (Mn, Li)-codoped ZnO are investigated based on density functional theory using the Perdew-Burke-Ernzerhof form of generalized gradient approximation. It is found Mn doped ZnO system favors antiferromagnetism (AFM) ordering, while four different geometrical configurations of (Mn, Li)-codoped ZnO prefer stable ferromagnetism (FM) ordering. These results indicate that dopant Li can effectively alter magnetic coupling in ZnMnO system and results in high Curie temperature FM ordering. We propose that dopant Li mediates FM coupling through double exchange interaction and RKKY interaction when Li locates near and far from Mn ions, respectively.

First-principles calculations were performed to investigate the magnetic properties of Zn(Mn,Li)O based on the Perdew-Burke-Ernzerhof form of the generalized gradient approximation. Antiferromagnetic (AFM) ordering is the ground state in Mn-doped ZnO system without the codopant of Li, while seven different geometrical configurations of Zn(Mn,Li)O prefer stable ferromagnetic (FM) ordering. We found that dopant Li can effectively change the magnetic coupling in the ZnMnO system. The Curie temperature (TC) of FM ordering depends on the geometric configuration, and the highest TC is about 1388 K. The FM stabilization is greatly affected by Mn-Mn distance rather than by the position of dopant Li. We propose that dopant Li mediates FM coupling through a double exchange interaction or an RKKY interaction when Li is located, respectively, near or far from Mn ions.